Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:20]1([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)CCCC2CCCCC2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.51 g) synthesized in Example 7 and 4-cyclohexylbutanoic acid (0.85 g) were dissolved in N,N-dimethylformamide (10 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (1.05 g) and hydroxybenzotriazole (HOBT) monohydrate (0.85 g) were successively added thereto, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) and the reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give 2-({4-[2-(4-cyclohexylbutanoylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (2.2 g) as a colorless oil. The obtained compound (2.2 g) was dissolved in tetrahydrofuran (10 mL), 1 M-borane/tetrahydrofuran complex (19.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (30 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (30 mL) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:28]=12)[NH2:22]>>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:28]=12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1)c1cccn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared by procedure G using 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (26.21 mg; 0.11 mmol; 1.20 eq.) instead of 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid and using 3-fluoro-4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline (30.00 mg; 0.09 mmol; 1.00 eq.) instead of 4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline, and was obtained as a beige solid (36 mg, 72%). (HPLC (method F): 89%, RT: 4.63 min); MS (m/z) 536 [M+H]+, RT: 4.2 min.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>CCCCCCC.CCOC(C)=O>[O:1]1[CH2:2][CH:3]([N:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:24](=[O:25])[C:23]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:21]([C:20]([F:19])([F:34])[F:35])[CH:22]=2)[CH2:4]1
Reactant: Cc1ccccc1-c1ccncc1NC1COC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1COC1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from oxetan-3-yl-(4-o-tolyl-pyridin-3-yl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow solid (34%). MS (ESI): m/z=481.13 [M+H]+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.CC(C)=CCBr.NCC1N=C([C:23]2[N:24]=[CH:25][N:26]3[C:32]4[CH:33]=[CH:34][S:35][C:31]=4[C:30](=[O:36])[N:29]4[CH2:37][CH2:38][C@H:28]4[C:27]=23)ON=1>C(Cl)Cl>[CH:23]1[N:24]=[CH:25][N:26]2[C:32]3[CH:33]=[CH:34][S:35][C:31]=3[C:30](=[O:36])[N:29]3[CH2:37][CH2:38][CH:28]3[C:27]=12
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)n1
Agent: CC(C)=CCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2sccc2-n2cncc2C2CCN12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.5 ml (8.6 mmol) of N-ethyldiisopropylamine and 0.28 ml (2.4 mmol) of dimethylallyl bromide were added to a solution of 453 mg (1.2 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of methylene chloride and the mixture was stirred at room temperature for 20 hours. The reaction solution was subsequently diluted with methylene chloride and washed three times with water. The organic phases were dried with magnesium sulfate, filtered and evaporated. The is residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). There were obtained 240 mg (43%) of (S)-1-[3-bis-[3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-5-yl]-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.55 (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH:10]2[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]2CC2C=CC=CC=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.[C].[Pd]>[C:1]1([CH2:7][C:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[OH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(Cc1ccccc1)(Cc1ccccc1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: OC(Cc1ccccc1)(Cc1ccccc1)C1CNCCN1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
α,α,1,4-Tetrakis(phenylmethyl)-2-piperazinemethanol (4.9 g, 10 mmol) was dissolved in ethanol/water (100 mL/5 mL). 10% Palladium carbon (0.49 g) was added thereto, and the mixture was stirred under hydrogen pressure (3.0 bar) at room temperature one whole day and night. The reaction system was filtered through a Celite, the Celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The resulting crystals were washed with diethyl ether to obtain the title compound (2.8 g, yield 91%).
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:22][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1)[C:18]([F:20])([F:21])[F:19]
Reactant: OC(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1ccc(C(O)C(F)(F)F)cc1

Procedure:
At 50° C. and a hydrogen pressure of 5 bar, 65.7 g (233 mmol) of 1-benzyloxy-4-(1-hydroxy-2,2,2-trifluoroethyl)benzene were hydrogenated in the presence of 5.2 g of palladium (10% on carbon) in 500 ml of glacial acetic acid. The catalyst was filtered off and the mixture was concentrated. This gave 44.1 g (99% of theory) of the product as a colourless oil.
Reaction SMILES: [C:1]12([CH:9]3[CH2:10][CH2:11][CH:6]1[C:7](=[O:12])[CH2:8]3)[CH2:5][CH2:4][CH2:3][CH2:2]2.C(O)(=[O:15])C>>[C:1]12([CH:6]3[CH2:11][CH2:10][CH:9]1[C:8](=[O:15])[C:7]3=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]2
Reactant: CC(=O)O
Reactant: O=C1CC2CCC1C21CCCC1
Product: O=C1C(=O)C2CCC1C21CCCC1
Temperature: 120 °C

