Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH2:3][OH:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].ClC1C=CC=C(C(OO)=[O:34])C=1>CO>[C:19]([O:4][CH2:3][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:34])=[CH:9][C:8]=2[N:7]=[CH:6]1)([CH3:18])[CH3:1])(=[O:21])[CH3:20]
Reactant: CC(C)(CO)n1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OCC(C)(C)n1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 67.8 g (0.281 mole) of beta,beta-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol and 170 mL of acetic anhydride was heated at about 100° C. for three hours. To this solution was added 1700 mL of methanol and the solution was refluxed for about 0.5 hour. The solution was evaporated in vacuo and the residue was basified with a saturated sodium bicarbonate solution. Scratching provided an off-white solid which was separated by filtration, washed with water and dissolved in chloroform. The solution was dried over magnesium sulfate and concentrated to a solid residue. The solid was dissolved in 750 mL of chloroform. To this solution was added 67.3 g (0.312 mole) of meta-chloroperbenzoic acid. The mixture was stirred for three hours, evaporated, then washed with saturated sodium bicarbonate solution. Sodium chloride was added, then the mixture was extracted with chloroform. The organic layer was then dried over magnesium sulfate and concentrated by evaporation in vacuo to provide 1-(2-acetoxy-1,1-dimethylethyl)-1H-imidazo[4,5-c]quinoline-5-oxide.
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Al](C)C.[Li]C.COCOC>C1(C)C=CC=CC=1>[CH3:2][C:1]([CH3:4])([S:5]([NH:7][C:8]1([CH3:22])[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:6])[CH3:3]
Reactant: C[Al](C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(=NS(=O)C(C)(C)C)CC1
Agent: [Li]C
Solvent: Cc1ccccc1
Solvent: COCOC
Product: CC1(NS(=O)C(C)(C)C)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
To a stirred solution of tert-butyl 4-(tert-butylsulfinylimino)cyclohexylcarbamate (0.6 g, 1.9 mmol) in 40 mL of toluene at −78° C. was added, under a nitrogen atmosphere, a solution of Me3Al 2M in toluene (2 mL, 4 mmol). The mixture was stirred for 20 minutes at −78° C., then a solution of MeLi, 3M in dimethoxymethane (2.8 mL, 8.4 mmol), was added slowly and the reaction mixture was stirred at −78° C. for 4 hours. The reaction was quenched by adding 2 mL of water and the solvents evaporated under reduced pressure. The residue was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(1,1-dimethylethylsulfinamido)-4-methylcyclohexylcarbamate (0.21 g, 33%) as crude yellow oil which was used for the next step without further purification. MS: (M+H)+=333.2.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].F[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8](F)[C:7]=1[F:16].C(O)(=O)C[C:19](CC(O)=O)(C(O)=O)[OH:20]>CO>[CH3:19][O:20][C:8]1[C:7]([F:16])=[C:6]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: C[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(OC)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A freshly prepared solution of sodium methoxide [0.58 g (25 mmol) of sodium dissolved in 3 mL of anhydrous methanol] was added dropwise to a solution of 2 g (11.2 mmol) of 1,2,3-trifluoro-4-nitrobenzene in 30 mL of anhydrous methanol under nitrogen at +4° C. The resulting mixture was stirred overnight at room temperature and quenched with 1 M aqueous citric acid (0.1 eq) and methanol was evaporated under reduced pressure. The residue was taken up with ether, washed with 1 M citric acid, brine and dried over anhydrous magnesium sulfate and filtered off. The filtrate was evaporated under reduced pressure to give 2.2 g (99% yield) of the crude product, which was purified by crystallisation from hexane. H1 NMR (CDCl3) 3.95 (s, 3H, OMe); 4.06 (d, 3H, J=1.6 Hz); 6.72 (dd, 1H, CH, J=9.4 Hz, J=7.5 Hz) 7.72 (dd, 1H, CH, J=9.4 Hz, J=2.23 Hz).
Reaction SMILES: [F:1][CH:2]([F:6])[CH2:3][NH:4][CH3:5].Cl.CCN(C(C)C)C(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([NH:35][CH3:36])=[CH:28][C:27]=2F)=[CH:20][C:19]=1[Cl:39]>CC#N>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:38])[C:26]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[C:29]([NH:35][CH3:36])=[CH:28][C:27]=2[N:4]([CH3:5])[CH2:3][CH:2]([F:6])[F:1])=[CH:20][C:19]=1[Cl:39]
Reactant: CNCC(F)F
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N(C)CC(F)F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(2,2-difluoroethyl)-N-methyl-amine×HCl (64 mg, 0.48 mmol), DIPEA (0.64 ml, 3.73 mmol), N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (150 mg, 0.44 mmol) and MeCN (5 mL) is stirred for two weeks at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, dried with Na2SO4 and concentrated and directly used in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:24]Br.O>CO>[Br:24][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:23])[C@H:8]([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrBr
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
A stirred solution of 3α-hydroxy-5α-pregnan-20-one (5 g., 15.7 mmole) in AR methanol (350 c.c.) was treated at 0° with a solution of bromine (1 c.c.) in methanol (23 c.c.) at such a rate that the yellow colour disappeared before further addition. The resultant suspension was poured into water and stirred for 30 minutes, and the precipitate was collected by filtration and dried in vacuo. The product was purified by column chromatography on silica gel MFC, (700 g.). Elution with benzene:ethyl acetate, 1:1) gave 21-bromo-3α-hydroxy-5α-pregnan-20-one (5.2 g.) [α]D + 105.5°.
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2/[C:14](=[CH:19]\[O:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16])C(=O)C2=CC=CC=C12.O.NN>CO.C(OCC)C>[NH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[CH:19]\[O:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CO/C=C(/C(=O)OC)c1ccccc1CON
Reaction time: 3 h
Yield: 93 %

