Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].C([Li])CCC.[Cl:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]([C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:11]=[CH:10][C:6]=2[N:7]=1)([OH:20])[CH2:18][Cl:17]
Reactant: N#Cc1ccc2ncsc2c1
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc2nc(C(O)(CCl)c3ccc(F)cc3F)sc2c1
Temperature: -98 °C
Yield: 42.5 %

Procedure:
After 6-cyanobenzothiazole (1.60 g) was dissolved in tetrahydrofuran (80 ml), and the solution was cooled to -98° C. in a nitrogen atmosphere, a 1.6M solution (5.9 ml) of n-butyllithium in hexane was added dropwise over 10 minutes, and the resultant mixture was stirred for 5 minutes. A solution of 2-chloro-2',4'-difluoroacetophenone (2.85 g) in tetrahydrofuran (20 ml) was added dropwise to this mixture. After the liquid reaction mixture was heated to -10° C., an aqueous solution of ammonium chloride was added thereto. After the mixture was heated to room temperature, an organic layer was taken out, and the solvent was distilled out under reduced pressure. A water layer was extracted with ethyl acetate and the extract was then put together with the residue of the organic layer. This organic layer was washed with water and then with saturated saline, dried over magnesium sulfate and then distilled under reduced pressure. The residue was subjected to column chromatography on silica gel (solvent: hexane/ethyl acetate=20/1, next, hexane/ethyl acetate=5/1), thereby obtaining the intended compound (1.49 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.ClCCl.Cl.CN(C)CCCN=C=NCC.[CH:27]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:32][CH2:33][NH:34][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: NCCC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask was charged 3-iodo-4-methylbenzoic acid (1.4 g, 5.4 mmol), dicloromethane (4 ml), and DMF (2 ml). This mixture was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.3 mmol) was added. The reaction mixture was stirred for 10 min before 2-cyclopentylethanamine (0.47 g, 4.2 mmol) was introduced. The reaction mixture was stirred at 0° C. for 1 h, then at RT under N2 for 16 h. The reaction was partitioned between DCM (60 ml) and brine (50 mL). The aqueous layer was back exacted with DCM (4×20 mL) and the combined DCM layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a Redi-sep pre-packed silica gel column (330 g), eluting with a gradient of 5% to 15% EtOAc in hexane, to provide N-(2-cyclopentylethyl)-3-iodo-4-methylbenzamide as a white solid. MS (ESI, pos. ion) m/z: 358.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[CH:4][C:3]=1[CH3:17].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc([C@H](C)N[S@](=O)C(C)(C)C)ccc1Br
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc([C@H](C)N)ccc1Br

Procedure:
The title compound was prepared from (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-3-methyl-phenyl)-ethyl]-amide following a procedure analogous to that described in Step 3 of Intermediate 1. LC-MS (Method 4): tR=3.56 min; Mass spectrum (ESI+): m/z=214/216 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=1
Reactant: Nc1ccccc1F
Reactant: O=C1CCNC(=O)C1
Product: O=C1C=C(Nc2ccccc2F)CCN1
Yield: 82.2 %

Procedure:
A mixture of 2-fluoroaniline (0.98 g) and 2,4-dioxopiperidine (1.0 g) was heated at 120° for 2 h. The cooled mixture was triturated with dry ether (5×40 ml) and the solvent was decanted to leave the title compound (1.495 g), m.p. 98°-100°.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.Cl>C(Cl)Cl>[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:2]([Cl:1])=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H]1CCCCN1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 184.4 %

Procedure:
To a pale yellow solution of triphosgene (742 mg, 2.50 mmol) and pyridine (0.404 mL, 5.00 mmol) in dry DCM (10 mL) at 10° C. under N2 was added (S)-2-methyl piperidine (Aldrich, 0.603 mL, 5.00 mmol) cautiously over 2 min. The vivid orange solution was stirred at RT for 18 h, then pyridine (0.404 mL, 5.00 mmol) and triphosgene (742 mg, 2.50 mmol) were added sequentially (CARE: exotherm on addition of triphosgene) and the orange solution stirred at RT for 4 h. Aqueous HCl solution (1M, 10 mL) was added and the mixture stirred vigorously until gas evolution ceased (30 min). The aqueous layer was extracted with DCM (10 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave the title compound as a dark red oil (745 mg, 92%). 1H NMR (300 MHz, CDCl3): 1.25 (3H, d, J 7.0), 1.42-1.77 (6H, m), 3.07 (1H, br s), 4.17 (1H, dd, J 13.8, 4.0), 4.62 (1H, apparent quin, J 6.3).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O.[Pd]>[CH2:25]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[CH3:24])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:27])[CH3:26]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C)c21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a solution of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (88.3 g) in DMF (540 mL) and EtOAc (1080 mL) was added 10% Pd—C (9.0 g) at room temperature under Ar atmosphere. The mixture was hydrogenated under balloon pressure at room temperature for 5 h. The reaction mixture was filtered through celite, and then insoluble materials were washed with EtOAc (500 mL). The filtrate was concentrated in vacuo. The residue was suspended in EtOAc (350 mL), and the mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration, washed with EtOAc (250 mL) and IPE (100 mL), and dried in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (56.0 g) as light purple powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH:14][C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=S)=[CH:12][CH:11]=[CH:10][N:9]=1.[S]>[Hg]=O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:13]=2[N:14]=[C:15]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cccnc2NCc2ccco2)CC1
Agent: O=[Hg]
Agent: [S]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Yield: 79 %

