Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccn3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccccn3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (30 mg, 0.07 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (14 mg, 0.33 mmol) in water (1 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (20 mg, 69%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38 (br s, 1H), 8.84 (d, J=3.9 Hz, 1H) 8.12-8.20 (m, 1H) 7.85-8.02 (m, 3H) 7.76 (dd, J=7.6, 4.6 Hz, 1H) 7.69 (s, 1H) 7.39 (t, J=8.6 Hz, 1H) 7.33 (s, 1H) 3.91 (d, J=11.7 Hz, 2H) 3.72 (s, 2H) 2.99 (t, J=11.7 Hz, 3H) 1.89 (d, J=12.7 Hz, 2H) 1.63-1.78 (m, 2H); MS cald. for C22H22FN2O4S [(M+H)+]: 429, obsd. 429.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6](F)[C:5]([F:11])=[CH:4][CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14]>>[Br:1][C:2]1[C:7]2[CH:8]=[C:13]([C:12]([O:16][CH3:17])=[O:15])[S:14][C:6]=2[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: O=Cc1c(Br)ccc(F)c1F
Reactant: COC(=O)CS
Product: COC(=O)c1cc2c(Br)ccc(F)c2s1

Procedure:
In a similar manner to Example 9 Method A, 1-(7-fluorobenzo[b]thiophen-4-yl)propan-1-one was prepared starting from 4-bromo-1,2-difluorobenzene (39.7 g). This was lithiated and reacted with dimethylformamide to give 6-bromo-2,3-difluorobenzaldehyde (41.3 g) as a yellow solid. The aldehyde was reacted with methyl thioglycolate (14.6 ml) to give methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (31.2 g) as a yellow solid. The ester was hydrolysed to give 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid (37.25 g) as a yellow solid which was decarboxylated using copper and quinoline at 170-180° C. for 4 hours to give 4-bromo-7-fluorobenzo[b]thiophene (18.2 g) as a white solid, m.p. 47-48° C. This compound (7.4 g) was reacted with magnesium (0.85 g) and then with N-methoxy-N-methylpropionamide (5.6 g) to give 1-(7-fluorobenzo[b]thiophen-4-yl)propan-1-one (2.1 g) as an oil which was used without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:23].[O:24]([NH2:26])[CH3:25]>C(O)C>[ClH:23].[CH3:25][O:24]/[N:26]=[CH:15]/[C:11]1[CH:12]=[N:13][CH:14]=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=1
Reactant: CON
Reactant: O=Cc1cncc(C#Cc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CO/N=C/c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Dissolve 5-phenylethynylpyridine-3-carbaldehyde (0.20 g, 0.97 mmol), (prepared essentially as described in EXAMPLE 5), in ethanol (2.0 mL) and sequentially add potassium carbonate (0.67 g, 4.8 mmol) and methoxylamine hydrochloride (0.64 g, 5.6 mmol). Heat at reflux overnight, cool to room temperature and filter. Concentrate and purify by silica gel chromatography, eluting with a linear gradient of 90:10 to 50:50 hexanes:ethyl acetate to obtain the free base of the title compound as a colorless oil as well as a minor amount of EXAMPLE 86.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH2:17])=[C:15]3[C:10]([CH:11]=[C:12]([F:19])[C:13]([F:18])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([NH:17][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:15]3[C:10]([CH:11]=[C:12]([F:19])[C:13]([F:18])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: Nc1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(NC3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 1.1, a mixture of 2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-ylamine and cyclohexanone ([108-94-1]) was reacted with sodium triacetoxyborohydride in the presence of acetic acid in CH2Cl2 under reflux conditions for 96 h to give the title compound as light brown solid. MS: m/e=362.5 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN.[CH2:20]([N:22](CC)CC)C>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH3:20])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
N,N-Dimethylformamide (10 uL) was added to a mixture of 4-bromo-2-methylbenzoic acid (1.0 g, 0.0046 mol) in oxalyl chloride (2.0 mL, 0.023 mol). The mixture was stirred at r.t. overnight. The volatiles were removed under reduced pressure. The residue was dissolved in methylene chloride (2 mL). To the solution was added to a mixture of methylamine (0.41 mL, 0.0093 mol) and triethylamine (1.3 mL, 0.0093 mol) in DCM (10 ml). After 30 min, the reaction mixture was quenched with aqueous sodium carbonate (10 mL) and extracted with DCM (3×20 mL). The organic layers were washed with brine, dried over Na2SO4, filtered. The solvents were removed under reduced pressure to give a crude product (980 mg, 92.4%). LCMS (M+H)+: m/z=228.1/230.2.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13](O)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:3][N:2]([CH2:4][CH:5]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)[CH3:1]
Reactant: CN(C)CC1CC(O)(c2ccc(Cl)cc2)c2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CN(C)CC1C=C(c2ccc(Cl)cc2)c2ccccc2O1
Yield: 84.8 %

