Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[F:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[CH:44][CH:45]=1>>[F:39][C:40]1[CH:45]=[C:44]([CH:43]=[CH:42][CH:41]=1)[O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: Oc1cccc(F)c1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3cccc(F)c3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and m-fluorophenol, to afford 357 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15]
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cccc(Br)c1
Temperature: 37 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
3-bromobenzaldehyde, 24-a, (30 g, 162 mmol) in dichloromethane (600 ml) were added (S)-2-methylpropane-2-sulfinamide (23.52 g, 194.5 mmol), PPTS (5.97 g, 16.2 mmol) and anhydrous CuSO4 (78 g, 486 mmol) and the resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to provide the product, 25-a, (24.5 g, 52%).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCNC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCCN(CCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from 3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide and 4-bromobutyl acetate. The protecting group is cleaved off as described by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.Cl.[NH2:30][C@H:31]([C:51]([N:53]1[C@H:57]([C:58](=[O:70])[NH:59][C@H:60]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][CH2:62][CH2:61]2)[CH2:56][Si:55]([CH3:72])([CH3:71])[CH2:54]1)=[O:52])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=2)=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([NH:30][C@H:31]([C:51]([N:53]1[C@H:57]([C:58](=[O:70])[NH:59][C@H:60]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:63][CH2:62][CH2:61]2)[CH2:56][Si:55]([CH3:72])([CH3:71])[CH2:54]1)=[O:52])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:49][CH:50]=2)=[CH:35][CH:34]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C#Cc2ccc(C[C@H](N)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#Cc2ccc(C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N3C[Si](C)(C)C[C@H]3C(=O)N[C@@H]3CCCc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (34 mg, 0.17 mmol) in DMF (2 mL) were added EDC (41 mg, 0.22 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (17 mg, 0.13 mmol), followed by a solution of methyl 4-((4-((S)-2-amino-3-((R)-3,3-dimethyl-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,3-azasilolidin-1-yl)-3-oxopropyl)phenyl)ethynyl)benzoate HCl salt (80 mg, 0.13 mmol) in DMF (2 mL) and DIEA (0.07 mL, 0.38 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow solid (85 mg, 86%). 1H NMR (CDCl3) δ 8.10-7.91 (m, 2H), 7.63-7.50 (m, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.24-7.00 (m, 5.5H), 6.56 (d, J=8.6 Hz, 0.5H), 5.26-5.06 (m, 2.5H), 4.11 (q, J=7.0 Hz, 0.5H), 3.92 (s, 3H), 3.21-2.55 (m, 6H), 2.49 (s, 3H), 2.14-1.70 (m, 5H), 1.47 (s, 9H), 1.31-0.90 (m, 5H), 0.52-0.19 (m, 6H); MS(ESI+) m/z 779.6 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40](O)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][S:7][CH2:6][CH2:5]4)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1
Reactant: OCCN1CCSCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCSCC1
Reaction time: 3.5 h
Yield: 22.3 %

Procedure:
4-(2-Hydroxyethyl)thiomorpholine (114 mg, 0.78 mmol), (J. Am. Chem. Soc. 1934. 56, 1720), in methylene chloride (1 ml) followed by 1,1′-(azodicarbonyl)dipiperidine (525 mg, 2.08 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 0.70 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (0.51 ml, 2.08 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hours and allowed to stand for a further 18 hours. Ether (8 ml) was added, the precipitate removed by filtration and the solvent removed from the filtrate by evaporation. The residue was dissolved in acetone and ethereal hydrogen chloride (2.5 ml of a 1 M solution) added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline (70 mg, 22%) as a pale yellow solid.
Reaction SMILES: C(=O)(O)N.[O:5]1[CH:10]2[CH:6]1[CH2:7][NH:8][CH2:9]2.C([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(OC(C)(C)C)=O>C(#N)C>[N:18]1([CH:10]2[CH2:9][NH:8][CH2:7][CH:6]2[OH:5])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: C1NCC2OC12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: NC(=O)O
Solvent: CC#N
Product: OC1CNCC1N1CCNCC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
3,4-Epoxypyrrolidine carbamate Wang resin (0.15 g, 0.18 mmol) was placed in a glass reaction vessel (4 mL). LiClO4 (57 mg, 3 eq.), N-Boc piperazine (186 mg, 5.5 eq.) and acetonitrile (2 mL) were added. The glass reactor was closed with a screw cap and the reaction mixture was heated at 80° C. for 43 h. The resin was transferred into syringes and washed with acetonitrile:H2O (1:1, 2×), DMF (3×), MeOH (3×), DMF (3×), and CH2Cl2 (5×). The BOC group was removed by treating the resin with 10% methyl sulfide in TFA (2 mL) for 1 hour. This solution was saved and later combined with a cleavage solution. The product was further cleaved from resin by shaking with a solution of TFA:CH2Cl2:H2O (2 mL of 70:30:1.5) for 2.5 h (2×). All the solutions were combined and condensed to afford 170 mg of crude 4-piperazin-1-yl-pyrrolidin-3-ol (bistrifluoroacetate salt, used without purification). The crude 4-piperazin-1-yl-pyrrolidin-3-ol was dissolved in DMF (dry, 2 mL). To this solution was added 4-chloro-benzoyl chloride (46L, 0.36 mmol), diisopropyl ethyl amine (620 μL, 3.6 mmol), and DMAP (2 mg). The solution was stirred at RT for 30 minutes, and then separated by preparative LC-MS to yield 16 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 448.3 (100).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>CN1C(=O)CCC1>[F:8][C:7]1[C:2]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: CC(C)(O)CN
Reactant: Fc1cc(I)cnc1F
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)(O)CNc1ncc(I)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
2,3-Difluoro-5-iodopyridine (500 mg, 2.07 mmol) was dissolved in NMP (500 μL) and pyridine (201 μl, 2.49 mmol, 1.2 equiv.) and 1-amino-2-methylpropan-2-ol (555 mg, 6.22 mmol, 3 equiv.) were added at room temperature. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (590 mg, 1.9 mmol, 91.7% yield) was obtained as a colorless oil, MS: m/e=311.0 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:19]([C:18]1[O:21][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1)[CH3:20]
Reactant: CCC(=O)Nc1ccc2c(c1O)C(CCNC(C)=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CCc1nc2ccc3c(c2o1)C(CCNC(C)=O)CC3
Yield: 84 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}propanamide (88.5 mg, 0.305 mmol) and pyridinium p-toluenesulfonate (15.3 mg, 0.061 mmol) were heated under reflux in xylene (3.1 mL) for 2.5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (69.8 mg, yield 84%).
Reaction SMILES: [CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:7].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:31]([C:26]1[C:25]([C:20]2[N:19]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:32]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1

