Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-:15].[Na+]>O.OO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:13]([NH2:14])=[O:15])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [OH-]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [Pd]
Agent: OO
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 50 °C

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-cyclobutane carbonitrile (70 g) prepared in a similar manner to that described in Example 1 in industrial methylated spirit (200 ml) was mixed with a solution of sodium hydroxide (3.7 g) in water (5 ml) and 30% hydrogen peroxide solution added dropwise. The mixture was heated at 50° C. for one hour and then stirred with 10% palladium on charcoal (0.5 g) for one hour. The mixture was filtered and evaporated to dryness to give 1-(3,4-dichlorophenyl)-1-cyclobutane-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH2:14][OH:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH:14]=[O:15]
Reactant: CC(=O)N(C)Cc1ccc(Cl)c(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)N(C)Cc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[4-chloro-3-(hydroxymethyl)benzyl]-N-methylacetamide from the previous step (1 eq.) in CH2Cl2 (0.8 M) was added Dess-Martin periodinane (1.2 eq.) portionwise. The resulting suspension was stirred at RT for 3 h. The reaction was quenched with MeOH and H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.I[C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C@H:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:23][CH2:22]3)=[CH:12][CH:11]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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].C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:23][CH2:22]4)=[CH:12][CH:11]=2)=[CH:2]1
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(I)cc3)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ccsc4)cc3)ccc21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of thiophene-3-boronic acid (53 mg, 0.42 mmol), ethyl {(1S)-5-[3-(4-iodophenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (50 mg, 0.10 mmol, Example 94) in toluene (1.8 mL), and 1,4-dioxane (0.45 mL), was added PdCl2(dppf)-CH2Cl2 (7.6 mg, 0.01 mmol), and argon was passed through the mixture for 30 min. Then Na2CO3 (2 N aqueous solution, 0.50 mL) was added, and the mixture was heated to 75° C. for 48 h. The reaction was cooled to rt, and extracted with EtOAc (2×). The combined organic phases were washed with NaHCO3 (saturated aqueous solution), dried, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel to give 33 mg (73%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H), 7.40-7.31 (m, 3H), 7.06 (d, 1H), 6.97 (d, 2H), 6.80 (s, 1H), 6.72 (dd, 1H), 4.24-4.10 (m, 6H), 3.60-3.48 (m, 1H), 2.98-2.90 (m, 2H), 2.72 (dd, 1H), 2.46-2.36 (m, 2H), 2.36-2.23 (m, 2H), 1.85-1.70 (m, 1H), 1.30 (t, 3H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:17]3[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=3)([OH:16])[CH2:12][CH2:11]2)[CH2:6]1.[O:25]=[C:26]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:27][CH2:28][C:29](O)=[O:30].CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[OH:16][C:13]1([C:17]2[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=2)[CH2:12][CH2:11][CH:10]([N:7]2[CH2:8][CH2:9][C@@H:5]([NH:4][C:29](=[O:30])[CH2:28][CH2:27][C:26](=[O:25])[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)[CH2:6]2)[CH2:15][CH2:14]1
Reactant: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](N)C3)CC2)s1
Reactant: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)CCC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a stirred solution of 4-[(3R)-3-aminopyrrolidin-1-yl]-1-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanol 3HCl salt (0.233 g, 0.557 mmol) and 4-oxo-4-[3-(trifluoromethyl)phenyl]butanoic acid (0.15 g, 0.61 mmol) in DMF (5 mL) was added Et3N (0.34 mL, 2.44 mmol) followed by BOP (0.296 g, 0.67 mmol). The mixture was stirred overnight at room temperature. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layer was dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.075 g of the title compound. MS (EI) calculated: MS (EI) calcd: (M+H)+=538.2; found: 538.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]4[C:23]([CH3:37])=[CH:24][C:25]([NH:29]C(=O)OC(C)(C)C)=[N:26][C:27]=4[CH3:28])=[O:19])[N:15]=[N:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:25]1[N:26]=[C:27]([CH3:28])[C:22]([CH2:21][NH:20][C:18]([C:16]2[N:15]=[N:14][N:13]([CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:17]=2)=[O:19])=[C:23]([CH3:37])[CH:24]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc3ccc(Cl)cc3n2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc3ccc(Cl)cc3n2)nn1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (5-((1-((7-chloroquinolin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (46.7 mg, 0.089 mmol) in DCM (0.6 ml) was added TFA (0.138 ml, 1.789 mmol). Reaction mixture was stirred overnight at 23° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([NH2:24])[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1>CN(C)C=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:2]([NH:23][CH:20]3[CH2:21][CH2:22][CH:17]([NH2:24])[CH2:18][CH2:19]3)=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: NC1CCC(N)CC1
Reactant: Clc1ncnc2scc(-c3ccccn3)c12
Solvent: CN(C)C=O
Product: NC1CCC(Nc2ncnc3scc(-c4ccccn4)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was charged with 2-[4-chlorothieno[2,3-d]pyrimidin-5-yl]pyridine (1.0 g, 4.04 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), TEA (1.2 g, 11.86 mmol, 2.94 equiv) and cyclohexane-1,4-diamine (2.8 g, 24.52 mmol, 6.07 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.9 g (69%) of 1-N-[5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine as yellow oil. MS: m/z 326 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C(=O)=O.CC(C)=O.C([Li])CCC.Cl>O1CCCC1>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[CH:3][CH:4]=1)#[N:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1ccccc1-c1ccc(Br)cc1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#Cc1ccccc1-c1ccc(B(O)O)cc1
Temperature: -73 °C
Yield: 26 %