Procedure:
A solution of 2-(N,N-dimethylaminomethyl)-4-hydroxy-4 (4'-chlorophenyl)-chroman (1.35 g) and tosic acid (10 mg) in benzene (75 ml) was heated under reflux with azeotropic removal of water for 31/2 hours. The solvent was removed under reduced pressure, the residue taken up in diethyl ether and washed with 2 N sodium hydroxide (20 ml). The organic phase was dried (MgSO4) and evaporated to give the title compound (1.08 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1CC#N)[CH:3]([F:5])[F:4].Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:19][C:18]([OH:21])=[O:20])[CH:3]([F:4])[F:5]
Reactant: N#CCc1ccccc1OC(F)(F)C(F)F
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccccc1OC(F)(F)C(F)F

Procedure:
2-(1,1,2,2-Tetrafluoroethoxy)phenylacetonitrile (0.49 g, 2.4 mmol) from Step 2 above was refluxed for 3 h in a 1:1 mixture of acetic acid and concentrated aqueous HCl. The solvents were removed under reduced pressure. The residue was partitioned between EtOAc (75 mL) and water (2×25 mL). The organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure to give 2-(1,1,2,2-tetrafluoroethoxy)phenylacetic acid as an amorphous solid (HPLC retention time=7.7 min (method A)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC(O)=O>CCO.[Pd]>[CH3:1][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]1
Reactant: COC(=O)c1cncc(C)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CNCC(C)C1
Reaction time: 48 h

Procedure:
To a reaction vessel containing methyl 5-methylnicotinate (Alfa Aesar, 1 g, 6.62 mmol) in EtOH (12.03 mL) was added AcOH (1.203 mL). The reaction vessel was purged with nitrogen gas (3×) and 10 weight percent palladium on carbon (0.5 g, 4.70 mmol) was added. The reaction vessel was then purged with hydrogen (balloon, 1 atm) (3×) and maintained under hydrogen while stirring. After 48 hours, the reaction was filtered over Celite® brand filter aid and concentrated under reduced pressure to give methyl 5-methylpiperidine-3-carboxylate. ESI-MS M+H 158.0.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(O)(=[O:15])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:15]
Reactant: CC(=O)O
Reactant: COc1cccc(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: COc1cccc(O)c1F
Reaction time: 65 h
Yield: 81 %

Procedure:
To a solution of 2-fluoro-3-methoxy-phenylboronic acid (10.0 g, 0.059 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2-fluoro-3-methoxy-phenol (6.77 g, 81%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
2.0 g of 4-chloro-3-nitrophenol was dissolved in 15 ml of N,N-dimethylformamide. Thereto was added 490 mg of sodium hydride (purity: 60%) in 10 minutes at 5°-10° C. Then, 1.53 g of benzyl chloride was added dropwise in 10 minutes. Stirring was conducted for 1 hour at 70° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was washed with n-hexane and then mixed with a mixture of diisopropyl ether and n-hexane. The resulting crystal was collected by filtration to obtain 1.8 g (yield: 59.4%) of 4-benzyloxy-2-nitro-chlorobenzene having a melting point of 50°-50.5° C.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH:10]([N:12]=[N+:13]=[N-:14])[CH3:11])C.[OH-].[Na+]>C(O)C>[N:12]([CH:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]([OH:15])=[O:3])[CH3:11])=[N+:13]=[N-:14]
Reactant: CCOC(=O)COCCOC(C)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(N=[N+]=[N-])OCCOCC(=O)O
Reaction time: 4 h

