Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1
Yield: 90.9 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.17 g (91%) of 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 188°-195°.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[CH2:16][CH2:17][CH3:18]>C(Cl)Cl.CCOC(C)=O>[Cl:3][CH2:6][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CCCc1c(CO)nc2ccccn12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(CCl)nc2ccccn12
Reaction time: 1 h

Procedure:
Thionyl chloride (125 mg, 1.06 mmol) is added to a solution of 2-hydroxymethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine (100 mg, 0.53 mmol) in CH2Cl2 (3 mL) at 0° C. under nitrogen with magnetic stirring. After 1 hour, the reaction is diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The solution is then dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain 2-chloromethyl-3-(1-propyl)-imidazolo[1,2-a]pyridine as a colorless oil. TLC (10% MeOH/CH2Cl2) Rf=0.60. Step 5. Preparation of 3-{1-[(3-propylimidazo[1,2-a]pyridin-2-yl)methyl]-1H-imidazol-2-yl}benzonitrile
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@@H:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C([O:34][C@@H:35]1[C@@:63]2(C)[C:39](=[CH:40][CH2:41][C@@H:42]3[C@@H:62]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(OC(=O)C)C(C)C)C[C@@H](OC(=O)C)C1)(=O)C>>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@@H:17]([O:21][C:2](=[O:1])[C:27]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:26]=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:30][C:35](=[O:34])[C:63]2[CH:62]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: CC(C)[C@H](O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Product: CC(C)[C@@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1

Procedure:
The 1α,3β,24(R)-trihydroxy-cholesta-5,7-diene was benzoylated in quite the same way as in Example 22, (A) to form 1α-hydroxy-3β,24(R)-dibenzoyloxy-cholesta-5,7-diene.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+]>O.CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Yield: 76.4 %