Procedure:
(E)-methyl 2-[phthalimidooxymethylphenyl]-3-methoxypropenoate (1.11 g, 3.02 mmol) (prepared as described in Example 4 of EP 0463488) was suspended in methanol (25 ml) at room temperature and hydrazine hydrate (0.151 g, 3.02 mmol) was added. The resulting solution was stirred for 3 hours. The white precipitate which formed was filtered off and the solvent removed to give a white semi-solid. This was diluted with diethyl ether, and the white solid filtered off to give (E)-methyl 2-[2-aminooxymethylphenyl]-3 -methoxypropenoate (93%) as a yellow oil which was used immediately in the next stage without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:11]#[N:12].[NH2:15][CH:16]([CH3:64])[CH:17]([N:19]1[C:23](=[O:24])[N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]5[CH2:49][O:48][C:47]([C:56]6[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=6[F:63])([CH2:50][N:51]6[CH:55]=[N:54][CH:53]=[N:52]6)[O:46]5)=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:21]=[N:20]1)[CH3:18]>C(Cl)Cl>[F:63][C:57]1[CH:58]=[C:59]([F:62])[CH:60]=[CH:61][C:56]=1[C:47]1([CH2:50][N:51]2[CH:55]=[N:54][CH:53]=[N:52]2)[O:46][CH:45]([CH2:44][O:43][C:40]2[CH:39]=[CH:38][C:37]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:27]=[CH:26][C:25]([N:22]5[C:23](=[O:24])[N:19]([CH:17]([CH3:18])[CH:16]([NH:15][CH:1]([C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)[C:11]#[N:12])[CH3:64])[N:20]=[CH:21]5)=[CH:30][CH:29]=4)[CH2:36][CH2:35]3)=[CH:42][CH:41]=2)[CH2:49][O:48]1
Reactant: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: CC(NC(C#N)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reaction time: 0.33 h

Procedure:
A mixture of benzaldehyde (0.0094 mol) and trimethylsilanecarbonitrile (0.01 mol) in CH2Cl2 (50 ml) was stirred for 20 minutes. Compound 37 (0.0022 mol) was added. The mixture was stirred overnight. The solvent was evaporated, yielding 2 g of [2S-[2α,4α(S*,R*)]]-α-[[2-[4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-1-methylpropyl]amino]benzeneacetonitrile (compound 122).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][N:16]1[C:20]([CH:21]([NH2:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][CH:18]=[N:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([O:15][N:16]1[C:20]([CH:21]([NH:27][S:34]([C:32]2[S:33][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:36])=[O:35])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:19][CH:18]=[N:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1ccnn1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1OCc1ccccc1
Yield: 62.5 %

