Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:23]2[O:27][C:26]([CH3:29])(C)C(C)(C)[O:24]2)=[C:17]([CH:20]=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:32](C)([O-:34])=[O:33]>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:23]([OH:24])[O:27][CH:26]([CH2:29][N+:32]([O-:34])=[O:33])[C:17]=2[CH:20]=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(c2c(C=O)cccc2OCCCOCc2ccccc2)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:16][N:17]1[CH:21]=[C:20]([CH:22]=O)[N:19]=[CH:18]1>O1CCCC1>[CH3:16][N:17]1[CH:21]=[C:20](/[CH:22]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[N:19]=[CH:18]1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: Cn1cnc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cn(C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
1 ml (5.5 mmol) of methyl diethylphosphonoacetate are added to a suspension of 220 mg (5.5 mmol) of sodium hydride at 60% in 5 ml of tetrahydrofuran cooled to 0° C. After stirring for 1 h, 500 mg (4.5 mmol) of 1-methyl-1H-imidazole-4-carbaldehyde are added and the mixture is stirred for 4 hours at ambient temperature and then hydrolysed with water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated. The product obtained is precipitated from heptane and filtered. 430 mg of methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate are obtained in the form of a yellow powder with a yield of 57%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)c3)cc2)cn1

Procedure:
(2-{(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (3.0 g) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.71 g) are dissolved in DME (93 mL), (Ph3P)3PdCl2 (580 mg) and 2M Na2CO3-solution (55 mL) are added and the resulting mixture is heated under reflux temperature under an inert gas atmosphere. The solution is filtered and evaporated. The residue is treated with water and dichloromethane. The organic phase is separated, dried and evaporated. The crude product is purified by silica gel flash chromatography. The title compound is obtained in 902 mg yield.
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](O)=[O:12])=[N:9][CH:10]=1.[NH3:16]>C(O)C.Cl>[Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:16])=[O:12])=[N:9][CH:10]=1
Reactant: N
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Agent: Cl
Solvent: CCO
Product: NC(=O)c1ccc(CCC(Br)CBr)cn1
Reaction time: 72 h

Procedure:
10 g of 5-(3,4-dibromobutyl)picolinic acid was dissolved in 200 ml of ethanol saturated with dry hydrochloride gas and resulting solution was refluxed for six hours. Reaction mixture was evaporated in reduced pressure and resulting pale yellow oil was dissolved in 300 ml of ethanol saturated with dry ammonia gas. The solution was kept to stand at room temperature for three days, and then evaporated in reduced pressure. Resulting solid was crystallized from benzene to give 6.5 g of the pure product as platelets.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH3:26][S:27][C:28]1[N:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][N:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:26][S:27][C:28]1[N:33]=[CH:32][C:31]([CH:34]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:35])=[CH:30][N:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cncnc21
Reactant: CSc1ncc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncncc23)cn1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
To a solution of 5-Iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (38, 4.00 g, 9.97 mmol) in 5.00 mL of tetrahydrofuran at −20° C. under nitrogen, isopropylmagnesium chloride (5.80 mL, 2.0 M in tetrahydrofuran, 11.6 mmol) was added slowly. The reaction was allowed to warm to 0° C. over 70 minutes, then cooled to −20° C., followed by addition of 2-methylsulfanyl-pyrimidine-5-carbaldehyde (54, 1.12 g, 7.26 mmol) in 15.0 mL of tetrahydrofuran. The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (55, 2.75 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][CH2:20][C:21]#[N:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:20]([CH2:21][NH:22][C:15]([C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])#[N:19]
Reactant: N#CCN
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To 5.05 g (20.75 mmol) of the acid of step 2 dissolved in 40 mL DMF was added 1.92 g (20.75 mmol) aminoacetonitrile hydrochloride, 3.98 g (20.75 mmol) of EDCI, 2.80 g (20.75 mmol) of HOBT and 7.98 mL (72.63 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to obtain 5.83 g of the crude tert-butyl (1S,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexylcarbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([CH:17]1[CH2:18][CH2:19]1)[OH:16]
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Reactant: Br[Mg]C1CC1
Product: Nc1ccc(-c2cccc(Cl)c2)cc1C(O)(C1CC1)C1CC1

