Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([F:51])[C:33]=1[CH2:34][CH2:35][C@H:36]1[O:41][CH2:40][C@@H:39]([CH2:42][OH:43])[N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:37]1)=[O:26])[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:57](N2C=NC=C2)=[O:58])C=1.[F:64][C:65]([F:69])([F:68])[CH2:66][NH2:67]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([F:51])[C:33]=1[CH2:34][CH2:35][C@H:36]1[O:41][CH2:40][C@@H:39]([CH2:42][O:43][C:57](=[O:58])[NH:67][CH2:66][C:65]([F:69])([F:68])[F:64])[N:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:37]1)=[O:26])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 60 °C
Yield: 73.3 %

Procedure:
tert-Butyl (2R,5R)-2-[2-(3-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-5-fluoropyridin-4-yl)ethyl]-5-(hydroxymethyl)morpholine-4-carboxylate (1.50 g, 2.10 mmol) and CDI (0.425 g, 2.62 mmol) were heated at 60° C. in Pyridine (21 mL) for 30 min. 2,2,2-Trifluoroethylamine (3.29 mL, 42.0 mmol) was added and the reaction heated at 60° C. for 24 hours, A further aliquot of 2,2,2-Trifluoroethylamine (1.65 mL, 21.0 mmol) was added and the reaction heated at 60° C. for a further 24 hours. The reaction was quenched with saturated aqueous KH2PO4 then brine and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (220 g) eluting with a gradient of 0-100% EtOAc/hexanes afforded the title compound (1.29 g, 1.54 mmol, 73% yield) as a white solid, MS (ESI): m/z=840.46 (MH+); 100% pure by LCMS.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14]1([CH2:20][C:21](=O)[CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[C:7](=[O:11])[NH:8][C:9]2[CH:10]=[C:2]3[C:3](=[CH:4][C:5]1=2)[C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:21]([CH3:22])[NH:1]3
Reactant: CC(=O)Cc1ccccc1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Solvent: ClCCl
Product: Cc1[nH]c2cc3c(cc2c1-c1ccccc1)C(C)(C)C(=O)N3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Analogously to Example 5, 4 g. (22.7 mmole) 6-amino-3,3-dimethylindolin-2-one are diazotised and reduced. Subsequently, 3 g. (22.3 mole) phenylacetone are added thereto and the reaction mixture further stirred for 18 hours at 25° C. The oil which separates out is shaken out several times with methylene chloride, evaporated and the residue worked up with cyclohexane and filtered off with suction. The solid residue is again dissolved in methylene chloride, washed twice with aqueous sodium hydrogen carbonate solution and once with water, dried with anhydrous sodium sulphate with the addition of charcoal and crystallised from methylene chloride. Yield 1.25 g. (19% of theory); m.p. 233°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19]CO>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][CH2:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOc1ccc2ccccc2c1
Reactant: COc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1csc(OCCOc2ccc3ccccc3c2)c1
Yield: 49.6 %

Procedure:
A solution of 2-methoxythiophene (2.28 g) and 2-(2-naphthalenyloxy)ethanol (4.0 g) in benzene (35 mL) containing para-toluenesulfonic acid (0.02 g) was stirred at reflux for 3 days in a flask equipped with a Soxhlet extractor charged with 4 Å molecular sieves. The mixture was cooled, washed with 0.5N sodium hydroxide solution, dried over anhydrous magnesium sulfate (MgSO4) and evaporated. Crystallization of the residual material from ethanol (30 mL) provided 2.68 g of 2-[[2-(2-naphthalenyloxy)ethyl]oxy]thiophene as colorless flakes, mp 129°-130 ° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:13]2([CH3:20])[O:19][CH:14]2[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[N:1]([C:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:20])[CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16])=[N+:2]=[N-:3]
Reactant: COC(=O)C1OC1(C)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)C(C)(N=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
19.5 g (300 mmol) of sodium azide and 16.0 g (300 mmol) of ammonium chloride are suspended in 400 ml of methanol and treated with 19.2 g (100 mmol) of methyl 3-phenyl-2,3-epoxybutyrate. The mixture is stirred for 9 hours under reflux and for 12 hours at room temperature, the majority of the methanol is distilled off and the residue is treated with 200 ml of water. It is then extracted with ethyl acetate, and the organic phases are dried and concentrated. The residual oil is treated with a little diethyl ether and the crystals formed are filtered off with suction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:14][CH:12]([CH2:13]2)[O:11][C:10](=[O:15])[NH:9]3)=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:24](=[O:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCCCCC>[C:26]1([CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]34[CH2:14][CH:12]([CH2:13]3)[O:11][C:10](=[O:15])[NH:9]4)=[CH:4][CH:3]=2)=[O:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)Cc1ccccc1
Reactant: O=C1NC2(c3ccc(Br)cc3)CC(C2)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NC2(c3ccc(C(=O)Cc4ccccc4)cc3)CC(C2)O1