Procedure:
Lipase from Rhizopus delemar (300 mg, ex Biocatalysts Ltd.) was stirred in deionised water (125 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient temperature (23° C.), was added a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoate (690 mg) (enantiomer ratio 8:92 as prepared in example 1) in acetone (5 ml). The resulting reaction mixture was stirred at ambient temperature and pH 7.0 was maintained by autotitration with 0.1M sodium hydroxide solution until hydrolysis was complete. 0.1M Sodium hydroxide solution was added to bring the reaction mixture to pH 9.5 after which it was washed with dichloromethane. The aqueous phase was acidified with hydrochloric acid to pH1 and the acid extracted into dichloromethane, washed, dried (magnesium sulphate), and evaporated. The resulting solid was triturated with hexane to yield 490 mg of (+)3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid as a white solid; m.p. 121°-123° C.; enantiomer ratio 92:8 (by HPLC assay); [α]D25 +13°, MeOH, c 0.5. Enantiomer ratios of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid were determined by HPLC on a chiral AGP column eluting with 4.8% acetonitrile in 0.01M sodium dihydrogen phosphate solution at pH 7.0 and detecting products by UV monitoring at 245 nm. Enantiomer ratios are quoted in the order of elution.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].C([O-])(O)=O.[Na+]>CCOCC.O>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([OH:15])([C:16]#[N:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=C1CCC(NCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
A suspension of 4-(benzylamino)cyclohexanone (5.8 g, 28.5 mmol) in ether (112 mL) was cooled to 0° C. To this mixture was added NaCN (1.538 g, 31.4 mmol) as a solution in NaHCO3 (4.79 g, 57.1 mmol) and water (71.4 mL, 3966 mmol). The reaction mixture was stirred at RT for 16 hours. The resulting mixture was diluted with ether (110 mL) and water (50 mL). The layers were separated, and the organic portion was dried over sodium sulfate and concentrated under reduced pressure to afford 4-(benzylamino)-1-hydroxycyclohexanecarbonitrile as a light yellow solid (5.6 g, 85% yield). MS m/z=231.2 [M+H]. Calc'd for C14H18N2O: 230.1.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11]1
Reactant: BrCc1ccccc1
Reactant: O=C1CCNCC1Cc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The amine (7.0 g, 23 mmol) from Example 102 and sodium carbonate (4.88 g, 46 mmol) were slurried in ethanol (50 ml). Benzyl bromide was added and the reaction was stirred for 18 hours at 25° C. The reaction was filtered and concentrated. The residue was partitioned between water and dichloromethane. The dichloromethane layer was dried (MgSO4), filtered, and concentrated to yield a crude yellow residue which was chromatographed on a silica gel column eluted initially with dichloromethane followed by methanol/dichloromethane (1:99). The title compound was eluted as a pale yellow oil (7.2 g, 88%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:10])=[C:3](/[CH3:9])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(#N)C>[NH2:1][CH:2]([CH3:10])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(C)=C(/C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)C(C)C(C)N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
To (Z)-ethyl 3-amino-2-methylbut-2-enoate (Org. Lett. 2003, 5(25) 4779-4782, 1.1 g, 7.68 mmol) in acetonitrile (15 mL) was added sodium triacetoxyborohydride (4.88 g, 23.05 mmol) in one lot at RT. After the addition of acetic acid (2.0 mL, 34.9 mmol) (pH of reaction mixture ˜6.0), the contents were stirred at RT for 2.5 h. The reaction mixture was concentrated and partitioned between dichloromethane (60 mL) and 20% NaOH (10 mL). The dichloromethane layer is dried over sodium sulfate and concentrated to yield the title compound (1.05 g, 7.23 mmol, 94% yield) as an oil, which was used as such for the subsequent step without further purification. MS found: (M+H)+=146.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=S.ICC.[H-].[Na+].[N:28]#[C:29][NH2:30]>O1CCCC1>[C:29]([NH:30][C:3]([C:5]1[C:15]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=1)=[N:2][CH3:1])#[N:28]
Reactant: CNC(=S)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Product: CN=C(NC#N)C1=CC2(CCCCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a mixture of 120 mg of N-methyl-6-nitro-spiro[2H-1benzopyran-2,1'-cyclohexane]-4-carbothioamide, 150 μl of iodoethane, and 3 ml of dried tetrahydrofuran was added 23 mg of sodium hydride (60%) with stirring and cooling with ice followed by refluxlng for 2 hours. After cooling to room temperature, 80 mg of cyanamide and 17 mg of sodium hydride (60%) were added thereto, followed by refluxing for 4 hours. Ice-water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: ethyl acetate:hexane=2:3) recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 90 mg of N-cyano-N'-methyl-6-nitrospiro[2H-1-benzopyran-2,1'-cyclohexane]-4-carboxamidine having formula shown below.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[C:15]2[C:23]3[C:28]([CH2:29][C:14]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.[C:30]([NH:34][Si:35]([CH3:38])([CH3:37])Cl)([CH3:33])([CH3:32])[CH3:31]>CCOCC>[CH3:37][SiH:35]([N:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3)[CH3:38]
Reactant: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Reactant: CC(C)(C)N[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2c(c1)c1c(n2C)C(N([SiH](C)C)C(C)(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
6.66 mL of n-BuLi 2.5 M in hexane (16.65 mmol) were added dropwise at 0° C. to a solution of 3.53 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole (Mw=233.32, purity 99.0%, 15.13 mmol) in Et2O. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for two hours. Subsequently, 3.34 g of (tert-butylamino)dimethylchlorosilane (Mw=165.74, purity 75.0% mol., d=0.887, 20.17 mmol) were added at 0° C. to the Li salt suspension and the resulting mixture was allowed to warm up to room temperature. After three hours stirring, the solvents were evaporated under reduced pressure and the residue was dissolved in 50 mL of toluene, obtaining a dark brown suspension, which was filtered. The filtrate was evaporated to dryness under reduced pressure, obtaining 5.86 g of a dark brown oil, which resulted to be 86.5% wt. pure (calculated by 1H-NMR). Yield=92.4%.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[N+:22]([O-])=O)=[N:6]1)=[O:4].[H][H]>C(O)C.[C].[Pd]>[CH3:1][NH:2][C:3]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[NH2:22])=[N:6]1)=[O:4]
Reactant: [H][H]
Reactant: CNC(=O)n1nc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)n1nc(Oc2ccc(C(F)(F)F)cc2N)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A solution of N-methyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole-1-carboxamide (2.1 g, 6.0 mmol) in ethanol (50 ml) was placed in an autoclave, and 10% palladium carbon (0.7 g) was added. An atmosphere in the autoclave was fully replaced with hydrogen gas, and hydrogen gas was charged up to 5 kg/cm2. Then, the reaction solution was stirred at room temperature for 5 hours. After completion of the reaction, the catalyst was removed by filtration using Celite, and the solvent was distilled off from the filtrate under reduced pressure, to give a yellowish solid of N-methyl-3-(2-amino-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (1.6 g, yield: 82.2%). mp: 93-94; 1H-NMR (CDCl3, TMS, ppm): δ 2.59 (d, J=0.7 Hz, 3H), 2.93 (d, J=5.0 Hz, 1H), 3.90-4.15 (br s, 2H), 5.71 (q, J=0.7 Hz, 1H), 6.80-6.95 (m, 1H), 6.97 (dd, J=1.7 and 8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([C@@:3]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:7][CH2:6][C@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4]1)[CH3:2].[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([C@@:3]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
tert-Butyl [(1S,3R)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (0.39 g, 0. 83 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (3.1 mL) and the solution was stirred at room temperature overnight. The reaction solution was evaporated to give the desird product as a yellow powder (0.36 g, 96%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[OH-].[K+].O.[CH3:18]S(C)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[N:8]([CH3:18])[C:7]1=[O:14]
Reactant: CS(C)=O
Reactant: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cn(CCCCCl)c(=O)n(C)c1=O

