Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH2:16].C(O)C.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CC(O)C.[Pt]=O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(CO)cc1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: CC(C)O
Solvent: CCO
Product: CC(Cc1ccc(CO)cc1)NCC(O)c1ccccc1

Procedure:
A mixture of 1-(4-hydroxymethylphenyl)propan-2-one (3.0 g) and 2-hydroxy-2-phenylethanamine (2.5 g) in benzene (200 ml) was refluxed for 4 hours under Dean and Stark conditions. The solvent was replaced with ethanol (200 ml), platinum oxide (200 mg) was added and the mixture was hydrogenated at ambient temperature and pressure. The solution was filtered and evaporated to give an oil which was taken up in propan-2-ol and treated with the theoretical amount of fumaric acid. The title compound was obtained as the hemi-fumarate salt m.p. 67°-70° (60:40 mixture of diastereoisomers).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][CH:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][CH:33]([CH3:34])[CH3:35])[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: CC(C)Oc1cnc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)Oc1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 60 °C
Yield: 102.8 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (64 mg, 0.12 mmol) in HCOOH (3 mL) was added Zn dust (40.4 mg, 0.62 mmol). The reaction was heated at 60° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:2) to give 3-(5-(4-chlorobenzyl)-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (55 mg, 99% yield) as a white solid. LCMS: MH+ 446 and TR=2.816 min.
Reaction SMILES: CON(C)[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([CH3:15])[CH:6]=1.[CH3:18][Mg]Br.C(OCC)C.Cl>C1COCC1.CCOC(C)=O>[CH3:15][C:7]1[CH:6]=[C:5]([C:4](=[O:16])[CH3:18])[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)c(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(C(F)(F)F)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-methoxy-3,N-dimethyl-4-trifluoromethyl-benzamide from step 7 (16.90 g, 68.36 mmol) in THF (280 mL) at −5° C. was added a 3 M methylmagnesium bromide solution in diethyl ether (45.6 mL, 136.7 mmol). The mixture was stirred at 0° C. for 1 h, then was warmed up to 23° C. and stirring was continued at 23° C. for further 1.5 h under nitrogen atmosphere. Then 1 N HCl (100 mL) was added drop wise to the mixture and stirring was continued for 30 min. The mixture was diluted with EtOAc and the aqueous layer was separated, the organic layer was washed with brine and dried over MgSO4. Removal of the solvent in vacuum left the title compound as a light brown liquid (12.87 g, 93.1%), which was used without further purification. MS (EI) 202.1 [M].
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C-:9]#[N:10].[K+].C(OCC)(=O)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1OCCOCCOCCOCCOCCOC1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: [C-]#N
Reactant: Nc1cnc(Br)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnc(N)cn1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A mixture of Example 1A (19.29 g, 105 mmol), freshly powdered KCN (16.9 g, 260 mmol), CuI (49.5 g, 260 mmol), 18-crown-6 (2.08 g, 7.8 mmol), and (PPh3)4Pd (1.8 g, 1.57 mmol) in N,N-dimethylformamide (600 mL) was stirred at room temperature for 30 minutes and heated to reflux in an oil bath preheated to about 200° C. The solution was stirred at reflux for 3 hours, cooled to room temperature, poured into ethyl acetate (1 L), filtered through diatomaceous earth (Celite®), treated with silica gel (100 g), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 60% ethyl acetate/hexanes to provide 11.9 g (94.4%) of the desired product. MS (APCI(+)) m/z 121 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J=0.7 Hz, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.47–7.69 (br s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([O:33]C4CCCCO4)[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](OC4CCCCO4)C3)c3ccccc3n2)CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](O)C3)c3ccccc3n2)CC1
Yield: 59.7 %

Procedure:
A solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-[4-[(RS)-(tetrahydropyran-2-yl)oxy]cyclopent-2-en-1-yl]oxy]quinazoline (12.57 g) in acetic acid (50 ml)--water (12.6 ml) is stirred at 60° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate and water, and then dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the resulting residue is purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=500:1, v/v)] to give 2-[4-(benzyloxycarbonyl) piperazin-1-yl]-4-[(1R,4S)-(4-hydroxycyclopent-2-en-1-yl) oxy] quinazoline (6.31 g) as crystals.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2=[O:16].O.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[CH3:18][O:17][C:5]1[C:4]([CH2:3][CH:2]=[O:1])=[C:13]2[C:8]([C:9](=[O:16])[CH2:10][C:11]([CH3:14])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc2c(c1CC(O)CO)OC(C)(C)CC2=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
171 mg of 8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxochroman was dissolved in 4 ml of tetrahydrofuran and 4 ml of methanol. Thereafter, 8 ml of water containing 0.26 g of sodium metaperiodate was added to the reaction solution while cooling on ice, and the obtained mixture was then stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 163 mg of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde. This compound was used in the following reaction without further purification.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)N1CCCCC1
Yield: 61.9 %