Procedure:
A solution of 5-(4-bromo-phenyl)-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (prepared according to WO2009/148916, 4 g) in dry THF (60 mL) was cooled to −78° C. and treated with n-BuLi (6.56 mL of a 2.5M solution in hexane) and stirred for 30 minutes at this temperature before addition of further n-BuLi (13.1 mL of a 2.5M solution in hexane). Stirring was continued at this temperature for 30 minutes before a solution of N-methoxy-N-methyl-benzeneacetamide (prepared according to US6407119B1, 4.6 g) in THF (10 mL) was added. After 10 minutes the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with EtOAc and the combined organic phases washed with brine, filtered and concentrated. The residue was triturated with hexane/EtOAc to give the title compound which was used in the next step without further purification.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(NCC)C.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Fmoc-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.02 g) was dissolved in chloroform (10 mL), and diethylamine (1.94 mL, 18.7 mmol) was added dropwise under ice-cooling. The mixture was warmed to room temperature, acetonitrile (5 mL) was added, and the mixture was stirred for 2.5 hr. Diethylamine (970 μL, 9.35 mmol) was added, and the mixture was further stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was precipitated with acetonitrile (10 mL) to give Leu-Leu-OBzl (2-MeO-4-OC12OC22) as wet crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[N:6]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.C([O:28][C:29](=O)[C@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31])(=O)C>>[OH:31][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([N:11]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:21][CH2:20][C:17]1[CH:18]=[N:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1)=[O:28]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Product: Cc1nc2cc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](O)c3ccccc3)ccc2o1

Procedure:
In analogy to example 49, 2-Methyl-benzooxazol-5-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled and hydrolysed to give the target compound. MS(m/e): 456.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].O>CN(C=O)C.O1CCCC1>[OH:28][CH:26]([CH3:27])[CH:25]([N:22]1[C:21](=[O:30])[N:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[CH:24]=[N:23]1)[CH3:29]
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: -10 °C

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.06 mol) in DMF (500 ml) was cooled to −10° C. and then stirred under N2 flow. Potassium tri-sec-butylborohydride, 1M solution in tetrahydrofuran (150 ml) was added dropwise. The mixture was allowed to warm to room temperature slowly and then poured out into water. The precipitate was filtered off, washed with CH3OH and crystallized from CH3OH. The precipitate was filtered off and dried. The residue was purified by HPLC over CHIRALPAC AD (eluent:ethanol). Two pure fractions were collected and their solvents were evaporated. Each residue was triturated in CH3OH. The precipitate was filtered off and dried, yielding 7.3 g [S-(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one. (interm. 1a) [α]20D=−10.81° (c=50.43 mg/5 ml DMF).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:29])[C:10](=[CH:25]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[C:14]=2[S:21]([CH3:24])(=[O:23])=[O:22])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:31]O>C(O)C>[CH:6]1([C:9]2[O:29][N:31]=[CH:25][C:10]=2[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[C:14]=2[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(F)c(F)c1S(C)(=O)=O)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1c(C(=O)c2cnoc2C2CC2)ccc(F)c1F
Reaction time: 2.5 h
Yield: 58.7 %