Procedure:
2.31 mmol (0.50 g) of 1-(4-chlorobutyl)-5-methylpyrimidine-2,4(1H,3H)-dione, 0.65 g (11.54 mmol) of KOH and 1.64 g (11.54 mmol) of methyl rodide in 20.5 ml of dimethyl sulfoxide (DMSO) were stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the aqueous mixture was extracted three times with methyl tert-butyl ether. The combined organic phase was then washed three times with saturated aqueous brine, and the organic phase was dried, filtered to remove the desiccant and concentrated. 0.53 g of a pale cloudy oil was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].O1CCOCC1.[Br:18]N1C(=O)CCC1=O>O>[Br:18][C:3]1[C:2]([OH:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C=O)cc1O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C=O)c(Br)c1O
Reaction time: 0.5 h
Yield: 75 %

Procedure:
3-Hydroxy-4-methoxybenzaldehyde (200 g, 1.31 mol), dioxane (1000 ml) and water (400 ml) were mixed, and N-bromosuccinimide (245.7 g, 1.38 mol) was added over 10 minutes. After 60 and 70 minutes, N-bromosuccinimide was further added in an amount of 16.4 g (92.1 mmol) and 7.02 g (39.4 mmol), respectively, and the mixture was further stirred for 30 minutes. Water (1600 ml) was added, and the precipitated crystals were collected by filtration. The crystals were washed with water (1000 ml) to give 2-bromo-3-hydroxy-4-methoxybenzaldehyde (227.1 g, 74.8%) as pale-red crystals.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([OH:33])([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH3:16])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([OH:33])([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[CH3:16])=[O:14])=[CH:34][CH:35]=1
Reactant: Cc1ccc(CC2(O)CCN(CCN(C)C(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(CC2(O)CCN(CCN(C)C(=O)c3ccc(O)cc3)CC2)cc1
Reaction time: 4 h
Yield: 73.5 %