Procedure:
(4-Amino-3′-chloro-biphenyl-3-yl)-dicylopropyl-methanol (mp 90-92° C.; MS ((+)ESI) m/z 314 (M+H)+) was prepared from (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone and cyclopropylmagnesium bromide according to Example 41.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:22](I)[CH3:23]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]([CH2:22][CH3:23])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCI
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(=O)Nc2ncnc(Cl)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.5 g; 0.0029 mol; 1.0 equiv) in THF (20 mL) and cool to −78° C. under argon atmosphere. Add drop-wise lithium hexamethyl-disilazide (5.89 mL, 0.0059 mol; 2.0 equiv; 1 M in THF). Stir at −78° C. for 30 min. Add drop-wise ethyl iodide (0.48 mL; 0.0059 mol; 2.0 equiv) and allow the reaction temperature to come to 0° C. slowly. Stir for 4 h. Quench with saturated ammonium chloride aqueous and extract with EA. Evaporate the organic layer to get the title compound (0.24 g; 41.38%).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](=[O:9])[CH:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1)[CH3:2].[CH3:15]CN(C(C)C)C(C)C>C(#N)C.CO>[CH2:1]([N:3]1[C:7](=[O:8])[C:6]([O:9][CH3:15])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C1CN(CC)C(=O)C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)C1=C(OC)C(=O)N(CC)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.2 %

Procedure:
To a solution of ethyl 1-ethyl-4,5-dioxopyrrolidine-3-carboxylate (200 mg, 1.0 mmol) and DIPEA (0.18 mL, 1.0 mmol) in ACN (1.8 mL) and MeOH (0.2 mL) was added TMS-CH2N2 (2.0 M in Et2O; 0.5 mL, 1.0 mmol). The reaction mixture was stirred at rt for 3.5 h, then evaporated in vacuo. The product was purified by silica gel chromatography (40 g silica gel; linear gradient of 0-50% MeOH:EtOAc (10:1) in hexanes over 15 min) to obtain Intermediate 9A (203 mg, 95% yield). HPLC/MS (Method D) RT=0.73 min, [M+H]+ 214.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS([O-])(=O)=O.[Na+].[CH3:25][CH2:26]OCC>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:25][CH3:26])([OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Reactant: CCOCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: CCC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a flame-dried b 25-mL rb flask containing ethylmagnesium bromide (4.0 mL of a 3.0M solution in Et2O, 12.0 mmol, 3.0 equiv), at -10° C. was added dropwise a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolone (1.0 g, 4.0 mmol) in Et2O (4 mL). The reaction mixture was stirred at -10° C. for 15 min, then allowed to warm to rt over 10 min. A 1.0M solution of NaHSO4 (10 mL) was then rapidly added. The resulting biphasic mixture was extracted with EtOAc (3×10 mL), and the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, 4:1), affording 800 mg (71%) of the desired product as a clear yellow oil (Rf 0.14, hexanes/EtOAc, 4:1). Data for 1-tert-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-4-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H, J=8.4, 8-H), 7.47 (dd, 1H, J=7.9, 1.7, 5-H), 7.21 (ddd, 1H, J=7.4, 7.4, 1.6, 6-H), 7.09 (ddd, 1H, J=7.8, 7.8, 1.1, 7-H), 4.03 (ddd, 1H, J=12.9, 7.1, 4.7, 2-H), 3.47 (ddd, 1H, J=13.1, 8.6, 4.3; 2-H), 2.11 (ddd, 1H, J=13.5, 8.6, 4.8, 3-H), 1.86 (m, 3H, 3-H, CH2CH3), 1.52 [s, 9H, C(CH3)3 ], 0.89 (t, 3H, J=7.5, CH3).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=CC=C([F:39])C=2N=1>>[F:39][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Fc1cccc2sc(Cl)nc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)cccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-4-fluoro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.22 (m, 2H), 2.23-2.31 (m, 2H), 3.06-3.18 (m, 2H), 3.42 (d, J=12.1 Hz, 2H), 4.48-4.57 (m, 1H), 7.42-7.49 (m, 1H), 7.50-7.57 (m, 1H), 8.00-8.07 (m, 2H), 8.30 (br. s., 1H), 8.37 (br. s., 1H), 8.54 (s, 1H). MS (ES+): m/z=395.12 [MH+]. HPLC: tR=2.05 min (ZQ2, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
A mixture of 4-bromo-2,6-dichlorophenol (10 g, 41.67 mmol), K2CO3 (11.5 g, 83.3 mmol) and CH3I (8.88 g, 62.5 mmol) in DMF (100 mL) was stirred at rt for 16 h. TLC (EtOAc/petroleum ether=1:2) indicated complete consumption of 4-bromo-2,6-dichlorophenol. The reaction mixture was poured into water (300 mL). The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo to give crude 5-bromo-1,3-dichloro-2-methoxybenzene, which was purified by column chromatography (silica gel, EtOAc/petroleum ether=1:5) to yield the ether product (9 g, yield 84.9%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.45 (s, H), 3.91 (s, 3H) ppm.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:59])([CH3:48])([CH3:46])[CH3:47]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.372 g, 1.1 mmol), HOBt (0.145 g, 1.1 mmol), EDCI (0.246 g, 1.32 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.275 g, 1.2 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclopentyl)-carbamic acid tert-butyl ester (592 mg, 99%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([F:28])[N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1)([OH:3])=[O:2].[CH2:29](I)[CH3:30].O>C1COCC1>[CH2:29]([O:2][C:1]([C:4]1[N:5]=[C:6]([F:28])[N:7]([C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=1)=[O:3])[CH3:30]
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-carboxy-2-fluoro-1-triphenylmethylimidazole (280 mg.) in THF (0.75 ml.) was treated, under argon with 1,5-diazabicyclo-5,4,0-undec-5-ene (0.112 ml.) followed by ethyl iodide (0.069 ml.). The mixture was stirred for two hours at room temperature, water was added and the mixture extracted, with ether. The ether extract was dried (MgSO4) and evaporated to give 4-ethoxycarbonyl-2-fluoro-1-triphenylmethylimidazole (185 mg.) as a yellow foam having the following n.m.r. in CDCl3 : 1.38 (t, 3H); 4.36 (q, 2H); 7.0-7.5 (m, 16H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[C:5]([F:20])=[CH:4][CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH:21]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[C:5]([F:20])=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)ccc(F)c2C1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)ccc(F)c2C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
A mixture of tert-butyl 9-bromo-6-fluoro-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.16 mmol), cyclopropylboronic acid (298 mg, 3.47 mmol), saturated aqueous sodium carbonate solution (6 ml), and tetrakis(triphenylphosphine)palladium(0) (36.1 mg, 0.0313 mmol) in dimethoxyethane (10 ml) was stirred under a nitrogen atmosphere at 90° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (270 mg, 75.7%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[O-:14][C:15]#[N:16].[Na+]>CO.C(O)(=O)C>[NH:1]([C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)[C:15]([NH2:16])=[O:14]
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: 0 °C
Yield: 169.6 %