Procedure:
In a manner similar to that described in Example 1, dodecanoyl chloride (21.88 g, 0.1M) was treated with piperidine (8.52 g, 01M). Work up and distillation gave 16.55 g (62%) of the product, b.p. 185/2 mm.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[C:5]=1[OH:19].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:33]>>[CH:3]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[C:5]=1[OH:19])=[O:33]
Reactant: CCS(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CCS(=O)(=O)c1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
0.615 g of 2-aminomethyl-4-(1,1-dimethylethyl)-6-ethylsulfonylphenol hydrochloride are reacted with 0.36 g of urotropine in 8 ml of trifluoroacetic acid to give 2-formyl-4-(1,1-dimethylethyl)-6-ethylsulfonylphenol in analogy to Example 1.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1>CCO.CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[C:44]([OH:48])=[C:43]([O:49][CH3:50])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(Cc4ccccc4)CC3)CC2)cc(C)c1O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc(C)c1O
Reaction time: 72 h

Procedure:
A suspension of 222 mg (0.30 mmol) (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 10.3) and 60 mg 10% Pd/C in 10 mL EtOH and 6 mL MeOH was hydrogenated at 60 psi and RT for 72 h. The catalyst was filtered off and the crude product was purified by HPLC-MS.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[CH2:24]1)(=O)=O.[Cl-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[N:36]1([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:25]3[CH2:26][CH2:27][C@@H:23]([N:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=5[CH2:12][O:11][C:10]5[CH:14]=[CH:15][CH:16]=[CH:17][C:9]4=5)[CH2:24]3)=[CH:31][CH:32]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)COc1ccccc1N2[C@@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (132 mg, 3.3 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (10 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (600 mg, 3.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 30 minutes. A solution of (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine (340 mg, 1.0 mmol) in dimethyl sulfoxide (5 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 42 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-pyrrolidinophenethyl)pyrrolidin-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (142 mg, 32%).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([O:77]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([O:46]CC4C=CC(OC)=CC=4)=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[S:43][CH:42]=[N:41][CH:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([OH:77])=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[S:43][CH:42]=[N:41][CH:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3cncs3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C=Cc4cncs4)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Reaction time: 3 h
Yield: 80.3 %

Procedure:
After 870 mg (0.69 mmol) of p-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethoxycarbonyl)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[-2-(5-thiazolyl)vinyl]-3-cephem-4-carboxylate was dissolved in 9 ml of methylene chloride and 4 ml of anisole, 16 ml of trifluoroacetic acid was added therein under ice-cooling and the reaction solution was reacted for 90 min. as it was. The residue obtained by evaporating off trifluoroacetate under the reduced pressure was powdered with ethyl ether-hexane (1:1). The powder obtained by filtering off was further dissolved in 45 ml of trifluoroacetic acid under ice-cooling, and then, 11 ml of water was added therein, and the reaction was effected for 3 hrs. at the room temperature. The residue obtained by evaporating off trifluoroacetic acid and water under the reduced pressure was powdered by adding ethyl ether, and filtered off to give 404 mg of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(R S)-(carboxy) (3,4 -diacetoxyphenyl)methoxy]imino]acetamido]-3-[-2-(5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid.trifluoroacetate, a crude product.
Reaction SMILES: C(OC(=O)NC1C=C[CH:11]=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)[CH:9]=1)(C)(C)C.C(Cl)(=O)[C:43](Cl)=[O:44].COC(C)(C)CN1C=CC(N)=N1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C:10]([O:44][CH3:43])([CH3:11])[CH3:9])[N:16]=2)=[O:40])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: COC(C)(C)Cn1ccc(N)n1
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a round bottom flask, 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 165 mg, 0.50 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.53 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (5 mL) and added dropwise into a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared in Example 94, 85 mg, 0.50 mmol), 2,6-lutidine (130 μL, 1.00 mmol) and methylene chloride (5 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol. This was then diluted with ethyl acetate with a very small amount of methanol (<10%) and the organics washed with a saturated 1N aqueous hydrochloric acid solution and a saturated aqueous brine solution it was dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (211 mg, 90%) as a white foam: [α]31589=−3.04° (c=0.23, methanol); ES-HRMS m/e calcd for C23H32N3O4SCl (M+H)+ 482.1875, observed 482.1873; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.36-1.80 (m, 8H, 4×CH2), 2.09 (m, 1H, CH), 3.13 (s, 3H, OCH3), 3.33 (s, 3H, SO2CH3), 3.92 (m, 1H, ArCHCO), 3.97 (s, 2H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.74 (d, J=2.2 Hz, 1H, Ar), 7.59 (dd, Jm=1.5 Hz, Jo=8.2 Hz, 1H, Ar), 7.70 (d, Jm=1.5 Hz, 1H, Ar), 8.00 (d, Jo=8.2 Hz, 1H, Ar), 10.80 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1([C:10]([NH:12][C@H:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH3:14])=[O:11])[NH:9][CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][C:2]1([C:10]([NH:12][C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[CH3:14])=[O:11])[N:9]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[CH2:8][CH2:7][C:4]2([CH2:5][CH2:6]2)[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2)CC3)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2Cc2ccc(C(F)(F)F)cc2)CC3)cc1

