Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)=[CH2:2].[O:22]1[C:26](=O)[CH2:25][NH:24]C1=O.Cl.N>C(Cl)Cl.O>[ClH:21].[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:24][CH2:25][C:26]1=[O:22])=[CH2:2]
Reactant: C=COCCNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C1CNC(=O)O1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: C=COCCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
To a solution of 0.3g of 2-(β-vinyloxyethyl)amino-5-chlorobenzophenone in 20 ml of dry methylene chloride is added 0.27g of oxazolidin-2,5-dione. To the mixture is added 20 ml of etheral hydrogen chloride under cooling. The mixture is allowed to stand at room temperature with occasional stirring. The reaction mixture is poured into water, basified with aqueous ammonia and extracted with methylene chloride. The extracts are combined and dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is dissolved in ether and treated with ethanolic hydrogen chloride to give 1-(β-vinyloxyethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride, m.p. 213° - 215° C (dec). Recrystallization from isopropanolchloroform gives colorless prisms, m.p. 216° - 218° C (dec.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:48]([O:47][C:45]([N:42]1[CH2:43][CH2:44][CH:39]([N:19]2[C:20]3[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:40][CH2:41]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A pressure tube was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (180 mg, 0.34 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol), cesium carbonate (332 mg, 1.02 mmol) and DMF (1.5 ml). The tube was flushed with argon, sealed and stirred at 100° C. in an oil bath overnight. The reaction was cooled to room temperature and additional tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol) and cesium carbonate (332 mg, 1.02 mmol) were added. The tube was again flushed with argon, sealed and stirred at 100° C. in an oil bath for 6 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 197 mg (81%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22](N1C=CC=CC1=O)=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:22]([O:21][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:23])[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCOC(=O)n1ccccc1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 91.8 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing heptyl-2-pyridyl-carbonate and heptyl-2-oxopyridine-1-carboxylate (0.45 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.3 g, 91%) as transparent oil, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 0.86 (t, J=6.8 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H), 1.18-1.36 (m, 8H), 1.46-1.61 (m, 2H), 3.87-4.01 (m, 3H), 4.01-4.14 (m, 1H), 6.67 (d, J=9.0 Hz, 1H) 12.20 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:16]2(C(OC(C)(C)C)=O)[C:28]3[NH:27][C:26]4[C:21](=[CH:22][C:23]([CH3:29])=[CH:24][CH:25]=4)[C:20]=3[CH2:19][CH2:18][NH:17]2)[CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.Cl>[CH3:29][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[NH:27][C:28]1[CH:16]([C:12]3([NH:11][C:9](=[O:10])[O:8][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:14][CH2:15]3)[NH:17][CH2:18][CH2:19][C:20]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3(C(=O)OC(C)(C)C)C1(NC(=O)OCc2ccccc2)CCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]c3c(c2c1)CCNC3C1(NC(=O)Oc2ccccc2)CCC1