Procedure:
In a flask containing a mixture of triethylamine (0.045 mL, 0.325 mmol) and {1-[1-(benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutyl}amine (0.081 g, 0.296 mmol) in CH2Cl2 (1 mL) at ambient temperature was added 5-chlorothiophene-2-sulfonyl chloride (0.064 g, 0.296 mmol). After 16 h the mixture was diluted with CH2Cl2 (10 mL) and poured into saturated aqueous NaHCO3 (10 mL). The organic phase was separated and washed sequentially with 1N HCl solution, distilled water, brine and then dried over MgSO4, filtered, and concentrated to an oil. Purification by flash chromatography (hexane/EtOAc, 4:1) afforded the product as a solid (0.084 g, 62%). Mass Spectrum (+ESI): 454 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([O:20]CC)=O)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)#[N:2].[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[C:1]([C:3]1[C:4]([C:18]([NH:28][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:20])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)#[N:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1C#N
Solvent: CCO
Product: N#Cc1c(C(=O)NC2CCCC2)noc1-c1ccc(C(F)(F)F)cc1
Temperature: 82 °C

Procedure:
A mixture of ethyl 4-cyano-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (150 mg, 0.48 mmol) and cyclopentylamine (0.24 mL, 2.4 mmol) in ethanol (5 mL) was heated to 82° C. for 16 hours. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography, eluting with 5% methanol in dichloromethane to afford the title compound: (130 mg, 0.37 mmol). 1H NMR (300 MHz, CDCl3) δ 8.27 (m, 2H), 7.86 (m, 2H), 6.68 (br. d, 1H), 4.43 (m, 1H), 2.11 (m, 2H), 1.85-1.45 (m, 6H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)CC1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CN1CCCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)CC1

Procedure:
A mixture of 5-bromo-6-(4-methyl-1,4-diazepan-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 146.1, 74 mg, 0.150 mmol), pyridin-3-ylboronic acid (18.5 mg, 0.150 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL), and water (0.64 mL) was flushed with argon. Pd(PPh3)2Cl2 (5.3 mg, 0.0075 mmol) was added and the mixture was subjected to MW irradiation at 125° C. for 30 min. The RM was evaporated to dryness under reduced pressure and the residue was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.71 min, m/z=472.1 [M+H]+, m/z=470.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH:11][CH:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH2:5][CH2:6]3)[O:13][CH2:14][C:15]=2[CH:21]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Product: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Yield: 98 %

Procedure:
Prepared from rac-N2-(5-fluoro-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 11) (300 mg, 1.01 mmol) and chloroacetyl chloride (85 ul, 1.06 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as a light brown foam (370 mg, 98%), MS (ISP) m/e=374.2 [(M+H)+] and 376 [(M+2+H)+].
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.COC(=O)[CH2:22][NH2:23]>CO.[Pd]>[CH:13]([C@@H:12]1[NH:11][C:9](=[O:8])[CH2:22][NH:23][C:16]1=[O:18])([CH3:15])[CH3:14]
Reactant: COC(=O)CN
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1NC(=O)CNC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of 27.14 g (84.19 mmol) N-Benzyloxycarbonyl-valine-glycine-methylester (82) in 600 ml dry methanol was hydrogenated by adding Pd/C-catalyst and stirring the resulting mixture under H2 at r.t. for 4 h. After that the mixture was filtered through celite and the remaining solution was refluxed for 24 h. Evaporation of the solvent yielded 13.17 g (84.33 mmol, 100%) 6-(S)-Isopropyl-piperazine-2,5-dione (83) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:5][O:6][CH2:7][CH2:8][N:9]=[N+]=[N-].C(N(CC)CC)C.C(O)CCO.[BH4-].[Na+]>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:5][O:6][CH2:7][CH2:8][NH2:9]
Reactant: Cc1ccc(COCCN=[N+]=[N-])cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: OCCCO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1ccc(COCCN)cc1C
Yield: 74.2 %