Procedure:
Sodium acetate (0.31 g) was added with stirring to a mixture of 3-cyclopropyl-1-[3,4-difluoro-2-(methylsulphonyl)phenyl]-2-ethoxymethylenepropane-1,3-dione (1.1 g) and hydroxylamine hydrochloride (0.26 g) in ethanol. The mixture was stirred for 2.5 hours. The mixture was evaporated to dryness and the residue was suspended in ethyl acetate, washed with water, dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was triturated with n-hexane and filtered to give 5-cyclopropyl-4-(3,4-difluoro-2-methylsulphonylbenzoyl)isoxazole (compound 283, 0.59 g) as an orange solid, m.p.115°-118° C.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:4](=[O:43])[O:5]/[C:6]/1=[CH:7]/[C:8]1[CH2:9][S:10][C@@H:11]2[C@H:31]([NH:32]C(=O)CC3C=CC=CC=3)[C:30](=[O:42])[N:12]2[C:13]=1[C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].CO.O>ClCCl>[NH2:32][C@@H:31]1[C:30](=[O:42])[N:12]2[C:13]([C:14]([O:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:15])=[C:8](/[CH:7]=[C:6]3\[C:2]([CH3:1])=[C:3]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:4](=[O:43])[O:5]\3)[CH2:9][S:10][C@H:11]12
Reactant: CC1=C(c2ccccc2)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1=C(c2ccccc2)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Diphenylmethyl 3-(E-2,5-dihydro-4-methyl-2-oxo-3-phenylfuran-5-ylidenemethyl)-7β-phenylacetamidoceph-3-em-4-carboxylate (0.6 g) in dichloromethane (5 mls) under argon, was cooled to -20° C. N-methylmorpholine phosphorous pentachloride (0.253 g) in dichloromethane (6.075 mls). The solution was maintained at -20° C. for 30-40mins. I.r. analysis showed no starting material present Dry methanol (5 mls) was added rapidly, in one portion. The reaction mixture was allowed to warm to room temperature over 30mins. Water (10 mls) was then added and the solution vigorously stirred for 30 mins. The organic phase was separated, washed with brine and then dried. After removal of solvent the residue was purified by flash chromatography on silica gel, eluting with 70% ethyl acetate/hexane. The title compound was obtained as a yellow foam, (0.453 g, 92%), νmax (CH2Cl2) 1780 (shoulder), 1760, 1720(w) and 1615(vw)cm-1 ; δH (CDCl 3) 2.06 (3H,s), 3.47 (2H,ABq,J18.6Hz), 4.87 (1H,d,J5.1Hz), 5.00 (1H,d,J5.1Hz), 6.33 (1H,s), 7.00 (1H,s) and 7.1-7.5 (15H,m); [mass spectrum: +ve ion (3-NOBA, Na+) MNa+, 573].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[CH2:7]([Li])CCC.CI.[CH3:14][C:15]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=O>C1COCC1>[CH3:14][C:15]1[C:24]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=[CH:21][C:16]=1[C:17](=[O:19])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C
Reactant: Cn1cncn1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)Cc2ncnn2C)ccc(C(F)(F)F)c1S(C)(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
683 mg (8.22 mmol) of 1-methyl-1,2,4-triazole in 20 ml of THF are admixed under argon at −78° C. with 3.3 ml (8.22 mmol) of butyllithium (2.5M, hexane). After 30 min, 1.22 g (8.63 mmol) of methyl iodide, dissolved in 2 ml of THF, are added, the cooling bath is removed and the mixture is left to reach RT. The mixture is cooled again to −78° C. and admixed with 3.3 ml (8.22 mmol) of butyllithium (2.5M, hexane). After 15 min, 1.22 g (4.12 mmol) of methyl 2-methyl-3-(methylsulfonyl)-4-trifluoromethylbenzoate are added and the mixture is left to thaw overnight. The mixture is quenched with ammonium chloride solution and extracted with EE. The organic phase is washed with NaHCO3 solution and NaCl solution, dried, evaporated and purified by means of RP-HPLC (acetonitrile/water). Yield 255 mg (17%). 1H NMR, CDCl3, 400 MHz: 7.90 (s, 1H), 7.82 (d, 1H), 7.72 (d, 1H), 5.57 (s, 1H), 3.85 (s, 3H), 3.27 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:21]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1>C1COCC1>[CH2:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][C:22]([CH:14]([C:13]([OH:20])=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])([OH:21])[CH2:23][CH2:24]1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCC(=O)O
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a solution of 15 mL (124 mmol) diisopropyl amine in 90 mL anhydrous THF at −40° C. was added dropwise 45 mL (113 mmol) of n-butyl lithium (2.5 M in hexanes) The reaction mixture was warmed to 0° C. A solution of 6.7 mL (62.1 mmol) hexanoic acid in 60 mL anhydrous THF was added dropwise. The reaction mixture stirred at −20° C. for an additional 20 m. The reaction mixture was cooled to −78° C. A solution of 15 g (64.3 mmol) benzyl 4-oxo-1-piperidine-carboxylate in 60 mL anhydrous THF was added dropwise. The reaction mixture slowly warmed to room temperature over 18 h. The reaction was quenched by addition of 25 mL of water. The mixture was acidified to pH 2 with 6N HCl. The aqueous layer was thrice extracted with EtOAc. The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. Toluene was added to the light, yellow oil and evaporated under reduced pressure to provide 21.5 g (99%) of 4-(1-carboxy-pentyl)-4-hydroxy-piperidine-1-carboxylic acid benzyl ester: ms [M]+=350.
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)=[S:6])[CH3:3].N.[H][H]>[Pd].[Pt].CO>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:5]([N:4]([CH:2]([CH3:3])[CH3:1])[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)=[S:6]
Reactant: [H][H]
Reactant: CC(C)N(C(=S)Nc1ccccc1[N+](=O)[O-])C1CCN(CCc2ccccc2)CC1
Agent: [Pd]
Agent: [Pt]
Agent: N
Solvent: CO
Product: CC(C)N(C(=S)Nc1ccccc1N)C1CCN(CCc2ccccc2)CC1
Yield: 100 %