Procedure:
0.9 g of the compound obtained in Example 97 are dissolved in 50 ml of ethyl acetate into which gaseous hydrogen chloride is bubbled. After reaction for one hour, the precipitate formed is filtered off, washed with diethyl ether and dried, enabling the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25](Br)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=1)#[CH:32]>>[CH2:1]([O:3][C:4](=[O:30])[C:5](=[O:6])[N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([C:32]#[C:31][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=3)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccc2occ(Br)c2c1
Product: CCCc1ccc(C#Cc2coc3ccc(CN(Cc4ccc(C(F)(F)F)cc4)C(=O)C(=O)OCC)cc23)cc1
Yield: 5 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{[(3-bromo-1-benzofuran-5-yl)methyl][4-(trifluoromethyl)benzyl]amino}(oxo)acetate and 1-ethynyl-4-propylbenzene under microwave conditions (300 W, 120° C., 10 min) gave the title compound as a yellow oil (5%). M−(LC/MS(ESI)): 545.8; M+(LC/MS(ESI)): 548.2 HPLC (Condition A), Rt: 5.85 min (HPLC purity: 92.4%).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:20])[NH:10][N:11]([C:16](=[O:19])[CH2:17][CH3:18])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:33][C@@H:34]1[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:38]([O:47][C:48](=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:37]([CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[O:36][C@H:35]1Br)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH2:1]([C:8]1[C:9]([O:20][C@@H:35]2[O:36][C@H:37]([CH2:54][O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[C@@H:38]([O:47][C:48](=[O:53])[C:49]([CH3:50])([CH3:51])[CH3:52])[C@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C@H:34]2[O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:29])[CH3:30])=[N:10][N:11]([C:16](=[O:19])[CH2:17][CH3:18])[C:12]=1[CH:13]([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a solution of 4-benzyl-1,2-dihydro-5-isopropyl-1-propionyl-3H-pyrazol-3-one (1.25 g) in acetonitrile (25 mL) were added potassium carbonate (0.951 g) and 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.79 g) under stirring at room temperature. In addition, the mixture was heated to 50° C. and stirred for 3 hours. After the completion of the reaction, the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1) to give 4-benzyl-5-isopropyl-1-propionyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (3.00 g).
Reaction SMILES: C(O[CH2:5][C:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[O:13][C:14]3([CH2:19][CH2:18][N:17](CC4C=CC=CC=4)[CH2:16][CH2:15]3)[C:9]2=[CH:8][CH:7]=1)(=O)C.C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:5][C:6]1[N:10]2[C:11]3[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=3[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc2n1-c1ccccc1OC21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2n1-c1ccccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.1 %

Procedure:
To a solution of (1′-benzylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl acetate (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was added acetic acid (17 μL, 0.30 mmol). The reaction was flushed with nitrogen then 10% Pd/C (40 mg, 0.37 mmol) was added. The reaction was placed under hydrogen gas and was stirred for 20 h at room temperature. The suspension was filtered through celite, concentrated, then purified by column chromatography (silica gel: 0.1-15% methanol in dichloromethane) to give 1-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (65 mg, 34%). ESI-MS m/z calc. 254.3. found 255.3 (M+1)+; Retention time: 1.93 minutes (3 min run). NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.9 Hz, 1H), 7.16-6.99 (m, 3H), 6.03 (d, J=3.2 Hz, 1H), 5.94 (d, J=3.4 Hz, 1H), 3.14 (t, J=12.2 Hz, 2H), 2.94 (d, J=12.3 Hz, 2H), 2.56 (s, 3H), 2.19 (m, 1H), 2.04 (d, J=12.7 Hz, 2H), 1.97-1.84 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:23])=[O:29])=[CH:20][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 31.9 %

Procedure:
A solution 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide (75 mg, 0.216 mmol) in methylene chloride (1 mL) was treated with 3-chloroperoxybenzoic acid (75% grade, 50 mg, 0.216 mmol). The reaction mixture was immediately monitored by thin layer chromatography, and the results indicated the immediate absence of starting material. The reaction mixture was partitioned between water and methylene chloride and then washed with a saturated aqueous sodium bicarbonate solution. The organic layer was further washed with water and then dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from 1/1 hexanes/ethyl acetate afforded 3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide (25 mg, 32%) as a white solid: mp 170-173° C.; EI-HRMS m/e calcd for C18H22N2O2S2 (M+) 362.1123,found 362.1121.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[O:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][C:23]2[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:17]1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:29][C:28]3[C:23]([O:22][C@@H:18]4[CH2:19][CH2:20][CH2:21][O:16][CH2:17]4)=[N:24][CH:25]=[CH:26][CH:27]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1cccnc1O[C@@H]1CCCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@@H]3CCCOC3)c2c1C

