Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:24])([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[NH2:18]>>[CH3:16][C:17]([NH:18][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH3:24]
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Reactant: CC(C)(N)c1nccs1
Product: Cc1ccc(C(=O)NC(C)(C)c2nccs2)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=332.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[O:14])[CH2:11][O:10][C:9]2([CH3:16])[CH3:15])[CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[C:19](=[N:32][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=[O:14])[CH2:11][O:10][C:9]2([CH3:16])[CH3:15])[CH:7]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)OCC(=O)N[C@]1(C)c1cc(Br)ccc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)OCC(=O)N[C@]1(C)c1cc(N=C(c2ccccc2)c2ccccc2)ccc1F
Temperature: 105 °C
Reaction time: 20 h
Yield: 112.5 %

Procedure:
In a sealed tube a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5,6,6-trimethyl-morpholin-3-one (1.0 g, 3.2 mmol) in toluene (8 ml) was treated consecutively with sodium tert-butylate (912 mg, 9.5 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-butyl-x-phos) (134 mg, 10 mol %) and tris(dibenzylideneacetone)-dipalladium chloroform complex [Pd2(dba)3.CHCl3] (98 mg, 5 mol %). Benzophenone imine (1.06 ml, 6.3 mmol) was added finally via syringe. The tube was sealed under argon and the mixture was stirred at 105° C. for 20 h. For the workup, the brown solution was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated at reduced pressure to give brown oil (1.5 g). The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one was obtained as a light yellow foam (1.13 g, 86% of theory). Mass (calculated) C26H25FN2O2 [416.493]; (found) [M+H]+=417.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:46])[C@H:14]([CH3:45])[NH:15][C:16](=[O:44])[C@H:17]([CH3:43])[NH:18][C:19](=[O:42])[C@H:20]([CH3:41])[NH:21][C:22](=[O:40])[C@@H:23]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:46])[C@H:14]([CH3:45])[NH:15][C:16](=[O:44])[C@H:17]([CH3:43])[NH:18][C:19](=[O:42])[C@H:20]([CH3:41])[NH:21][C:22](=[O:40])[C@@H:23]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=2)=[N:5][CH:4]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCNc1ncc(CO)s1
Reaction time: 1.17 h
Yield: 100 %

Procedure:
Following the general procedure as described in Example 109, except using material from Example 75 (20 mg, 0.026 mol), methanol (3 mL), sodium borohydride (5 mg, 0.13 mmol) and stirring for 70 min, the title compound (0.026 mol) is obtained as a white solid in quantitative yield. LC/MS (Condition A): ret. T=1.32 min, (M−Boc−17) 563.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20][C:14]=2[CH:13]=[CH:12][CH:11]=1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:21][C:19]1([CH3:22])[CH2:18][CH:17]=[CH:16][C:15]2[C:10]([CH2:9][OH:8])=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:20]1
Reactant: CC1(C)CC=Cc2c(CO[Si](C)(C)C(C)(C)C)cccc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=Cc2c(CO)cccc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (6,6-dimethyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane (7.306 g, 23.08 mmol) in tetrahydrofuran (30 ml) was added a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (27.7 ml, 27.7 mmol) at room temperature, and the mixture was stirred at room temperature for 15 min. The reaction solution was poured into water, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>C(O)C>[C:25]1([CH2:24][CH2:23][CH2:22][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccccc2)CC1