Procedure:
As described in Example 1 Step B]: from spiro[bicyclo[2.2.1]heptane-7,1′-cyclopentan]-2-one, 1.05 g, SeO2 (1.56 g) in acetic acid (5 ml) on heating at 120° C. for 12 h, purification crude product by flash chromatography (heptane/AcOEt 100-90%, there was obtained spiro[bicyclo[2.2.1]heptane-7,1′-cyclopentane]-2,3-dione (0.88 g) as yellow solid. MS (ESI): 196.2 (M+NH4)+.
Reaction SMILES: Br[C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>C(#N)C>[C:10]([S:12][C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])(=[O:13])[CH3:11]
Reactant: CC([O-])=S
Reactant: CC[C@H](C)[C@@H](Br)C(=O)O
Agent: [K+]
Solvent: CC#N
Product: CC[C@H](C)[C@@H](SC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
2.11 g (10.8 mmol) of (2R,3S)-2-bromo-3-methylpentanoic acid obtained in the Synthesis Example C-1 was dissolved in 43 ml of acetonitrile and 1.42 g of potassium thioacetate was added thereto at 0° C. The mixture was stirred at0° C. for 30 minutes and then at room temperature for 5 hours. After filtering off the insoluble matters, the filtrate was concentrated. To the residue were added ether and a saturated aqueous solution of sodium hydrogencarbonate, followed by separation. The aqueous phase was acidified by adding a 2N aqueous solution of hydrochloric acid at a low temperature and then extracted with ether. The ether phase was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. Thus, 1.68 g of the title compound was obtained as a colorless oil (yield 82%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:23]=1
Reactant: Cc1ccc2nc(-c3ccc(F)cc3)c(CCl)n2c1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Product: Cc1ccc2nc(-c3ccc(F)cc3)c(CNc3nc(C)cc(Cl)n3)n2c1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. H-NMR (400 MHz, CDCl3) 8.021 (s, 1H), 7.73 (m, 2H), 7.51 (d, J=9.164 Hz, 1H), 7.10 (m, 2H), 6.50 (s, 1H), 5.28 (broad, 1H, D, NH), 4.98 (d, J=5.032 Ha, 2H, D, CH2), 2.29 (s, 3H, D, CH3), 2.26 (s, 3H) ppm; m/e+ 382.0, 384.1 for C20H17ClFN5 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:33])[N:14]([CH2:31][CH3:32])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][O:21]CC4C=CC(OC)=CC=4)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:33])[N:14]([CH2:31][CH3:32])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][OH:21])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(COCc3ccc(OC)cc3)nc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CO)nc12
Yield: 93.8 %

Procedure:
6-benzyl-7-cyclopentyl-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one (1.03 g) is dissolved in 20 ml of dichloromethane and 1.2 ml of water are added. At ambient temperature, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 0.68 g) is added with stirring and the mixture is stirred for a further 4 hours. After the 2,3-dichloro-5,6-dicyanobenzoquinone precipitate has been separated off, the remaining solution is washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulphate. The solvent is distilled of and the residue remaining is crystallised from diethyl ether. 0.74 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-hydroxymethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are obtained in the form of slightly reddish crystals which can be used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([NH2:19])=[O:18])[CH2:12]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([NH2:19])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCC1CCCN(C(N)=O)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Product: NCCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.8 %

Procedure:
3-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (392.7 mg, 1.45 mmoles) (prepared as described in Preparative Example 242, Step A above) was dissolved in methanol (7.5 mL) and 10% conc. sulfuric acid in 1,4-dioxane (19.5 mL) was added. The mixture was stirred at 25° C. for 1.25 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the diluted with methanol and BioRad AG1-X8 resin (OH−form) was added until the dryness and chromatographed on a silica gel column (30×2.5 cm) using 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-aminoethyl)piperidine-1-carboxamide (233 mg, 94%): FABMS: m/z 172.1 (MH+); HRFABMS: m/z 172.1444(MH+). Calcd for C8H18N3O requires: m/z 172.1450; δH (CDCl3+3% CD3OD) 1.14 (1H, m, CH2), 1.40 (2H, m, CH2), 1.49 (1H, m, CH), 1.58 (1H, m, CH2), 1.69 (1H, m, CH2), 1.85 (1H, m, CH2), 2.55 (1H, m, CH2), 2.67 (5H, m, CH2/NH2), 2.76 (1H, bm, CH2), 2.84 (1H, m, CH2) and 3.82 ppm (2H, m, CONH2); δc (CDCl3+3% CD3OD) CH2: 24.8, 30.9, 36.6, 38.9, 44.9, 50.0; CH: 33.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.FC(F)(F)S(OCC(F)(F)F)(=O)=O.C(N(CC)CC)C>CC(C)=O>[F:16][C:17]([F:22])([F:21])[CH2:18][N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2C12CCN(CC(F)(F)F)CC2

