Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH2:6]([NH:13][CH2:14][CH:15]([CH:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=1)[OH:21])[C:16](OC)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:6]([NH:13][CH2:14][CH:15]([CH2:16][OH:17])[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=1)[OH:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a suspension of calcium chloride (27.6 g) in THF (234 mL) and ethanol (176 mL) was added, under a nitrogen stream, sodium borohydride (12.5 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of methyl (2RS,3RS)-2-[(benzylamino)methyl]-3-(4-chloro-3-fluorophenyl)-3-hydroxypropanoate (58.2 g) in THF (200 mL) and ethanol (150 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added 6 N aqueous hydrochloric acid solution (28 ml), the mixture was neutralized with 8 N aqueous sodium hydroxide solution, and the mixture was filtered through celite. The obtained oil was diluted with ethyl acetate, and the diluted solution was washed with distilled water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (44.5 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9].[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][C:34]1[CH:42]=[CH:41][C:37]([CH:38]=[N:39][OH:40])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:40][N:39]=[CH:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:29]2[NH:30][CH:31]=[CH:32][N:28]=2)=[CH:42][CH:41]=1)=[O:9]
Reactant: ON=Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCON=Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
##STR36## 301 mg (0.763 mM) of 2-chloroethyl methyl 1,4-dihydro2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate and 155 mg (0.763 mM) of 4-(1-imidazolylmethyl)benzaldoxime were dissolved in 5 ml of dried acetonitrile, and then to the solution 58 mg (0.42 mM) of anhydrous potassium carbonate was added. After the mixture was heated under reflux for 15 hours, acetonitrile was distilled away and dichloromethane was added to the residue. After washing with water, the residue was dried over anhydrous sodium sulfate and dichloromethane was distilled away, and then the crystals were recrystallized from methanol, whereby the captioned compound was obtained. The yield was 400 mg (94%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[ClH:1].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:31])[CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccccc1)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 35.2 mg (259 mmol) phenylacetic acid are dissolved in 5 ml DMF, 119 mg (1.18 mmol) triethylamine, 90.2 mg (470 μmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 127 mg (941 μmol) 1-hydroxy-1H-benzotriazole hydrate are added, while cooling with ice, and the mixture is stirred overnight at RT. The precipitate is filtered off and the filtrate is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]([CH3:9])=[CH2:8]>C1CCCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: C=C(C)C
Reactant: OCCCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OCCCCl
Temperature: 25 °C

Procedure:
A two liter, three-necked round bottom flask was fitted with a mechanical stirrer, a gas inlet tube, and a Claisen adapter equipped with a dry ice condenser, and a thermocouple. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 141.81 grams (1.50 moles, 1.00 equivalent) of 3-chloro-1-propanol and 500 ml. of cyclohexane. The resultant two-phase solution was stirred at 400 RPMs. Amberlyst 15 resin catalyst, 35 grams, was added, followed by an additional 250 ml. of cyclohexane. A total of 93 grams (1.657 moles, 1.105 equivalents) of 2-methylpropene was discharged from the cylinder in two and a third hours. A modest exotherm was noted during the addition. The reaction mixture was stirred at 20°-25° C., and periodically monitored by gas chromatography (GC) for the disappearance of 3-chloro-1-propanol. After stirring at room temperature for twenty-eight hours, the conversion to the desired product was 94.7%. The catalyst was removed by filtration through a piece of fluted filter paper. The reaction flask was rinsed with fresh cyclohexane (2×100 ml.). The product was purified by distillation from 10.72 grams of potassium carbonate through a twelve inch Vigreux column, at atmospheric pressure. This afforded a clear, colorless oil, yield=158.42 grams (70.2%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH3:16][NH:17][C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>>[C:14]([C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:3]2[N:4]=[CH:5][N:6]([CH3:7])[C:2]=2[C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:17][CH3:16])=[O:19])[CH:13]=1)#[N:15]
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: CNC(=O)c1cccc(-c2c(-c3cc(C#N)ccn3)ncn2C)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-(N-methylaminocarbonyl)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H15N5O, 318. Found, 318.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].I[C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1>[Cu]I.COCCOCCOC>[CH3:24][C:22]1[CH:23]=[C:18]([N:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=2)[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH2:16])[CH:19]=[C:20]([CH3:25])[CH:21]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: Cc1cc(C)cc(N(c2cc(C)cc(C)c2)[C@@H]2CCCC[C@H]2N)c1
Temperature: 140 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (40 mg, 0.210 mmol), K3PO4 (1.30 g, 6.12 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (240 μL, 2.00 mmol), 5-iodo-m-xylene (900 μL, 6.24 mmol) and 2-methoxyethyl ether (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 140° C. for 24 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; chloroform—chloroform saturated with aq NH3—methanol 40:40:1; 15 mL fractions). Fractions 7-14 provided 465 mg (72% yield) of the product as a tan solid. 1H NMR (400 MHz, CDCl3): δ 6.67 (s, 1H), 6.57 (s, 2H), 3.65−3.55 (m, 1H), 2.68−2.58 (m, 1H), 2.28 (s, 12H), 2.08−1.92 (m, 2H), 1.83−1.64 (m, 2H), 1.58−1.10 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][C:7]=12)#[N:2].[H][H]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][C:7]=12
Reactant: [H][H]
Reactant: N#Cc1cnn2c1[nH]c(=O)c1ccccc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cnn2c1[nH]c(=O)c1ccccc12