Procedure:
To a solution of 5-aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) in methanol (10 ml.) and acetic acid (5 ml.) was added dropwise 2 ml. of aqueous solution of sodium cyanate (130 mg.), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added ice-water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give colorless needles of 5-ureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.74 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6]2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=CC(C)=O)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Yield: 69.7 %

Procedure:
4-(6-Methoxy-2-naphthyl)-3-butene-2-one (32 g) in ethyl acetate (500 ml) was shaken at room temperature over 10% Pd/C (3 g) under atmospheric pressure hydrogen until no further uptake of hydrogen occurred to yield 4-(6-methoxy-2-naphthyl)butan-2-one (22.5 g), mp. 78.5° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[N:13]/[CH2:12][C:11]([O:10][CH3:9])=[O:14])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C/N=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.6 mL, 33 mmol) and glycine methyl ester hydrochloride (3.8 g, 30.26 mmol) were successively added to a solution of p-anisaldehyde (2.0 g, 14.7 mmol) in dichloromethane (150 mL) at 0° C. Sodium sulfate (10 g) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then filtered and concentrated to dryness. The resulting residue was portioned in ethyl acetate and filtered in order to remove the triethylamine salts. The title compound was obtained as a pale yellow solid (4.43 g, 100%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>ClCCl>[C:22]1([CH3:23])[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CCCCc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 1.1 g of 4-(4-butylphenyl)butanol, 1.05 g of tosyl chloride, 0.48 ml of pyridine and a catalytic amount of dimethylaminopyridine in dichloromethane was allowed to stand at room temperature overnight. The reaction mixture was poured into 50 ml of ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6) to give 1.2814 g of 4-(4-butylphenyl)butyl p-toluenesulfonate as a colorless, oily substance.