Procedure:
Palladium on carbon (10%, 60 mg) was added to a solution of 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-N-methyl-benzamide (226 mg, 0.48 mmol) in acetic acid (6 ml). The hydrogenation was complete after 4 h. The catalyst was removed by filtration through celite and the solvent was evaporated. Sodium bicarbonate (10% aq. solution, 2 ml) was added, and the aqeous layer extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and to give 4-hydroxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl ]-N-methyl-benzamide (135 mg, 74%) as a white solid. MS: me/e=383 (M+H)+.
Reaction SMILES: Cl([O-])=[O:2].[Na+].[F:5][C:6]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][NH:8][C:9]1[C:10]([F:19])=[C:11]([CH2:16][CH:17]=[O:18])[C:12]([Cl:15])=[CH:13][CH:14]=1.Cl>O.CS(C)=O>[F:26][C:6]([F:5])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[C:10]([F:19])=[C:11]([CH2:16][C:17]([OH:2])=[O:18])[C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=CCc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of sodium chlorite (692 mg, 6.11 mmol) in H2O (6.1 mL) was added over a period of 30 minutes to a stirred mixture of 2{-3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}ethanal (1.43 g, 4.37 mmol), as prepared in the preceding step, in DMSO (4.5 mL) and of NaH2PO4 (141 mg, 1.18 mmol) in H2O (1.7 mL). After the addition, the mixture was stirred at ambient temperature overnight, acidified with 10 M HCl to pH 1, and extracted with DCM (3 times). The extracts were combined, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was flash chromatographed on silica gel eluting with MeOH/DCM (0, 2, and 4%) to give the title compound (0.77 g, 51% yield) as a pale brown solid. 1H-NMR (400 MHz, CD3OD) δ 7.53-7.51 (m, 2H), 7.44-7.41 (m, 3H), 6.93 (dd, J=8.9, 1.8 Hz, 1H), 6.62 (t, J=9.1 Hz, 1H), 3.80 (t, J=13.7 Hz, 2H), 3.74 (d, J=2.2 Hz, 2H). Mass spectrum (LCMS, ESI) calc'd for C16H14ClF3NO2 (M+H): 344.1. Found: 344.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH2:38][CH3:39])[C:34](=[O:37])[CH2:35]Cl)[CH3:32].O>CC(C)=O>[CH2:31]([N:33]([CH2:38][CH3:39])[C:34]([CH2:35][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:13])=[O:37])[CH3:32]
Reactant: CCN(CC)C(=O)CCl
Reactant: C[C@H](Cc1c[nH]c2c(O)cccc12)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N3C(=O)c4ccccc4C3=O)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A residue 10.27 g containing (R)-7-hydroxy-3-(2-phthalimidopropyl)indole was dissolved in 200 ml of acetone, and 8.00 g of potassium carbonate was added thereto. After addition of N,N-diethylchloroacetamide 15.5 ml, the solution was heated to reflux in an oil bath of 80° C. For 3 hours. After cooling down 200 ml of water was added, and a deposited crystal was collected by filtration and washed with water, whereby 9.56 g of the title compound was obtained in the form of a pale yellowish white substance.
Reaction SMILES: OCCN[N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20].O1CCOCC1>O>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1)[CH3:20]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1
Reactant: CCOC(CN)OCC
Solvent: O
Solvent: C1COCCO1
Product: CCOC(CNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1)OCC

Procedure:
A mixture composed of 9.8 g. of 2-(2-chloro-5-thiadiazole)-1-methyl-5-nitroimidazole, (Example 16), 11.0 g. of 2,2-diethoxyethylamine, and 250 ml. of dioxane is stirred and heated on the steam bath for 12 hours. It is then diluted with 500 ml. of cold water, cooled, and the precipitated yellow solid collected and dried. Recrystallization from 50% aqueous ethanol gives the pure compound melting at 154°-155° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]([F:16])([F:15])[CH:7]([OH:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([CH3:5])[CH3:4].[NH:17]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20]>>[C:25]([NH:17][C@H:18]([C:22]([NH:1][CH:2]([C:6]([F:15])([F:16])[CH:7]([OH:14])[CH:8]([NH:13][C:22](=[O:23])[C@H:18]([CH:19]([CH3:21])[CH3:20])[NH:17][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]([CH3:4])[CH3:5])=[O:23])[CH:19]([CH3:21])[CH3:20])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)CC(N)C(O)C(F)(F)C(N)C(C)C
Product: CC(C)CC(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(O)C(F)(F)C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Yield: 56 %

Procedure:
Using the procedure described in Example 182, the product from Example 263 was coupled to Cbz-Val to give the desired compound (56%). Mass spectrum: (M+H)+ =705. 1H NMR (CDCl3) δ0.82 (m, 12H), 3.90 (m, 1H), 4.02 (m, 1H), 4.30 (m, 1H), 4.55 (m, 1H), 5.02 (s, 4H), 5.80 (br d, 1H), 7.20 (br d, 1H), 7.35 (m, 10H), 7.70 (br d, 1H).
Reaction SMILES: C(ON=O)CC(C)C.N[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:26]=3[C:27]([F:30])([F:29])[F:28])[C:17]2=[O:20])=[CH:12][C:11]=1[F:31].CO.C(Cl)(Cl)(Cl)[Cl:35]>C(Cl)(Cl)Cl>[Cl:35][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:26]=3[C:27]([F:30])([F:29])[F:28])[C:17]2=[O:20])=[CH:12][C:11]=1[F:31]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Nc1cc2c(cc1F)CCN(c1cnccc1C(F)(F)F)C2=O
Agent: CC(C)CCON=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(Cl)c(F)cc2CCN1c1cnccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
Isoamylnitrite (107.7 mg, 0.91 mmol) was added to the stirred solution of 7-amino-6-fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-79b: 100 mg, 0.306 mmol) in CCl4 (10 mL). The resulting mixture was stirred for 1 hour at 70° C. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 10 mg of the product (10% yield).