Procedure:
Add 2-(4-bromophenyl)benzenecarbonitrile (1.29 g, 0.005 moles, preparation 61), tetrahydrofuran (52 mL), and triisopropyl borate (2.82 grams, 0.015 moles) to a 100 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, dry ice-acetone bath, and addition funnel. Stir the mixture under nitrogen and cool the contents of the 100 mL 3-neck round-bottom flask to −73° C. Transfer a solution of n-butyl lithium 1.6 M in hexanes (8.7 mL, 0.0139 moles) via cannula to the addition funnel. Add n-butyl lithium (4.7 mL, 0.0075 moles) to the reaction mixture over 7 minutes while maintaining −65 to −73° C. Slowly warm the reaction mixture to −15° C. Cool the reaction mixture to −70° C. Add n-butyl lithium (3.0 mL, 0.0048 moles) to the reaction mixture dropwise. Slowly warm the reaction mixture to −15° C. Cool the reaction mixture to −60° C. Add n-butyl lithium (1.0 mL, 0.0016 moles) to the reaction mixture dropwise. Slowly warm the reaction mixture to −15° C. Cool the reaction mixture to −30° C. Add 1.0 N hydrochloric acid (20 mL, 0.02 moles). Remove the dry ice-acetone bath, and allow the reaction mixture to warm to 23° C. Transfer the reaction m mixture to a separatory funnel. Separate the phases and concentrate the organic phase to a solid under reduced pressure (15-25 mm). Add water (50 mL), 5N NaOH until pH 11.5 is observed, dichloromethane (40 mL), and tetrahydrofuran (20 mL). Transfer the reaction mixture to a separatory funnel and separate the phases. Acidify the aqueous phase and concentrate the suspension under reduced pressure (15-25 mm) to remove residual organic solvents. Collect the precipitate by filtration. Vacuum (15-25 mm) dry the filter cake at 45° C. to provide the title compound (0.30 g, 0.0013 moles) in 26.9% yield. 1H NMR (DMSO-d6, 500.0 MHz): δ 8.21 (s, 2H); 7.98 (dd, 1H, J=1.5, 8); 7.95 (d, 2H, J=8); 7.82 (dt, 1H, J=1.5, 7.5); 7.66 (d, 1H, J=7); 7.61 (dt, 1H, J=1, 8); 7.57 (d, 2H, J=8).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[C:7]([CH2:9][O:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].CCN(CC)CC.[BH4-].[Na+]>O1CCOCC1.O=[Mn]=O>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:8]=[C:7]([CH2:9][O:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:16][CH:15]=2)[CH3:13])[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=NOCc1ccc(-c2ccccc2)c(C(F)(F)F)c1)c1ccc(CO)cc1
Reactant: NCCC(=O)O
Agent: O=[Mn]=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=NOCc1ccc(-c2ccccc2)c(C(F)(F)F)c1)c1ccc(CNCCC(=O)O)cc1
Temperature: 50 °C