Procedure:
To a solution of 7.06 g (37.9 mmol.) of 1-tert-butoxycarbonylpiperazine in ethanol (50 ml) were added, at room temperature, 8.0 ml (57.4 mmol.) of triethylamine and 7.09 g (39.7 mmol.) of 1-bromo-3-phenylpropane. The mixture was heated under reflux for 16 hours under nitrogen atmosphere. To the reaction system was added ethyl acetate. The mixture was washed with water and a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane=25-50%). The solvent was distilled off under reduced pressure to give the object compound as a pale yellow liquid product. The yield was 8.69 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=1.C(N(CC)CC)C>C(O)C>[C:33]([C:29]1[CH:28]=[C:27]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:25])[CH2:24][CH2:23]2)[CH:32]=[CH:31][N:30]=1)([OH:35])=[O:34]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N2CCC(CNc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 45.1 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-yl-methyl)aminobenzamide (200 mg, 0.55 mmol), 4-chloropicolinic acid (130 mg, 0.83 mmol), triethylamine (111 mg, 1.10 mmol), and ethanol (4 ml) yielded 120 mg (45%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21](O)[CH2:22]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:21]=[CH2:22])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: CCCO
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.70 g, 1.969 mmol) was combined with potassium vinyl trifluoroborate (0.396 g, 2.95 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (1:1) (0.058 g, 0.079 mmol) and TEA (0.412 mL, 2.95 mmol) in n-propanol (10 mL) and heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was filtered through Celite™ and concentrated to dryness. The residue was dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on silica gel (eluted with 0 to 10% CH3OH/DCM) to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.52 g, 1.718 mmol, 87% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (s, 1H), 7.45-7.55 (m, 2H), 7.40 (s, 1H), 7.25 (s, 1H), 6.75 (dd, 1H), 6.04 (d, 1H), 5.43 (d, 1H), 3.77 (s, 2H), 2.05 (br. s., 2H). LC-MS (ES+) m/z 303.32, 305.30 [M+H].
Reaction SMILES: [CH:1](=[N:8][C:9](=[CH:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCN(CC)CC.C(Cl)(=[O:34])C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH:8][C:1](=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:15][CH2:16][CH2:17][CH3:18])[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC=C(N=Cc1ccccc1)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC=C(NC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Schiff base (6) (97.1 g, 0.4M) is dissolved in THF (250 ml) and shaken in a separatory funnel with 10% aqueous HCl (1 l) for 5 minutes. This mixture is washed with Et2O (3×250 ml), the aqueous phase separated, neutralized with solid NaHCO3 and extracted with CHCl3 (3×250 ml). The combined CHCl3 extracts are dried over anhydrous MgSO4, filtered and evaporated to yield a pale yellow liquid, 57.9 g (93% yield). 'H-N.M.R. (CDCl3 /TMS): δ=1.30 (t, 3H, --CH2CH3); 1.50 (s, 2H, --NH2); 1.47-2.38 (m, 4H, --CH2CH2 --); 3.43 (dd, 1H, >CH--CH2 --, J=6 and 8 Hz); 4.20 (q, 2H, --CH2CH3); 4.80-5.20 (m, 2H, --CH=CH2); 5.45-6.20 ppm (m, 1H, --CH=CH2). The latter is stirred in CH2Cl2 (600 ml) containing Et3N (51 ml, 0.37M) and cooled in an ice bath before benzoyl chloride (43 ml, 0.37M) in CH2Cl2 (100 ml) is added dropwise over a period of 1/2 hour. The reaction mixture is allowed to warm to room temperature and stirred overnight. The formed Et3N HCl is removed by filtration and the filtrate is evaporated to dryness. The residue is taken up in Et2O, filtered, washed with 5% aqueous HCl (3×100 ml), saturated aqueous NaHCO3 (3×100 ml), saturated aqueous NaCl (3×100 ml), dried over anhydrous MgSO4 and evaporated to dryness. The white solid thus obtained is recrystallized twice from Et2O/hexane to yield 64.3 g of the desired product (7) (67% yield) m.p. 68°-70° C. The two recrystallizations are required in order to remove an impurity which turned out to be the bis alkylated material (m.p. 46°-49° C.) that is carried along. 'H-N.M.R. (CDCl3 /TMS): δ=1.3 (t, 3H, --CH2CH3); 1.80-2.34 (m, 4H, --CH2CH2 --); 4.28 (q, 2H, --CH2CH3); 4.64-5.15 (m, 3H, >CH=CH2 and CHCO2Et); 5.53-6.0 (m, 1H, CHCH2); 6.70 (d, 1H, >NH); 7.30-7.85 ppm (m, 5H, Ph).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:22]([N:9]1[C:10]2[C@@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2F)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and benzyl bromide (130 μL, 1.09 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes to give (4S,7R)-1-benzyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 30%) as an light brown solid. ES(+)-MS (M+H) 377.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH2:38][CH2:39][F:40])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24]CC4C=CC(OC)=CC=4)=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:41][N:42]([CH2:44][C:45]1[S:49][CH:48]=[N:47][C:46]=1[CH3:50])[CH3:43]>>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH2:38][CH2:39][F:40])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:42]([CH3:43])([CH3:41])[CH2:44][C:45]4[S:49][CH:48]=[N:47][C:46]=4[CH3:50])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: COc1ccc(COC(=O)C2=C(/C=C/CI)CS[C@@H]3[C@H](NC(=O)/C(=N\OCCF)c4nsc(N)n4)C(=O)N23)cc1
Reactant: Cc1ncsc1CN(C)C
Product: Cc1ncsc1C[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCCF)c3nsc(N)n3)[C@H]2SC1
Yield: 34.5 %