Procedure:
A mixture of 74 parts of ethyl 4-[[[2-[(2-furanylmethyl)amino]-3-pyridinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate, 96 parts of mercury (II) oxide, 0.1 parts of sulfur and 800 parts of ethanol was stirred and refluxed for 3 hours. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 52.5 parts (79%) of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-]pyridine-2-yl]amino]-1-piperidinecarboxylate; mp. 149.2° C. (intermediate 32).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][C:17]([OH:25])([CH2:18]3)[CH2:16]1)[CH2:22]2>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:14][C:15]23[CH2:24][C@H:19]4[CH2:20][C@H:21]([CH2:23][C:17]([OH:25])([CH2:18]4)[CH2:16]2)[CH2:22]3)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC12C[C@@H]3C[C@@H](CC(O)(C3)C1)C2
Reaction time: 48 h

Procedure:
To a stirred solution of Example 8D (0.06 g, 0.305 mmol) in acetonitrile (3 mL) at room temperature under nitrogen, was added 3-amino-1-adamantanol (0.1 g, 0.61 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 5-7% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 328 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (14H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C=O)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
2-Bromoacetonitrile (0.473 ml, 6.78 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.444 ml, 2.49 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2k-A) (700 mg, 2.26 mmol) in DMF (5 ml), and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution (1 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-A) (748 mg, 95%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:51]2[C:52]3[C:32]([CH2:33][C@@H:34]4[C:46]([C:47]=3[CH:48]=[CH:49][CH:50]=2)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:36][N:35]4[CH3:53])=[CH:31]1.C(N(CC)CC)C>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[C:51]4[C:52]5[C:32]([CH2:33][C@@H:34]6[C:46]([C:47]=5[CH:48]=[CH:49][CH:50]=4)=[CH:45][C@@H:37]([C:38](=[O:44])[N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])[CH2:36][N:35]6[CH3:53])=[CH:31]3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Cl)c1ccc(-c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCN)C[C@H]2N(C)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCNC(=O)c3ccc(-c4ccc(C(=O)ON5C(=O)CCC5=O)cc4)cc3)C[C@H]2N(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A solution of 850 mg (2.375 mmol) of 12 in 65 mL of dry THF under argon was cooled to 0° C. in an icebath, then treated with a solution of 900 mg (2.365 mmol) of 10 in 50 mL of dry THF and 0.6 mL (4.3 mmol) of triethylamine added dropwise over a 20 minute period. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature, with stirring, for 1 hour. The mixture was concentrated at reduced pressure and the residue was dissolved in 100 mL of methylene chloride. The solution was washed with 100 mL of H2O, 100 mL of saturated sodium bicarbonate solution, 100 mL of saturated brine solution, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a brown residue. This was chromatographed on a short column of 100 g of silica gel using first methylene chloride as eluent, then 9:1 methylene chloride-ether as eluent to elute front running impurities, then 14:1 methylene chloride-isopropyl alcohol as eluent to elute the product to yield 650 mg (39%) of 13 as a cream colored solid [α]D=+34.3° (c=0.45%; CHCl3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.6 g), triethylamine (2.8 cc) and 4-(4-bromophenyl)piperazine (4.8 g) in toluene (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-bromophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd ]isothiazole 1,1-dioxide (4.3 g) is obtained, m.p. 149° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][CH3:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:27])[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 28.7 %

