Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:24])([F:23])[C:10]([N:12]1[CH2:17][C:16]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:15][CH2:14][CH2:13]1)=[O:11].[Si:25]([O:32][CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:40]=O)[S:38][CH:39]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Si](OCCC1C=CSC=1C=O)(C(C)(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O.CC(O)=O>[Si:25]([O:32][CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([CH2:40][N:20]2[CH2:21][CH2:22][C:16]3([O:15][CH2:14][CH2:13][N:12]([C:10](=[O:11])[C:9]([F:8])([F:23])[F:24])[CH2:17]3)[CH2:18][CH2:19]2)[S:38][CH:39]=1)([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)[Si](C)(C)OCCc1ccsc1C=O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCc1csc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1
Reaction time: 0.08 h

Procedure:
2,2,2-Trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (1.084 g) was added to a stirred solution of a 4:1 mixture of 4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde and 3-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (example 27, step b) (1.0 g), and AcOH (0.16 mL) in N-methyl-2-pyrrolidinone (15 mL). After 5 min, sodium triacetoxyborohydride (1.57 g) was added. After 16 h water was added and the mixture extracted with ethyl acetate. The ethyl acetate layer was washed three times with water and evaporated in vacuo. Purification by silica gel chromatography eluting with ethyl acetate:isohexane:triethylamine, 1:20:1 separated the two isomeric products and gave the subtitled compound as an oil. Yield 1.04 g.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11]O)[CH:3]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:20]>>[Cl:20][CH2:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: OCc1cc(F)c2c(c1)OCO2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cc(CCl)cc2c1OCO2
Temperature: 25 °C
Yield: 92 %

Procedure:
To SOCl2 (20 mL) was added (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 4.7 mmol) in portions at 0° C. The mixture was warmed to room temperature over 1 h and then was heated at reflux for 1 h. The excess SOCl2was evaporated under reduced pressure to give the crude product, which was basified with saturated aqueous NaHCO3 to pH˜7. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[C:8]2=[O:25])[S:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]2=[O:25])[S:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCN(CCOS(=O)(=O)c3ccc(C)cc3)C2=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(2-(tosyloxy)ethyl)imidazolidin-1-yl)thiophene-2-carboxylate (0.16 g, 0.35 mmol), phenol (0.03 g, 0.36 mmol) and potassium carbonate (0.05 g, 0.35 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 16 h, cooled to ambient temperature, and partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-40% ethyl acetate in hexanes to afford the title compound as a colorless solid 72% yield (0.10 g): 1H NMR (300 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.00-6.94 (m, 1H), 6.89 (d, J=7.6 Hz, 2H), 6.14 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.17 (t, J=4.9 Hz, 2H), 3.81 (br s, 4H), 3.72 (t, J=4.9 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H): MS (ES+) m/z 375.2 (M+1).
Reaction SMILES: [S:1]=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[Br:10]Br>C(OCC)(=O)C>[Br:10][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:1][N:9]=1
Reactant: BrBr
Reactant: N#Cc1ccc[nH]c1=S
Solvent: CCOC(C)=O
Product: Brc1nsc2ncccc12
Temperature: 25 °C

Procedure:
To a solution of 2-thioxo-1,2-dihydropyridine-3-carbonitrile (2.1 g, 15.44 mmol) in ethyl acetate (50 mL), bromine (5.9 g, 37.11 mmol) was added drop wise at 0° C. The reaction mixture was allowed to warm to room temperature and then refluxed for 3 h. The reaction mixture was concentrated under reduced pressure. Trituration with hexanes:methylene chloride (1:1) mixture gave 3-bromoisothiazolo[5,4-b]pyridine, as light brown solid which was carried forward without further purification. MW=215 confirmed by LC-MS, tr=16.08 min (Method Y) MH+=216.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:13]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([CH2:11][OH:12])[CH2:5]2)#[N:14]
Reactant: OC[C@H]1Cc2ccc(Br)cc2C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)C[C@@H](CO)C2
Temperature: 175 °C
Yield: 78 %

Procedure:
The (S)-5-bromoindan-2-yl-methanol (600 mg, 2.64 mmol) was mixed with zinc cyanide (480 mg, 4.09 mmol) in DMF (15 mL). To this solution was added palladium tetrakistriphenylphosphine (180 mg, 0.15 mmol). The mixture was heated in a microwave at 175° C. for 20 minutes. Solvents were evaporated and the residue was extracted with ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with brine and dried over Na2SO4. Solvents were evaporated and the residue was purified through a Biotage flash column chromatography using hexanes and ethyl acetate (2:1 to 1:1 ratio) to give (S)-5-cyanoindan-2-yl-methanol as a colorless oil (357 mg, 78%). Chiral HPLC analysis indicated no racemization.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[OH:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cccc(O)c2)CC1
Yield: 43 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(C1C=CC=CC=1)(=O)C.COC1C=C2C(CC[C@H](N)C2)=CC=1>Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1=O
Agent: COc1ccc2c(c1)C[C@@H](N)CC2
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)c1ccccc1
Product: N[C@H]1CCN(Cc2ccccc2)C1