Procedure:
A solution of (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 50 mg, 0.192 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 46 mg, 0.231 mmol), triethylamine (80 ul, 0.576 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (34 mg, 0.250 mmol) and EDC (48 mg, 0.250 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. The reaction was partitioned between DCM (20 ml) and a saturated solution of sodium bicarbonate (10 ml). The aqueous layer was further extracted with DCM (20 ml) and the combined organics were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl.[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](C3C=CC=C(OC)C=3)([OH:15])[CH:11](CN(C)C)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:28][C:29]([O-:32])(C)C.[K+].O1C2(CCC(=O)CC2)OCC1.O>C1(C)C=CC=CC=1>[CH:2]1([CH2:7][CH:8]=[C:9]2[CH2:10][CH2:11][C:12]3([O:15][CH2:28][CH2:29][O:32]3)[CH2:13][CH2:14]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C(CC1CCCC1)=C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 245.4 %

Procedure:
The reaction was conducted in a nitrogen atmosphere with the exclusion of moisture. 21.9 g (50 mmole) of compound (52) were added to 5.6 g (50 mmole) potassium tert-butylate in 400 ml toluene. The mixture was stirred for 30 minutes at room temperature and for 1 hour at 80° C., and was subsequently cooled to 60° C. 7.8 g (50 mmole) 1.4-dioxa-spiro[4.5]decan-8-one were added. The mixture was then stirred for 18 hours at 60° C. and cooled. 100 ml water were added drop-wise. The organic phase was separated off, the aqueous phase was extracted twice with toluene and dried over sodium sulphate, and the solvent was removed by distillation. 29 g oil were obtained, which was purified with 1:4 diisopropyl ether/n-hexane on a silica gel column.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(CCl)c(SC(C)C)n1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: Cc1ccc(COc2ccc(CCC(=O)O)cc2Cl)c(SC(C)C)n1
Yield: 49.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine (34 mg, 0.17 mmol) obtained in Step D of Preparation Example 9 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.18 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C@H:17]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:34][CH:35]1[CH2:40][CH2:39][N:38]([C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C@H:17]([NH:16][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[CH3:13])=[O:15])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[CH2:37][CH2:36]1
Reactant: CC1CCNCC1
Reactant: Cc1c(C(=O)N[C@@H](CCCC(=O)O)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@@H](CCCC(=O)N2CCC(C)CC2)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.8 %