Procedure:
To a suspension of MnO2 (10 eq) in dioxane is added 1-(4-hydroxymethyl-phenyl)-ethanone O-(2-trifluoromethyl-biphenyl-4-ylmethyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with β-alanine (2 eq) and Et3N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes. After cooling to room temperature, NaBH4 (3 eq) is added in portions. Purification by preparative LCMS results in 3-{4-[1-(2-trifluoromethyl-biphenyl-4-ylmethoxyimino)-ethyl]-benzylamino}-propionic acid; 1H NMR (400 MHz, CD3OD) δ 2.28 (s, 3H), 2.75 (t, J=6.8 Hz, 2H), 3.26 (t, J=6.8 Hz, 2H), 4.22 (s, 2H), 5.30 (s, 2H), 7.26-7.77 (m, 12H). MS: (ES+): 471.1 (M+1)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:17]1([CH2:27][CH2:28][CH:29]=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1.CCCCCC>[OH:30][CH:29]([CH2:28][CH2:27][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=CCCc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)CC(O)CCc1cccc2ccccc12
Temperature: -60 °C
Yield: 38.6 %

Procedure:
A solution of 5.2 g (0.04 mole) of ethyl acetoacetate in a small quantity of anhydrous tetrahydrofuran was added dropwise to 1.2 g (0.04 mole) of sodium hydride (in the form of a 55% w/w suspension in oil) in 100 ml of anhydrious tetrahydrofuran, with ice-cooling and stirring. The mixture was then stirred for 30 minutes. after which it was cooled to a temperature of from -10° C. to -5° C. To the mixture were added dropwise 30 ml of an n-hexane solution containing 0.04 mole of n-butyllithium. The mixture was stirred at a temperature from 5° C. to 0° C. for 30 minutes, after which it was cooled to -60° C. 6 g (0.033 mole) of 3-(1-naphthyl)propionaldehyde in 50 ml of anhydrous tetrahydrofuran were then added all at once to the reaction mixture. After stirring the mixture for 30 minutes, it was poured into about 500 ml of ice-water. It was then acidified by the addition of hydrochloric acid, with stirring, and the tetrahyrofuran layer was separated. The aqueous layer was extracted three times, each time with 100 ml of ethyl acetate. The tetrahydrofuran layer and the ethyl acetate extracts were combined, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. The solvent was then evaporated off under reduced pressure. The resulting residue was adsorbed on a silica gel column chromatography and the fractions eluted with a 10:3 by volume mixture of ethyl acetate and n-hexane were evaporated to dryness to give 4.0 g (yield 30%) of ethyl 5-hydroxy-7-(1-naphthyl)-3-oxoheptanoate.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH:33][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)C(c3ccccc3)c3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 15.5 %