Procedure:
[2-(1-Azido-ethoxy)-ethoxy]-acetic acid ethyl ester (0.10 g, 0.46 mmol) was stirred with 4 M aqueous sodium hydroxide (1.15 ml, 4.6 mmol) and ethanol (1.15 ml) at room temperature. After 4 hrs, all the solvents were removed under reduced pressure and the residue was dissolved in 5 ml water. The solution was adjusted to pH 5 with 1 N KH2PO4 and then extracted with DCM (2×15 ml). The aqueous layer was then acidified with 1 N HCl to pH 2 and then extracted with DCM (3×25 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The title compound was obtained as a colourless solid (42 mg, 48.3%).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]([O:20][CH3:21])[O:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[NH:22]C(=O)OCC1C=CC=CC=1)=[C:14]([O:16][CH:17]([F:19])[F:18])[CH:13]=[CH:12][CH:11]=3>[Pd].CO.C1COCC1>[F:19][CH:17]([F:18])[O:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:6]1[CH:5]=[CH:4][C:3]([NH2:22])=[CH:2][C:7]=1[CH:8]([O:20][CH3:21])[O:9]2
Reactant: COC1Oc2cccc(OC(F)F)c2-c2ccc(NC(=O)OCc3ccccc3)c(Br)c21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC1Oc2cccc(OC(F)F)c2-c2ccc(N)cc21

Procedure:
A mixture of Example 96A (82 mg, 0.16mmol) and 10% palladium on carbon (8 mg) in methanol (10 ml) and THF (10 ml) was stirred under hydrogen gas for 1.5 hour, filtered through diatomaceous earth (Celite®), and concentrated to provide the desired product. MS (ESI(+)Q1MS) m/z 294 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1ccccc1
Yield: 95.2 %

Procedure:
The title compound (7.07 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (5.0 g) and 2-bromoacetophenone (4.18 g) according to the method of description 36.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]([C:8]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:9]=1[CH2:10]O)([CH3:7])[CH3:6].CCO>CCOCC>[CH:5]([C:8]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:9]=1[CH2:10][Br:2])([CH3:7])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CC(C)c1cc(C(C)C)c(CO)c(C(C)C)c1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Reaction time: 1 h

Procedure:
A solution of PBr3 (2.7 9, 10 mmol) in ether (10 mL) was added slowly to a solution of 2,4,6-triisopropylbenzyl alcohol (4.68 9, 20 mmol) in 20 mL of ether at room temperature. The mixture was stirred for 1 hour, 5 mL of absolute EtOH was added, and stirring was continued for another 0.5 hour. The solvent was removed and the residue distributed between EtOAc and saturated Na2CO3. The EtOAc layer was separated, washed with brine, and dried over MgSO4. The solvent was evaporated and the pure product was isolated by column chromatography (100% CH2Cl2, 3.5 g, 59%); NMR (CDCl3):δ 1.2-1.4 (m, 18H), 2.8-3.0 (m, 1H), 3.2-3.45 (m, 2H), 4.7 (s, 2H), 7.04 (s, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([OH:16])=O)=[N:3]1.[CH3:17][N:18]1C(C(O)=O)=C2C(C=C([N+]([O-])=O)C=C2)=N1>>[CH3:17][NH:18][C:14]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:16]
Reactant: Cn1nc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1C(=O)O
Product: CNC(=O)c1nn(C)c2cc([N+](=O)[O-])ccc12

Procedure:
is obtained by reacting a mixture of 1-methyl-6-nitro-1H-indazole-3-carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid. The product is purified by chromatography on silica gel.
Reaction SMILES: [CH:1]([CH:4]([CH:14]1[CH2:17][C:16](=[O:18])[C:15]1(Cl)Cl)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].C(OCC)C>C(O)(=O)C.[Zn]>[CH:1]([CH:4]([CH:14]1[CH2:15][C:16](=[O:18])[CH2:17]1)[C:5]([CH:11]([CH3:12])[CH3:13])([CH:8]([CH3:9])[CH3:10])[O:6][SiH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)C(C1CC(=O)C1(Cl)Cl)C(O[SiH3])(C(C)C)C(C)C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)C(C1CC(=O)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 60 °C