Procedure:
p-methoxybenzyl 7β[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoroethoxyiminoacetamido]-3-[(E)-3-iodo-1-propen-1-yl]3-cephem-4-carboxylate(1.1 g) and 5-dimethylaminomethyl-4-methylthiazol (0.36 g) were reacted in the same manner as discribed in Example 13 to obtain the target product(330 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]#C)[C:3]=1[CH2:12][CH2:13][CH3:14].[F-].[Cs+].[CH2:17](OCC)C>CCN(C1C=CC=CC=1)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:17]=[C:9]([CH3:10])[O:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14]
Reactant: C#CCOc1cccc(F)c1CCC
Reactant: CCOCC
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(F)ccc2cc(C)oc12
Yield: 40 %

Procedure:
A suspension of 1.5 g (7.8 mmol) of 1-fluoro-2-propyl-3-prop-2-ynyloxy-benzene and 1.7 g (11.15 mmol) of caesium fluoride in 14 ml of diethylaniline was heated at reflux in a metal bath for 4 hours. After cooling to room temperature 100 ml of diethyl ether were added thereto and insoluble constituents were filtered off. The diethyl ether phase was washed three times with 60 ml of 1 N hydrochloric acid, dried over sodium sulfate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:2). There was obtained 0.6 g (40%) of 6-fluoro-2-methyl-7-propyl-benzofuran as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[OH:12].Cl[CH2:14][C:15]([OH:17])=[O:16].Cl>O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1c(Cl)cc(Cl)cc1Cl
Yield: 92.3 %

Procedure:
26.4 g (0.66 mol) of sodium hydroxide and 59.1 g (0.299 mol) of 2,4,6-trichlorophenol were respectively added to 450 ml of water for dissolution at normal temperature. Adding 28.11 g (0.299 mol) of monochloroacetic acid hereto, the reaction mixture was heated and refluxed for 9 to 10 hours, while the external temperature was maintained at 110°-120° C. On completion of the reaction, it was lowered to normal temperature to be followed by the filtration of product precipitate. The above reaction product was dissolved in 100 g of water and acidified with concentrated hydrochloric acid to obtain 70.5 g of 2,4,6-trichloropnenoxyacetic acid as a raw product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12](CC)[CH:11](S)[CH:10]([CH2:16][NH2:17])[O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([CH:21]=[O:22])C>CO>[C:1]([O:5][C:6]([N:8]1[CH:12]([O:22][CH3:21])[CH2:11][CH:10]([CH2:16][NH2:17])[O:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC1C(S)C(CN)ON1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Solvent: CO
Product: COC1CC(CN)ON1C(=O)OC(C)(C)C

Procedure:
In the same manner, N-tert-butoxycarbonyl-5-aminomethyl-3-ethylthiyl-4,5-dihydroisoxazole was made by using sodium ethyl thiolate in dry DMF instead of sodium methoxide in methanol.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.OO.C([OH:22])C>O.CO>[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:22])[C:11]([CH3:17])=[N:10]1
Reactant: CCO
Reactant: Cc1nn(C2CCCC2C)c(N)c1C#N
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn(C2CCCC2C)c(N)c1C(N)=O
Temperature: 25 °C
Yield: 84 %

Procedure:
85% Potassium hydroxide (5.8 g, 88.5 mmol) was dissolved in water (50 ml) and the solution was cooled in an ice bath for 1 hour. The 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (2.6 g, 12.7 mmol) in methanol (5.0 ml)/water (25 ml) was then added, followed by 30% hydrogen peroxide (6.5 ml, 63.2 mmol). The reaction mixture was stirred with ice-bath cooling for 4 hours, then was warmed slowly to room temperature. Ethanol was added to the reaction mixture to completely dissolve the starting material and the mixture was stirred at room temperature for 60 hours. The ethanol was removed in vacuo and the oily residue was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous MgSO4 and the solvents were removed in vacuo to afford an amber solid. Recrystallization from acetonitrile and air drying then afforded 2.4 g (84%) of 1-(2-methylcyclopentyl)-3-methyl-5-amino- 1H-pyrazole-4-carboxamide as an off-white solid, m.p. 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: COCCBr
Product: COCCOc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1