Procedure:
Diphenyl-acetic acid (42.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (13.3 mg, 0.0310 mmol, 15.5%) ESI-MS m/z calc. 429.2, found 430.2 (M+1)+. Retention time of 3.47 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:7]=[C:8]([F:13])[C:9]=1[O:10][CH2:11][CH3:12])(=[O:3])[CH3:2].C1COCC1.[BH4-].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C.CO>[CH2:11]([O:10][C:9]1[C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]([C:14]2[O:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:7][C:8]=1[F:13])[CH3:12]
Reactant: CCOc1c(F)cc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1C(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1c(F)cc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1C(C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a mixture of N-((2S)-1-((2-(3-acetyl-4-ethoxy-5-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (660 mg), THF (10 mL) and methanol (5 mL) was added sodium borohydride (60.3 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was diluted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate-ethyl acetate/methanol) to give the title compound (420 mg).
Reaction SMILES: C1N=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])C=1.CN.Cl.N1CC(N2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)(=[O:37])=[O:36])[CH:26]=3)[CH:22]=[N:21]2)C1.CCN(CC)CC>C1COCC1>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:23]3[CH:22]=[N:21][N:11]([CH:10]4[CH2:9][N:8]([C:6]([NH:3][CH3:4])=[O:7])[CH2:12]4)[CH:24]=3)=[CH:26][N:27]2[S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CNC3)c2)c2ccc(F)cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reaction time: 1 h
Yield: 101 %

Procedure:
A mixture of CDI (62 mg; 0.38 mmol) and MeNH2 (0.20 ml; 0.40 mmol; 2.0 M in THF) of THF (10 mL) was stirred for 1 hour and added a premixed mixture of 3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole hydrochloride (Intermediate 24; 200 mg; 0.46 mmol) and Et3N (0.10 ml; 0.72 mmol) in THF (2 mL) was stirred at rt for 10 min. The reaction mixture was stirred overnight and concentrated. The residue was diluted with EtOAc (50 mL), washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 174 mg (100%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])=[CH:9][C:6]=1[C:7]#[N:8].CO>C(Cl)(Cl)Cl>[NH2:8][C:7]1[C:6]2[C:5](=[CH:12][CH:11]=[C:10]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])[CH:9]=2)[NH:3][N:2]=1
Reactant: Cc1ccncc1N1CCN(c2ccc(F)c(C#N)c2)C1=O
Reactant: NN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3[nH]nc(N)c3c2)C1=O
Temperature: 170 °C
Yield: 45.3 %

Procedure:
Hydrazine hydrate (5 mL) was added to solution of 2-fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (103A: 265 mg) in 2-methoxymethanol (5 mL). The resulting mixture was heated to 170° C. and maintained for 20 hours. The reaction was monitored by TLC (20% MeOH in CHCl3). The reaction mixture was partitioned between ice water and DCM. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (10% MeOH in CHCl3) afforded 125 mg of the product (45.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:28]([CH3:29])[CH3:27])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(C)CCCCOC[C@H]1CC[C@H](CN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with dimethylamine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-[4-(4-dimethylamino-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 411 (MH+, 1Cl).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[O:23]([CH2:30][C:31]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:33][C:31](=[O:32])[CH2:30][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)COc1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)COc3ccccc3)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 3.7 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 100 ml of benzene is treated at room temperature with 4.7 g of phenoxyacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-7-oxo-6-(2-oxo-3-phenoxypropylidene)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as a yellow oil [Rf: 0.44; cyclohexane/ethyl acetate (6:4); NMR (CDCl3), δ (ppm): 1.21 (9H); 1.51 (3H); 1.56 (3H); 4.58 (1H); 5.66 (2H); 5.83 (2H); 6.05 (1H); 6.8-7.45 (6H)].
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:4].C.O.NN>CO>[CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH3:4]
Reactant: COC(C)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: CO
Product: COC(C)C1CCCN1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(1-Methoxy-ethyl)-1-(4-nitro-benzyl)-pyrrolidine (250 mg, 0.95 mmol) is dissolved in MeOH (10 mL). To this solution is added FeCl3.6H2O (25 mg, 0.09 mmol) and active charcoal (12 mg, 1.0 mmol). The suspension is heated to reflux. Hydrazine hydrate (1.0 mL) is added, and reflux is continued for 4 h. After the mixture is cooled to room temperature, the active charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue (200 mg, 90%) is used directly in the next step.