Procedure:
The recombinant E. coli obtained in Example 14 was examined for resistance to (S)—N-benzyl-3-aminopyrrolidinone. A cell-free extract of each multiply-mutated strain was obtained using the same process as in Example 13. Subsequently, 900 μL of a 0.1 M potassium phosphate buffer (pH 6.3) containing 0.83% of (S)—N-benzyl-3-aminopyrrolidinone was added to 100 μL of the cell-free extract and incubated at 35° C. The mixture was sampled in an amount of 100 μL at reaction times 0 and 2.5 hours, respectively, and each sample was diluted 200 times with an aqueous 0.1 M potassium phosphate solution (pH 7.5). Subsequently, 200 μL of each dilution was added to 800 μL of a substrate solution having the composition shown below. After the mixture was allowed to react at 30° C. for 1 hour, 50 μL of 6 N hydrochloric acid was added to stop the reaction. The concentration of the produced acetophenone was measured using HPLC under the same conditions as in Example 4. Table 15 shows the remaining activity at reaction time 2.5 hours, which was determined relative to the activity at reaction time 0 normalized as 100%. As a result, the mutated enzymes shown in Table 15 had (S)-7-methoxy-2-aminotetralin resistance higher than that of the wild-type enzyme.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:36])[CH:30]=2)[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:36])[CH:30]=3)[CH:26]=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cn1cc(-c2cccc(Br)n2)ccc1=O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cn1cc(-c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)ccc1=O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (38 mg, 0.12 mmol) and 6-bromo-1′-methyl-2,3′-bipyridin-6′(1′H)-one (33 mg, 0.12 mmol) as starting materials.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[NH2:2].[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>C(#N)C.CO.C(Cl)Cl>[C:1]([CH2:4][C:5]1[C:13]2[C:8]([N:9]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[CH:10]=[CH:11][CH:12]=2)=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[NH2:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=O)Cc1c(-c2ccccc2)[nH]c2ncccc12
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)Cc1c2cccn(CC(=O)c3ccccc3)c-2nc1-c1ccccc1

Procedure:
3-(Carbamoylmethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.35 g, 1.4 mmol) and phenacyl bromide (0.33 g) in acetonitrile (5 ml) were refluxed under argon for 3 h. The resulting yellow suspension was isolated by filtration (0.4 g). The sparingly soluble raw product was dissolved in a mixture of methanol (20 ml) and methylene chloride (480 ml), loaded on a flash chromatography column (SiO2 /CH2Cl2 :MeOH 96:4), and eluted with a) 1000 ml MeOH:CH2Cl2 2.5:97.5; b) 1000 ml MeOH:CH2Cl2 5:95; c) 1000 ml MeOH:CH2Cl2 1:9 to afford pure 3-(carbamoylmethyl)-7-phenacyl-2-phenylpyrrolo[2,3-b]pyridine which was isolated as its hydrobromide (0.14 g, 22%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 21 %

Procedure:
Using cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol (0.14 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.15 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.05 g, 31%) was obtained as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:9]=1[C:10](=[O:13])[CH2:11]Br.[CH3:19][C:20]1[C:21]([CH3:29])=[N:22][C:23]([SH:28])=[C:24]([CH:27]=1)[C:25]#[N:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:27]=[C:24]2[C:25]([NH2:26])=[C:11]([C:10](=[O:13])[C:9]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:8]=3[F:7])[S:28][C:23]2=[N:22][C:21]=1[CH3:29]
Reactant: Cc1cc(C#N)c(S)nc1C
Reactant: O=C(CBr)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(N)c(C(=O)c3cc(F)ccc3F)sc2nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.399 g, 2.89 mmol), 2,5-difluorophenacyl bromide (0.408 g, 1.73 mmol) and 5,6-dimethyl-2-mercaptonicotine nitrile (0.19 g, 1.16 mmol) in dry DMF (4 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound with a m.p. of 188° C.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C)=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:7]([C:4]2[CH:3]=[C:2]([Br:1])[S:6][CH:5]=2)=[O:9])=[CH:13][CH:12]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: O=C(O)c1csc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCc1ccc(F)cc1)c1csc(Br)c1
Reaction time: 1.5 h