Procedure:
A stirred solution of 2-trifluoromethylpyridin-4-ol (12.5 g, 76.6 mmol) and dimethylformamide (3.00 mL) in phosphorus oxychloride (75 mL) is heated under reflux for 2 hours before excess phosphorus oxychloride is removed in vacuo. The residue is poured onto an ice-water mixture and extracted into ethyl acetate (×5). The combined organic extracts dried (sodium sulfate), filtered and concentrated in vacuo. The non-basic components of the mixture are eluted through a SCX column washing with a 1:1 mixture of methanol-dichloromethane. A stirred suspension of the residue, 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (1.11 g, 4.85 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 90° C. for 13 hours. Excess dimethylformamide is removed in vacuo, the residue is taken into chloroform and washed with 2.5% hydrogen chloride solution. The aqueous layer is extracted into chloroform (×3) and the combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine (520 mg, 2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 91 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (85 mg, 91%) which was obtained as a white solid. MS: m/e=370.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([CH:9]=[O:10])[CH:11]=1)[CH3:2]
Reactant: CCOc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1ccc(OCC)cc1C=O

Procedure:
2.49 g of 5-ethoxy-2-hydroxy-benzaldehyde, 2.7 ml of ethyl 5-bromovalerate, 15 ml of DMSO, 3.1 g of K2CO3 and 75 mg of KI were stirred for 2.5 hrs. at 55° C. After working up and chromatography on silica gel there were obtained 4.7 g of ethyl 5-(4-ethoxy-2-formyl-phenoxy)-pentanoate. MS: 294 (M)+.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][OH:19])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Cl:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[O:29])[CH2:27]Br)[N:25]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH2:18][O:19][C:26]([OH:29])([C:24]3[N:25]=[C:21]([Cl:20])[S:22][CH:23]=3)[CH2:27]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(Cl)n1
Product: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3csc(Cl)n3)C2)cc1

Procedure:
from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2- hydroxy-ethanamine and 2-chloro-4-bromoacetyl-thiazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][OH:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30](Cl)([CH3:33])(=[O:32])=[O:31]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CO)NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 65 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (674.0 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxy-propanamide (582.16 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:28]Cl>ClC1C=CC=CC=1>[Cl:28][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: O=C(c1ccccc1)c1ccc(CCl)cc1

Procedure:
196.2 g of 4-methylbenzophenone are dissolved in chlorobenzene and then gassed at 80° C. in the presence of 1.6 g of AIBN (azodiisobutyronitrile) with a total of 71.0 g of chlorine. The reaction mixture is concentrated and the solid material obtained recrystallized from 1 L of ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C[O:23][CH:24]1[CH:28]([CH:29]=O)[CH2:27][CH:26](OC)O1.O>C(O)(=O)C>[CH:24]([C:28]1[CH:27]=[CH:26][N:1]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]3)=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH:29]=1)=[O:23]
Reactant: CCOC(=O)C1Nc2cc(N)c(C(F)(F)F)cc2NC1=O
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1Nc2cc(-n3ccc(C=O)c3)c(C(F)(F)F)cc2NC1=O
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
To a solution of ethyl 7-amino-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate (3.60 g, 11.9 mmol) in acetic acid (60 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (2.01 ml, 14.2 mmol) at 50° C., and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was poured into water (300 ml), which was extracted with ethyl acetate. After dried over anhydrous sodium sulfate, solvent was distilled off. Methylene chloride was added to the residue obtained and the crystals were collected by filtration. These were washed with methylene chloride and then air-dried to obtain 2.57 g of the title compound as yellow powder. The filtrate and the washings were combined, concentrated under reduced pressure, and purified by means of silica gel column chromatography [ethyl acetate-hexane=2:1] to obtain further 973 mg. Total yield by weight 3.54 g. Yield 78%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=2.Cl.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>ClC=CCl>[C:15]([C:11]1[CH:12]=[CH:13][C:6]2[S:5][CH2:9][CH2:8][C:7]=2[CH:10]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: c1ccc2c(c1)CCS2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC=CCl
Product: CCC(=O)c1ccc2c(c1)CCS2
Temperature: 10 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 0.3M of aluminum chloride in 500 ml of 1,2-dichloroethylene, 0.21M of propionyl chloride are added, then slowly while stirring 0.2M of 2,3-dihydrobenzo[b]thiophene are added, temperature being maintained at about 10° C. The mixture is then still stirred for 3 hours at room temperature, then decomposed with a mixture of ice and hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 1,2-dichloroethylene. The combined organic phases are dried on MgSO4, filtered and solvent is evaporated in a vacuum. The residence obtained is solidified by addition of petroleum ether: 25 gr. of 5-propionyl-2,3-dihydrobenzo[b]thiophene are so obtained.