Procedure:
Prepared analogously to example 1.1 from 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 2-[(R)-(Tetrahydro-pyran-3-yl)oxy]-pyridin-3-ylamine
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:28]3[S:29][C:30](I)=[CH:31][CH:32]=3)=[C:10]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])[C:11]=2[P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:43][C:42]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[C:41]([P:49]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])=[O:50])[C:40]=1[P:57]([O:62][CH2:63][CH3:64])([O:59][CH2:60][CH3:61])=[O:58])CCC.[F-].[K+]>C1COCC1.[Cu]Cl>[CH2:15]([O:14][P:12]([C:11]1[C:10]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([C:28]2[S:29][C:30]([C:9]3[S:8][C:7]([C:5]4[S:6][C:2]([C:39]5[S:43][C:42]([C:44]6[S:45][CH:46]=[CH:47][CH:48]=6)=[C:41]([P:49]([O:51][CH2:52][CH3:53])([O:54][CH2:55][CH3:56])=[O:50])[C:40]=5[P:57]([O:59][CH2:60][CH3:61])([O:62][CH2:63][CH3:64])=[O:58])=[CH:3][CH:4]=4)=[C:11]([P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[C:10]=3[P:20]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])=[O:21])=[CH:31][CH:32]=2)[S:8][C:7]=1[C:5]1[S:6][CH:2]=[CH:3][CH:4]=1)([O:17][CH2:18][CH3:19])=[O:13])[CH3:16]
Reactant: CCOP(=O)(OCC)c1c(-c2ccc(I)s2)sc(-c2ccc(I)s2)c1P(=O)(OCC)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccs2)c(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1c(-c2cccs2)sc(-c2ccc(-c3sc(-c4ccc(-c5sc(-c6cccs6)c(P(=O)(OCC)OCC)c5P(=O)(OCC)OCC)s4)c(P(=O)(OCC)OCC)c3P(=O)(OCC)OCC)s2)c1P(=O)(OCC)OCC
Yield: 77 %

Procedure:
In THF, 0.155 g (0.201 mmols) of the 5,5″-diiodo-3′,4′-bis(diethoxyphosphoryl)-[2,2′;5′,2″]-terthiophene obtained in Example 7(4) and 0.307 g (0.422 mmols) of 5-tributylstannyl-3,4-bis(diethoxyphosphoryl)-[2,2′]-bithiophene obtained in Example 6(5) were dissolved, to which 0.0438 g (0.442 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 18 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 1 hour. Subsequently, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column to obtain the specified substance in the form of a yellow oil at a yield of 0.216 g (yield: 77%).
Reaction SMILES: [C:1]1([CH:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:8]([OH:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl.O>[Cl:23][CH2:24][C:25]([NH:10][CH2:9][CH:8]([OH:11])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1OC(c1ccccc1)C(O)CNC(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A mixture of 2.73 g of 3-phenyl-2-hydroxy-3-(2-methoxy-phenoxy)-propylamine in 50 ml of methylene chloride and 0.56 g of NaOH in 15 ml of water was stirred at 0° C. Under vigorous stirring dropwise addition was made to the mixture over 30 minutes, again at 0° C., of 1.58 g of chloroacetyl chloride in 2 ml of methylene chloride. After the addition, the stirring was continued at 0° C. for 30 minutes. The layers were separated and the aqueous phase extracted with CH2Cl2. The organic extracts were combined and washed with water, dried over Na2SO4 and evaporated to dryness. There was obtained 3.49 g of N-chloroacetyl-2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)propylamine (oil). Yield 100%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16].[H][H]>C(O)C.O=[Pt]=O>[CH3:16][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=1)[NH2:13]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1cc(N)ccc1OCc1cccc(F)c1
Yield: 100.3 %

Procedure:
A mixture of 1-[(3-fluorobenzyl)oxy]-2-methyl-4-nitrobenzene (3.2 g, 12.2 mmol) and PtO2 (320 mg) in ethanol (250 ml) was stirred under an atmosphere of hydrogen (1.2 bar) until completion of the reaction (the reaction being complete when 3 mole equivalents of hydrogen have been reacted). The mixture was then filtered over celite and the solvent evaporated to give 3-methyl-4-[(3-fluorobenzyl)oxy]aniline as a yellow oil (2.83 g, 100%);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.Cl.[NH:15]1[CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: C1CNC1
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Agent: Cl
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCC1