Procedure:
To a solution of 5-bromo-thiophene-3-carboxylic acid (5 g) and [2-(4-fluorophenyl)-ethyl]methyl-amine (the compound of Preparation Example 14) (3.7 g) in dichloromethane (150 mL) was added 1-Ethyl-3-(3-dimethylamino propyl)-carbodiimide.hydrochloride (5.1 g) was added. After stirring for 1.5 hours, the residue resulting from evaporation of the reaction solution in vacuo was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (6 g) was obtained as a colorless oily matter.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[C:13][Si](C)(C)C)=[C:6]([CH2:8][C:9]([NH2:11])=[O:10])[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[C:12]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[CH2:8][C:9]([NH2:11])=[O:10])#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccc(F)cc1CC(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccc(F)cc1CC(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetamide (A34) (0.239 g, 0.958 mmol) in DCM (10 mL) at 0° C. was added TBAF (1.0 M in THF; 1.44 mL, 1.44 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, then poured into water (50 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and the volatiles removed in vacuo. The residue was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A35 as a white solid (0.114 g, 67%); 1H NMR (400 MHz, d6-DMSO) δ 7.50 (dd, J=8.6, 5.9 Hz, 1H), 7.44 (s, 1H), 7.17 (dd, J=10.0, 2.7 Hz, 1H), 7.10 (td, J=8.6, 2.8 Hz, 1H), 6.99 (s, 1H), 4.32 (s, 1H), 3.61 (s, 2H). LCMS-A: rt 4.843 min; m/z 178 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[Cl-].[NH4+].Br[CH2:20][CH:21]=[CH2:22]>C1COCC1.[Zn]>[CH2:22]([C:2]1([OH:1])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)[CH:21]=[CH2:20]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC1(O)CC[C@@H](C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of (R)-benzyl 3-oxocyclopentanecarboxylate (1 g, 4.58 mmol) in THF (10 mL) was added zinc powder (2.098 mL, 229 mmol), saturated aqueous ammonium chloride solution (20 mL) followed by 3-bromoprop-1-ene (1.663 g, 13.75 mmol) slowly at room temperature. The resulting mixture was heated to 80° C. for 3 hours, then allowed to stir at room temperature for additional 12 hours. The reaction mixture was filtered and the filtrate concentrated. To the residue was added ethyl acetate (20 mL) and the resulting mixture was washed with water (5 ml), brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield (1R)-benzyl 3-allyl-3-hydroxycyclopentanecarboxylate (580 mg, 2.228 mmol, 48.6% yield) as an oil. It was used as such for the next step without further purification. MS (ESI+) m/z 283 (M+Na)+
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=O>C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCc2ccoc2)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: c1ccc(CN2CCc3ccoc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 5.603 g (27.838 mmol) of N-benzyl-2-(3-furyl)ethylamine in 50 ml of acetic acid, 2.71 g (33.4 mmol) of 37% aqueous formaldehyde was added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])[CH2:29][CH2:28]1)=[O:26].Cl.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH:20]([O:22][C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:21]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])[CH2:28][CH2:29]1)=[O:26]
Reactant: CN(C)CC(=O)O
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CC(O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)OC1CN(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 8 h
Yield: 46.9 %

Procedure:
N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (38.9 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under a nitrogen atmosphere, and N,N-dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added at room temperature, followed by stirring overnight. N,N-Dimethylglycine hydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added again at room temperature, and the reaction mixture was stirred for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added tert-butyl methyl ether (1 ml)—heptane (2 ml) to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (21.1 mg, 47%).
Reaction SMILES: O.[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([OH:13])[CH2:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:7]([O:8][C:2]1([O:13][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC1(OCCCC)CCCCC1
Temperature: 125 °C
Yield: 187.7 %

Procedure:
In a 300-ml three-necked flask equipped with a water separator, 98 g (1 mole) of cyclohexanone, 148 g (2 moles) of n-butanol, 2.4 mg of stannous chloride dihydrate and 40 g of toluene were charged. The resulting mixture was heated at 125° C. under atmospheric pressure for 6 hours in a nitrogen atmosphere while removing the water formed from the reaction mixture by azeotropic distillation. When water was no longer distilled, the solvent (toluene) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 214.3 g of cyclohexanone dibutyl acetal [R1, R2 =a pentamethylene group and R3 =a n-butyl group] (boiling point: 102° C./3 mmHg) (yield: 94.0%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[N:27]3)[N:17]=1.ClCCl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:19]2[N:18]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:17]=[C:16]([CH3:15])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 5.7 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.59 g, 2.5 mmol) and crude 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.47 g, 2.1 mmol) in pyridine (0.6 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 1-10% methanol containing 10% ammonium hydroxide in dichloromethane) to give the title compound as a white solid (0.18 g, 0.12 mmol, 6%). 1H NMR (400 MHz, CDCl3) δ 8.87 (dd, J=1.2, 4.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.58-7.53 (m, 4H), 7.42 (s, 1H), 7.40 (s, 1H), 7.29-7.23 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.28 (s, 1H), 2.34 (s, 3H), 1.36 (s, 9H); MS: (ES) m/z calculated for C23H25N4O2S [M+H]+ 421.2. found 421.3.
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].[O:14]1[CH2:16][C@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:17][C@@H:15]2[CH2:16][O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CO2)CC1
Yield: 68 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from piperazine-1-carboxylic acid tert-butyl ester and (S)-(+)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as a yellow oil in a 68% yield.