Procedure:
A mixture of 43 parts of N-(1-methylethyl)-N'-(2-nitrophenyl)-N-[1-(2-phenylethyl)-4-piperidinyl]thiourea and 800 parts of methanol, saturated with ammonia is hydrogenated at normal pressure and at room temperature with 6 parts of palladium-on-charcoal catalyst 10% and 6 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalysts are filtered off over Hyflo and the filtrate is evaporated, yielding 39 parts (100%) of N-(2-aminophenyl)-N'-(1-methylethyl)-N'-[1-(2-phenylethyl)-4-piperidinyl]thiourea as a residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[NH2:5].C[Al](C)C.[NH:18](/[C:22](/[CH3:28])=[CH:23]\[C:24](OC)=[O:25])[C:19]([CH3:21])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:28])[N:18]=[C:19]2[CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(-n2cccn2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(-n3cccn3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 3-fluoro-4-(1H-pyrazol-1-yl)aniline (0.65 g, 3.68 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (18.4 mL, 36.8 mmol, 2 M in heptane) slowly. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (634 mg, 4.04 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:2) to give the title compound as a white solid (400 mg, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na].C(O)(=O)C.O>CO>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=O)cc1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Oc1ccc(CO)cc1
Yield: 41 %

Procedure:
To the solution of 4-formylphenol acetate (6.0 g, 36.4 mmol) in 60 ml of methanol was added sodium boronhydride (1.50 g, 39.6 mmol) at 0° C. The resultant mixture was stirred for 1 hour, neutralized with acetic acid and then poured into water. The mixture was extracted three times with ether and the combined organic layer was dried over magnesium sulfate. After removal of solvent, the compound was purified by flash chromatography using heptane/ethyl acetate (80/20-70/30) as eluent in a yield of 41%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[NH:11][C:10]2=[O:16].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32]I)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][N:11]2[C:10](=[O:16])[C:9]3[C:14](=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][CH:8]=3)[N:13]=[C:12]2[CH3:15])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCI)CC1
Reactant: COc1cccc2c(=O)[nH]c(C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)n(CCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C)nc12
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (91 mg, 2.37 mmol) was added to a solution of 8-methoxy-2-methyl-3H-quinazolin-4-one (300 mg, 1.58 mmol) in DMF (30 mL). The reaction mixture was stirred at 80° C. for 0.75 h and cooled to room temperature, then a solution of 4-(3-iodo-propyl)-piperidine-1-carboxylic acid tert-butyl ester (837 mg, 2.37 mmol) in DMF (1 mL) was added. The reaction mixture was heated at 85° C. for 17 h and diluted with EtOAc. The organic solution was washed with water and sat'd aq NaCl, dried and concentrated. Purification on SiO2-gel chromatography (50% EtOAc/hexanes) provided the desired product as a yellow oil. API-MS: 416 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[O:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-hydroxy-1-indanone (25.0 g, 169 mmol) in DMF (500 ml) was triethylamine (22.2 g, 220 mmol) added, to the resulting solution was tert-butyldimethylchlorosilane (28.0 g, 186 mmol) added. The reaction mixture was stirred overnight at room temperature and treated with water (500 ml) and extracted with diethyl ether (500 ml). The organic phase was collected and dried over sodium sulfate. Evaporation gave a yellow oil which was distilled under reduced pressure to give the indanone (36.68 g, 140 mmol, 82.7%) as a colourless oil (120–121° C./0.1 mbar).