Procedure:
2.29 g (11.2 mmol) of 2-(3,4-dimethylbenzyloxy)ethylazide obtained in step 2 was dissolved in 15 ml of isopropanol while stirring, and 3.1 ml (22 mmol) of triethylamine was added thereto. The mixture was added to an isopropanol solution containing 1.1 ml (11 mmol) of 1,3-propanediol and then 4.22 g (0.11 moles) of NaBH4 was added thereto. The mixture was stirred at an ambient temperature for 1 hour and the solvent was distilled off under a reduced pressure. The residue was dissolved in 10% aqueous citric acid and the resulting solution was washed three times with 30 ml of ether: hexane (1:1). The pH of the aqueous layer was adjusted to 12 with a 6N sodium hydroxide solution and then a saturated sodium chloride solution was added thereto. Thee aqueous layer was extracted with 30 ml of dichloromethane 3 times. The organic layer was dried and the solvent was evaporated under a reduced pressure to obtain 1.49 g (yield 75%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[S:21](=[O:23])(=[O:22])[N:20]([C:24](=[CH2:26])C)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[O:30]CC1.O>C(OCC)(=O)C.O=[Os](=O)(=O)=O>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH:26]=[O:30])[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=C(C)N1CCCC(CCC2CCN(C(=O)OC(C)(C)C)CC2)S1(=O)=O
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCCN(CC=O)S2(=O)=O)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 89 (0.50 g, 1.29 mmol), THF (16 mL), H2O (12 mL), and NaIO4 (0.69 g, 3.2 mmol) was added OsO4 (1 mL, 0.1 mmol; 2.5 %/tertbutanol) to effect a white precipitate. After 3.0 h, the reaction mixture was diluted with ethyl acetate and washed with H2O, 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give aldehyde 90 as an oil. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.08 (m, 2H), 4.00 (d, J=17 Hz, 1H), 3.89 (d, J=17 Hz, 1H), 3.62 (m, 1H), 3.14 (m, 1H), 2.96 (m, 1H), 2.66 (m, 2H), 2.20 (m, 1H), 2.08 (m, 1H), 2.00-1.35 (m, 9H), 1.10 (m, 2H).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13](O)=O)=O)C1C=CC=CC=1.NC1C=CC=CC=1O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:26]=1[NH2:38].C(OC(NCC(N[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C1)=O)=O)(C)(C)C.C(OC([NH:73][CH2:74][C@H:75]1[CH2:79][N:78](C(OC(C)(C)C)=O)[C@@H:77]([C:87]([OH:89])=O)[CH2:76]1)=O)(C)(C)C>>[NH2:73][CH2:74][C@H:75]1[CH2:79][NH:78][C@@H:77]([C:87]([NH:11][CH2:12][C:13]2[NH:38][C:26]3[CH:27]=[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:30][C:25]=3[N:24]=2)=[O:89])[CH2:76]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nc1ccc(Cc2ccccc2)cc1N
Agent: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Nc1ccccc1O
Product: NC[C@H]1CN[C@@H](C(=O)NCc2nc3ccc(Cc4ccccc4)cc3[nH]2)C1

Procedure:
This compound was prepared as in Compound M77, replacing N-(Benzyloxycarbonyl)-D-homophenylalanine with N-(Benzyloxycarbonyl)glycine, 2-aminophenol with 1,2diamino-4-benzylbenzene and trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline with cis-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-D-proline.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][CH:35]=[C:26]([CH2:25][N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:13]2=[O:21])[CH:27]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)n(Cc3cccc4ccccc34)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
To a solution of 1-Naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.37 mmol) in DMF (3 mL) was added 60% NaH (22 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 10 min and then Methyl 3-(bromomethyl)benzoate (0.1 g, 0.44 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. When the reaction was complete, the mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 100% CH2Cl2 as an elunet to afford 0.14 g of the desired product as a white foam. LCMS (ESMS): m/z 423.84 (M+H+).
Reaction SMILES: C(C1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[C:5]([F:16])[CH:4]=1)#N.C1COCC1.CO.[OH-].[Na+].CC[O:28][C:29]([CH3:31])=[O:30]>>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7]([C:6]1[CH:14]=[CH:15][C:31]([C:29]([OH:28])=[O:30])=[CH:4][C:5]=1[F:16])=[O:8])[CH3:13]
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)c1ccc(C#N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(=O)O)cc1F
Temperature: 65 °C
Yield: 66 %

Procedure:
To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) at room temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol) followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g, 5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc and washed with brine solution. The organics were separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc-DCM (10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H), 7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24 (td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75 g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4 N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heated at 65° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc and washed with 2 M HCl solution. The organics were separated, dried and concentrated in vacuo to give 4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid. ESI-MS m/z calc. 239.24. found 240.2 (M+1)+; Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([Cl:12])[C@H:3]1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[C:14]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([Cl:12])[C@H:3]1[OH:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(N[C@@H]1Cc2ccccc2[C@@H](Cl)[C@H]1O)c1ccccc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a mixture of (±)-(1R,2S,3R)-3-amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (547 mg) in water (10 ml) and benzoylchloride (367 mg) in toluene (6 ml) was added dropwise a solution of sodium bicarbonate (420 mg) in water (10 ml) over a period of 30 minutes. Stirring was maintained at room temperature for an additional period of 30 minutes. The mixture was extracted with chloroform, washed with saturated aqueous sodium chloride and evaporated in vacuo. Recrystallization of the residue from a cyclohexane/ethyl acetate mixture yielded the title compound (357 mg) as a white solid.