Procedure:
The title compound was prepared in analogy to Example 120 from 4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) and 1-bromo-2-methoxy-ethane (0.031 mL). MS (m/e)=423.1 (MH+).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH3:4][C:5]1[C:9]([Zr+3:11])([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14].[CH-:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[Li+]>CCOCC>[Cl-:1].[Cl-:1].[CH3:4][C:5]1[C:9]([Zr+2:11][CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH3:10])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=1[CH3:14]
Reactant: c1ccc2[cH-]ccc2c1
Reactant: CC1=C(C)C(C)([Zr+3])C(C)=C1C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C(C)([Zr+2]C2C=Cc3ccccc32)C(C)=C1C
Reaction time: 16 h

Procedure:
To a yellow suspension of (pentamethylcyclopentadienyl)zirconium trichloride, Cp*ZrCl3, (5.00 g, 15.0 mmol, 1.00 equiv.) in ether (50 mL) was added lithium indenide (1.83 g, 15.0 mmol, 1.00 equiv.). The reaction turned slightly more manila-colored. The mixture was stirred 16 hours and then evaporated in vacuo, leaving yellow solid. The solid was extracted with dichloromethane (30 mL, then 3×5 mL) and the extracts were filtered to give light manila solid and a bright yellow solution. The solution was evaporated in vacuo, leaving yellow crystalline solid. The solid was washed with pentane (20 mL) and dried in vacuo. Yield 5.92 g (96%). 1H NMR(CD2Cl2): δ 2.03 (s, 15H, Me), 6.18 (d, 2H, Ind-H), 6.34 (t, 1H, Ind-H), 7.24 (m, 2H, Ind-H), 7.54 (m, 2H, Ind-H).
Reaction SMILES: CC1(C)CC(C)CC1=O.CC1CC(C)(C)CC1=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CN.ClCC(Cl)=O.CN(C)C.[CH3:37][C:38]1([CH3:50])[CH2:42][CH:41]([CH3:43])[C:40]([N:44]([CH3:49])[C:45](=[O:48])[CH2:46][Cl:47])=[CH:39]1.CC1CC(C)(C)C(N(C)C(=O)CCl)=C1>C1C=CC=CC=1>[CH3:43][C:41]1[CH2:42][C:38]([CH3:37])([CH3:50])[CH2:39][C:40]=1[N:44]([CH3:49])[C:45](=[O:48])[CH2:46][Cl:47]
Reactant: CC1CC(C)(C)C=C1N(C)C(=O)CCl
Agent: CC1C=C(N(C)C(=O)CCl)C(C)(C)C1
Agent: CC1CC(=O)C(C)(C)C1
Agent: CC1CC(C)(C)CC1=O
Solvent: c1ccccc1
Product: CC1=C(N(C)C(=O)CCl)CC(C)(C)C1

Procedure:
By the same procedure as in Example 1 using a mixture comprising 2,2,4-trimethylcyclopentanone and 2,4,4-trimethylcyclopentanone (about 1:1) (25.2 parts by weight) in 150 milliliters of benzene, one part by weight of ammonium sulfate and 6.2 parts by weight of methylamine, further reacted with 22.6 parts by weight of chloroacetyl chloride and 24.6 parts by weight of trimethylamine, a mixture of isomers consisting of N-(3,3,5-trimethylcyclopenten-1-yl)-N-methyl-α-chloroacetamide, N-(3,5,5-trimethylcyclopenten-1-yl)-N-methyl-α-chloroacetamide, and N-(2,4,4-trimethylcyclopenten-1-yl)-N-methyl-α-chloroacetamide was obtained. The yield of partially crystalline dark brown product amounted to 33 parts by weight. The molecular weight was determined to be 198 (215). The content of organically combined chlorine was 17.5% (16.5%). The nitrogen content was 6.3% (6.5%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[S:18]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]1=2.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:23]([C:22]2[S:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH:21]=2)(=[O:24])=[O:25])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4ccccc4s3)C2=O)c1
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride (0.36 g, 1.43 mmol) in 15 mL of CH2Cl2 is added benzo[b]thiophene-2-sulfonyl chloride (0.32 g, 1.38 mmol). To the resulting solution is added triethylamine (0.29 g, 2.88 mmol). After 16 h, the solution is diluted with EtOAc. The solution is washed with 1N HCl, saturated NaHCO3, and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound (0.45 g, 1.09 mmol) is obtained as white solid.