Procedure:
was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid and azetidine hydrochloride following Method A. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (1H, d, J=5.1 Hz), 7.96 (1H, s), 7.70 (1H, d, J=5.1 Hz), 4.62 (2H, t, J=7.4 Hz), 4.12 (2H, t, J=7.7 Hz), 2.34 (2H, tt, J=7.4, 7.7 Hz).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][NH2:10])[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:11][C:12]1[C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[S:15][C:16]=1[C:17](Cl)=[O:18]>>[Cl:11][C:12]1[C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[S:15][C:16]=1[C:17]([NH:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:18]
Reactant: NCCn1ccnc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Agent: Cl
Product: O=C(NCCn1ccnc1)c1sc2ccccc2c1Cl

Procedure:
A 1.47 g. portion of 1H-imidazole-1-ethanamine dihydrochloride was reacted with 3-chloro-benzo[b]thiophene-2-carbonyl chloride as described in Example 1, giving 0.75 g. of the desired product, m.p. 132°-134° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[N:4]=[CH:5][C:6]=3[CH2:12]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: FC(F)(F)c1ncc2c(n1)CCNC2
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ncc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (CA [74737-17-7]; WO2004069162) and 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.3). MS (m/e): 498.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:7]([O:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
The compound of step 1 (20 g, 89.2 mmol) was dissolved in DMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added. This mixture was stirred for 30 min at room temperature, poured on a mixture of 2 N hydrochloric acid and diethyl ether, filtered and washed repeatedly with diethyl ether. The combined ethereal phases were washed with water, dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (21 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-oxoazepane-1-carboxylate (0.60 g, 2.81 mmol), in MeOH (11 mL) was cooled to 0° C. NaBH4 (0.266 g, 7.03 mmol) was added and the mixture was slowly warmed to ambient temperature where the reaction stirred overnight. The mixture was concentrated in vacuo and the residue was taken up in EtOAc (20 mL) and saturated aqueous NH4Cl solution (20 mL) The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL) The combined organic extracts were washed with brine and dried over Na2SO4, then filtered and concentrated. The product was isolated as a thick colorless oil that solidified overnight to a white solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:22]>>[C:1]1([S:7]([C:10]2[CH:11]=[N:12][N:13]3[C:18]([Cl:22])=[CH:17][C:16]([CH3:19])=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccn2ncc(S(=O)(=O)c3ccccc3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)n2ncc(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
A suspension of 0.91 g (3.14 mmol) of 3-benzenesulphonyl-5-methyl-pyrazolo[1,5-a]pyrimidine in 15 ml of POCl3 was heated at reflux for 1 hr. The reaction solution was cooled to RT and evaporated. The residue was treated with 30 ml of ice-water and the pH value of the solution was adjusted to 8 with sat. NaHCO3 solution. The aqueous phase was extracted three times with 20 ml of CH2Cl2, and the organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/AcOEt 19:1) of the residue yielded 0.84 g (87%) of 3-benzenesulphonyl-7-chloro-5-methyl-pyrazolo[1,5-a]pyrimidine as a beige solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10]Br.C(=O)([O-])O.[Na+]>ClCCl.[Fe]>[Br:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH2:5][CH2:4][C:3]=2[CH:6]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CCS2
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCS2
Yield: 62.6 %

Procedure:
Iron powder (10.4 mg, 1.47 mmol) was added to a solution of 2,3-dihydrobenzo[b]thiophene 112 (400 mg, 2.94 mmol) in dichloromethane (5.9 mL). Bromine (0.15 mL, 2.94 mmol) was added dropwise to the mixture with stirring under ice-cooling. This mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture and this was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired product 113 (396 mg, 63%).