Procedure:
A mixture of spiro[indoline-3,4′-piperidin]-2-one, [PCT Int. Appl. WO 0145707 A1 (2001)] trifluoroacetic acid salt (3.66 g, 11.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.63 mL, 11.6 mmol), and triethylamine (8.06 mL, 57.9 mmol) in acetone (30 mL) was heated at reflux for 16 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was further extracted with CH2Cl2 (2×25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=285 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[CH:4][CH:3]=1
Reactant: CCCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-heptanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=391.3 [M+H]+.
Reaction SMILES: [Br-:1].C[N+](C)(C)C1C=CC=CC=1.BrBr.[CH3:14][C:15]1[S:16][C:17]([C:21](=[O:23])[CH3:22])=[C:18]([CH3:20])[N:19]=1.Br>C(OCC)C.C(#N)C.C(O)(=O)C>[Br:1][CH2:22][C:21]([C:17]1[S:16][C:15]([CH3:14])=[N:19][C:18]=1[CH3:20])=[O:23]
Reactant: CC(=O)c1sc(C)nc1C
Reactant: [Br-]
Agent: Br
Agent: BrBr
Agent: C[N+](C)(C)c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)CBr)s1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
N,N,N-Trimethylanilinium bromide-bromine (1:1:1) (1.84 g, 4.9 mmol) was added to a solution of 1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanone (800 mg, 5.15 mmol) in diethyl ether (9 mL) and acetonitrile (3 mL), and HBr in acetic acid (33% w/w, 4 mL). The mixture was stirred for 1 h. The reaction mixture was diluted with diethyl ether (25 mL) and washed with aqueous Na2S2O5 solution (5% w/v, 20 mL). The organic phase was separated off, and the aqueous phase was extracted with diethyl ether (25 mL). The organic phases were combined, then washed with saturated aqueous NaHCO3 solution (2×25 mL) and brine. The residue was dried over sodium sulfate, then filtered and concentrated under vacuum, to give the title compound (764 mg, 63%) as a light brown oil. δH (250 MHz, CDCl3) 4.22 (s, 2H), 2.69-2.76 (br s, 6H).
Reaction SMILES: C(C([N:7]([CH2:20][C@@H:21]1[C@@H:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][N:23]([C:32]([C:34]2[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:36][CH:35]=2)=[O:33])[CH2:22]1)[C@@H:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9])=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[C:10]1([C@H:8]([NH:7][CH2:20][C@@H:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][N:23]([C:32]([C:34]3[CH:35]=[CH:36][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)=[O:33])[CH2:22]2)[CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(C(=O)N2C[C@H](CN(C(=O)C(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(C(=O)N2C[C@H](CN[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
A mixed solution of 264 mg of ethyl (4-{[(3R,4S)-3-({(tert-butylcarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetate and 3.0 ml of 1,4-dioxane was mixed with 1.0 ml of 4 M hydrogen chloride/1,4-dioxane and stirred at room temperature for 24Hours. The reaction solution was concentrated under a reduced pressure, and the residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 174 mg of ethyl (4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetate as a colorless amorphous substance. FP: 537.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[C:32]([F:31])=[CH:38][C:37]([F:39])=[CH:36][C:35]=3[F:40])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1c(F)cc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3c(F)cc(F)cc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 11.2 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.100 g, 0.268 mmol), thionyl chloride (3.0 mL), 2,4,6-trifluoroaniline (0.059 g, 0.403 mmol), THF (10.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.52 (s, 6H), 2.24 (s, 3H), 3.10 (s, 2H), 7.24-7.32 (m, 4H), 7.41 (d, J=7.2 Hz, 1H), 7.45 (s, 1H), 9.12 (s, 1H), 10.91 (s, 1H); MS [M+H]+: 501.37.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.Br.Br[CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.C1C=CC=CC=1.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][CH2:20][CH2:21][N:22]=2)=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: NCCBr
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)ccc1C1=NCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
Oxalyl chloride (5 mL) was added to a solution of 4-bromo-2-methylbenzoic acid (1.1 g, 4.72 mmol) in methylene chloride (20 mL) and DMF (2 drops) and stirred at rt for 1 h. The reaction mixture was concentrated and dried. 2-Bromoethylamine hydrobromide (0.88 g, 4.29 mmol) was dissolved in benzene (20 mL) and triethylamine (3.01 mL; 21.45 mmol) was added. The acid chloride was slowly added to the reaction mixture which was stirred vigorously at 90° C. for 18 h. The reaction mixture was poured into 50 mL of water and the product was extracted with methylene chloride (2×200 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% ethyl acetate/hexanes, then 15% ethyl acetate/hexanes yielded 0.33 g of the desired product: 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.41 (t, J=9.5 Hz, 2H), 4.11 (t, J=9.6 Hz, 2H), 2.60 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:30][NH:31][C:32](=[O:37])C(Cl)(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:32]([NH:31][CH3:30])=[O:37])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CNC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Solvent: CN(C)C=O
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
(+)-4-(5-Chloro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman ##STR58## (+)-4-(5-Chloro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman is prepared analogously to Example 1 from optically active 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point: 242° C.; [α]D20 : +63.4° (c=1, DMF); HPLC: ee 100%.