Procedure:
A solution of (S)-5-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-5-(3-trifluoromethyl-phenyl)-pentanoic acid (60 mg, 0.13 mmol) and 4-methylpiperidine (40 mg, 0.40 mmol) in DMF (3 mL) is treated with O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU) (64 mg, 0.20 mmol). The reaction mixture is stirred at room temperature for 16 hours. The crude reaction mixture is purified directly by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-5-(4-methyl-piperidin-1-yl)-5-oxo-1-(3-trifluoromethyl-phenyl)-pentyl]-amide (21 mg, 30% over 2 steps).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 50 ml sinfle neck round bottom flask, under a nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (100 mg, 0.19 mmol) was added to ethyl acetate (4 ml). To this solution was added 10% palladium on activated carbon (100 mg), followed by the addition of a hydrogen balloon. The reaction mixture was stirred for three hours at room temperature, then filtered through a bed of CELITE™. The desired title product was further purified by radial chromatography.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[CH2:16][CH2:17][CH2:18][CH:9]([C:10]=23)[C:8]1=[O:19].C(Br)C#C>CN(C)C=O.O>[CH2:3]([C:9]12[CH2:18][CH2:17][CH2:16][C:11]3[C:10]1=[C:15]([CH:14]=[CH:13][CH:12]=3)[NH:7][C:8]2=[O:19])[C:2]#[CH:1]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC12CCCc3cccc(c31)NC2=O
Reaction time: 0.25 h

Procedure:
Potassium tert.-butoxide, 4.94 g (0.044 mol), was added to a solution of 6.92 g (0.04 mol) of rac-2a,3,4,5-tetrahydro-benz[cd]indol-2(1H)-one in 50 ml of dimethylformamide. After stirring for 15 minutes under nitrogen, 5.23 g or 3.9 ml of propargyl bromide was added and stirring was continued for 30 minutes. The mixture was diluted with water and ice and the precipitate was collected by filtration, washed with water and sucked dry. The solids were dissolved in methylene chloride and the solution was dried and evaporated. Crystallization of the residue from ethyl acetate gave crude product of rac-2a,3,4,5-tetrahydro-2a-(2-propynyl)benz[cd]indol-2(1H)-one with m.p. 174-177° which was recrystallized from ethyl acetate to melt at 177°-180°.
Reaction SMILES: [Li+].[OH-].O.[CH2:4]([C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16]C)=[O:15])[C:9]1=[O:21])[CH:5]([CH3:7])[CH3:6].Cl>C1COCC1>[CH2:4]([C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([OH:16])=[O:15])[C:9]1=[O:21])[CH:5]([CH3:7])[CH3:6]
Reactant: C=CC[C@@H](C(=O)OC)N1CC[C@H](CC(C)C)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](C(=O)O)N1CC[C@H](CC(C)C)C1=O
Reaction time: 72 h
Yield: 66.9 %

Procedure:
Step M (5): A solution of LiOH/H2O (2M, 40 mg in 1.0 mL) was added to the diastereomer A, (S)-methyl 2-((S)-3-isobutyl-2-oxopyrrolidin-1-yl)pent-4-enoate (138 mg, 0.55 mmol) from Step M (4) in THF (1.0 mL) at RT. The reaction was stirred for 3 days. The mixture was poured into 1N HCl and the aqueous layer was extracted with EtOAC. The combined organic layers were washed with brine, dried over NaSO4 and concentrated in vacuo to give 88 mg (67%) of the title compound as white solid: LC-MS (M+H)+=240.04. 1H NMR (300 MHz, CDCl3) δ ppm 0.82-0.95 (m, 7H) 1.16-1.30 (m, 1H) 1.59-1.79 (m, 3H) 2.09-2.26 (m, 1H) 2.39-2.60 (m, 2H) 2.68-2.80 (m, 1H) 3.24-3.48 (m, 2H) 4.67-4.76 (m, 1H) 5.01-5.20 (m, 2H) 5.60-5.79 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:3]=1>ClCCl>[CH3:22][N:24]([CH2:26][C:3]1[C:4]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:5][C:6]2[N:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:8]([CH3:11])=[N:9][C:10]=2[C:2]=1[OH:1])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)cc(C(=O)N(C)C)cc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(O)c(CN(C)C)c(C(=O)N(C)C)cc32)cc1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
To a solution of 4-hydroxy-N,N,2-trimethyl-1-[(4-methylphenyl)sulfonyl]-1H-benzimidazole-6-carboxamide (1.00 g, 2.68 mmol, Step 4) in dichloromethane (50 mL) was added N,N-dimethylmethyleneiminium iodide (545 mg, 2.95 mmol) at room temperature and the mixture was stirred at 40° C. for 15 hours. The reaction was quenched by saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow amorphous (1.04 g, 90%).
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[Na+]>C(O)C>[N:16](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[OH:17]
Reactant: O=C(O)CCCC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCC(=NO)c1ccccc1
Temperature: 120 °C

Procedure:
4-benzoylbutyric acid (4.26 g, 22.2 mmol), a 5 mL solution of aqueous hydroxylamine hydrochloride (1.80 g, 25.9 mmol), and a 2.0M solution of aqueous sodium hydroxide (14 mL, 28.0 mmol) were combined in 15 mL of absolute ethanol. The mixture was refluxed at 120° C. for 1 hour, then evaporated in vacuo to remove ethanol. A few drops of a 2.0M solution of aqueous hydrochloric acid were added to the solution to achieve a pH of 6. Then more water was added, and the slurry was filtered to isolate the title compound as a solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.