Procedure:
Zinc dust (25.5 g, 0.39 mol) was added to a solution of 3-(triisopropyl -siloxyethyl)-2,2-dichlorocyclobutanone (22.21 g, 65.4 mmol) in glacial acetic acid (110 mL) at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in dichloromethane, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=12:1) to give a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 1.03-1.08 (m, 21H), 1.80-1.85 (m, 2H), 2.49-2.60 (m, 1H), 2.71-2.80 (m, 2H), 3.12-3.21 (m, 2H), 3.74-3.77 (t, J=6.0, 2H). 13C NMR (CDCl3, 100 MHz): δ 12.12, 18.22, 21.38, 39.36, 52.92, 62.37, 209.00. MS (FAB): expected for C15H30O2Si (M+H)+ 271.48. Found 271.20887. IR (neat) νmax 3053, 2925, 2866, 1778, 1462, 1265, 1103, 1013, 883, 740, 705.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([NH:11]C(OC(C)(C)C)=O)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:19].O1CCOCC1>CCOC(C)=O>[ClH:19].[NH2:11][C@@H:9]([CH3:10])[CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](N)COC(=O)C(C)(C)C
Reaction time: 2.5 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)-amino]-propyl pivaloate (1.0 eq.) in EtOAc (0.6 M) was added 4N HCl in dioxane (10 eq.). The reaction mixture was stirred for 2.5 h and then the solvent was evaporated in vacuo to give a solid that was washed with Et2O and dried.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9]C)=O)=[O:4].[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:14][CH2:13][CH2:15][N:16]1[CH2:2][C:3](=[O:4])[NH:5][C:6]([CH3:12])([CH3:11])[C:7]1=[O:9]
Reactant: NCCO
Reactant: COC(=O)C(C)(C)NC(=O)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)NC(=O)CN(CCO)C1=O
Temperature: 155 °C
Yield: 42.3 %

Procedure:
A solution of methyl 2-(2-chloroacetamido)-2-methylpropanoate (2.5 g, 13 mmol), ethanolamine (1.3 g, 21.3 mmol), and N,N-diisopropylethylamine (4.0 mL, 23 mmol) in 250 mL of anhydrous tetrahydrofuran was heated at reflux temperature for 24 hours. The mixture was concentrated to a residue in vacuo and dissolved in ethanol (approximately 300 mL). The mixture was heated in a sealed tube at 155° C. for 24 hours then concentrated to a crude residue and purified by column chromatography (5 to 12% methanol in dichloromethane) to give the title compound as a white solid (1.03 g, 5.5 mmol, 42%). 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 6H), 3.32-3.35 (t, J=5.7, 2H), 3.48-3.53 (q, J=5.7, 2H) 4.02 (s, 2H), 4.75-4.77 (t, J=5.4 Hz, 1H). LRMS (ESI/APCI) m/z 187 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 57 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 57% of theory, C35H43N7O5 (641.8); Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=642; (M+H+Na)++=332.8; (M+Na)+=664.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:35])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:35])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[CH2:12]1
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a suspension of 60% sodium hydride (800 mg, 20 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (2.4 g, 20 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A52. A solution of 4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1 g, 2.86 mmol) and 1,1′-carbonyldiimidazole (930 mg, 5.71 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B52. Solution B52 was added to Solution A52 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (107 mg, 8%) as a brown solid: MS (ESI) M+1=454.2.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH2:9][N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:27]1([Mg]Br)[CH2:29][CH2:28]1>[Cu](I)I.C1COCC1>[CH:27]1([C:10]2[CH2:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)=C[C@H]1c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C2CC2)=C[C@H]1c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Tert-butyl (2S)-2-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydro-1H-pyrrole-1-carboxylate (5-4, 100 mg, 0.254 mmol, 1 equiv) was added to a solution of dry THF (5 ml) containing copper iodide (5 mg, 0.025 mmol, 0.2 equiv) at −10° C. Cyclopropyl magnesium bromide (0.508 mL, 0.508 mmol, 2 equiv) was added drop wise and the resulting solution was stirred at −10° C. for 15 minutes. The reaction mixture was partitioned between aqueous ammonium chloride solution (15 mL) and ethyl acetate (3×10 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give tert-butyl (2S)-4-cyclopropyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (32-1), which is converted to (2S)-4-cyclopropyl-N,N-dimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (32-2) in the experimental mentioned above. 1H NMR (300 MHz, CDCl3) δ 7.22 (m, 5H), 5.82 (m, 1H), 5.35 (m, 1H), 4.43 (dd, J=14.5, 5.5 Hz, 1H), 4.00 (d, J=14.5 Hz, 1H), 2.82 (s, 6H), 1.40 (m, 1H), 0.76 (m, 2H), 0.54 (m, 2H). LRMS m/z (M+H) 257.2 found, 257.3 required.