Procedure:
The title compound (D130) (19 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-(5-methyl-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D92) (16 mg) and 4-(Trifluoromethyl)benzylbromide (0.011 ml). (Na2CO3: 3 eq; reaction time: 18 hrs; 68° C.)
Reaction SMILES: C(O[C:5](=O)[CH3:6])(=O)C.N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:9][CH:10]=[CH:11][CH2:12][CH2:5][CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Product: CCCC=CCCCCCC

Procedure:
Subsequently, compound (10a) is acetylated with acetic anhydride-pyridine etc., thereby giving compound (11), followed by treatment with 1,8-diazabicyclo 5.4.0.!-7-undecene (DBU) in a solvent e.g. pyridine, whereby compounds (12) and (12') are formed. Compounds (12) and (12') are then hydrolyzed with a base such as sodium hydroxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, etc., whereby compound (1) can be obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](CO)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:16][Br:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.8 %

Procedure:
To a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g) in anhydrous tetrahydrofuran (50 ml) was added carbon tetrabromide (6.2 g) and triphenylphosphine (4.88 g). the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through celite. The filtrate was taken up in ethyl acetate, washed with water then brine, dried (MgSO4) and the solvent removed in vacuo give a crude product. This was purified using flash chromatography which yielded Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.287 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]([CH2:21][CH2:22][C:23]#[N:24])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2.[C:25]1(=[O:31])[NH:29][C:28](=[O:30])[CH:27]=[CH:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:27]2[C:28](=[O:30])[NH:29][C:25](=[O:31])[C:26]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:21][CH2:22][C:23]#[N:24])[C:10]=2[CH:9]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2c(c1)cc(/C=C/c1ccccc1Cl)n2CCC#N
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC#N)C(=O)NC3=O
Yield: 80.2 %

Procedure:
Diene (236) (1.30 g, 3.86 mmol) prepared as described in example 96 was reacted with maleimide (0.49 g) following The procedure described in example 68 and then aromatized according to the procedure described in example 70 to give crude material that was chromatographed on silica eluting with ethyl acetate/hexane (1:1). Trituration from methanol gave nitrile (237) (1.33 g, 80%) as a yellow powder, mp 287–288° C. 1H NMR δ [(CD3)2SO] 11.16 (br s, 1H), 8.53 (d, J=2.6 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.59 (m, 1H), 7.49 (m, 3H), 7.33 (dd, J=9.0, 2.6 Hz, 1H), 4.86 (t, J=6.7 Hz, 2H), 3.91 (s, 3H), 3.04 (t, J=6.7 Hz, 2H). Found: C, 65.32; H, 4.15; N, 9.60. C24H16ClN3O3.3/4H2O requires: C, 65.01; H, 3.98; N, 9.47.
Reaction SMILES: [OH:1][C@H:2]([CH2:30][OH:31])[CH2:3][C:4]1[C:12]2[C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:5]=1.O[C@H](CO)CC1C2C(C#N)=CC=CC=2N(C2C=CC(OC3C=CC(F)=CC=3)=CC=2)C=1>CCO.O>[OH:1][C@H:2]([CH2:30][OH:31])[CH2:3][C:4]1[C:8]2[C:7](=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=2)[N:6]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:5]=1
Reactant: NC(=O)c1cccc2c1c(C[C@H](O)CO)cn2-c1ccc(Oc2ccc(F)cc2)cc1
Agent: N#Cc1cccc2c1c(C[C@H](O)CO)cn2-c1ccc(Oc2ccc(F)cc2)cc1
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2c(C[C@H](O)CO)cn(-c3ccc(Oc4ccc(F)cc4)cc3)c2c1
Temperature: 84 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
General procedure for the preparation of compounds 122 and 123: To a mixture of compound 120 (100 mg, or 105) in EtOH/water (6 mL/2 mL) at room temperature was added the catalyst 121 (10 mg). The resulting mixture was shaken at 84° C. for 16 hours. The solvent was evaporated and the residue was purified by column (TCM/MeOH 10/0.5) to get the desired product as a white solid (˜80%).