Procedure:
A suspension of 1.5 g of 3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one in 150 mL of 20% ammonia in methanol was shaken with 15 g of aqueous Raney nickel at ambient temperature under 60 psi of hydrogen for 70 minutes. The suspension was diluted with 150 mL of methanol and warmed to dissolve the precipitated product. Filtration through a nylon membrane and concentration of the filtrate yielded the title compound. MS (ESI) m/z 198 (M+H—NH3)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([S-:13])[CH3:12].[Na+].Cl>CN(C)C=O>[CH2:11]([S:13][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: CC[S-]
Reactant: Cc1ccc(F)c(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(C)cc1C#N
Yield: 87.1 %

Procedure:
(Step 1) A mixture of 2-fluoro-5-methylbenzonitrile (7.5 g) and sodium ethanethiolate (4.9 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 3 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 2-(ethylsulfanyl)-5-methylbenzonitrile (8.57 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[C:35]([O:34][C:32]([NH:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:7]2[C:6]3[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:5]=3[O:4][CH2:3][C:2]2=[O:1])[CH2:30][CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Yield: 85 %

Procedure:
Methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (Intermediate 86) (330 mg, 1.59 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (5.6 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 85% yield as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+].S([NH:27][N:28]=[CH:29][CH:30](Cl)Cl)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])O.[Na+].[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]>O.CO.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:38][S:39]([OH:42])(=[O:41])=[O:40].[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][N:2]2[CH:30]=[CH:29][N:28]=[N:27]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCCCN)cc1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (2.0 g, 9.27 mmol) was dissolved in water (10 ml). Toluene (20 ml) and 2N-sodium hydroxide (10 ml) were added and the mixture was partitioned. The organic layer was washed with 20% brine (10 ml) twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added methanol (5 ml) and the mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). This methanol solution was added dropwise to a suspension of 2,2-dichloroacetaldehyde tosylhydrazone (5213 mg, 18.54 mmol) in methanol (30 ml) at 20-25° C. The mixture was stirred at room temperature for 1 hour 20 min. To the mixture of toluene (20 ml) and saturated aqueous sodium hydrogen carbonate (60 ml) was added this reaction mixture, and the mixture was stirred at room temperature for 50 min. The organic solvent was evaporated under reduced pressure and the residue was extracted with toluene (40 ml). 4N-Sodium hydroxide (30 ml) was added, and the mixture was heated to 50-60° C. and partitioned. Water (30 ml) was added, and the mixture was heated to 50-60° C. and partitioned. Water (30 ml) was added, and the mixture was heated to 50-60° C. and partitioned. The organic layer was washed with a mixture of 20% citric acid (15 ml) and saturated brine (15 ml). After washing with saturated aqueous sodium hydrogen carbonate (30 ml), it was washed with water (30 ml) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 ml) and methanesulfonic acid (0.49 ml, 7.55 mmol) was added under ice-cooling. Ethyl acetate (2 ml) was added and the mixture was stirred under ice-cooling for 50 min. The precipitated crystals were collected by filtration, washed with ice-cooled ethyl acetate (8 ml) and dried under reduced pressure to give 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate (2.19 g, yield 72%).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:6]([N:12]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=O)[NH:13]2)=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.P(Br)(Br)([Br:25])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Br:25][C:14]1[CH2:15][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:6]2[C:5]([Cl:4])=[CH:10][C:9]([Cl:11])=[CH:8][N:7]=2)[N:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)C1CC(=O)NN1c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CC(Br)=NN1c1ncc(Cl)cc1Cl
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a 250 mL flask, acetonitrile (65 mL), ethyl 2-(3,5-dichloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate (3.0 g, 9.8 mmol, the product of Step (3), Example 3) and phosphoryl bromide (2.8 g, 9.8 mmol) were added. The reaction mixture was heated to reflux for 2 hours. The reaction mixture was distilled to remove 30 mL solvent and added to the mixture of sodium carbonate (10 g, 120 mmol) and water (40 mL). The mixture was stirred for 20 minutes until no gas released. The reaction mixture was diluted with dichloromethane (100 mL), stirred for 50 minutes and extracted with dichloromethane (3×100 mL). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under vacuum to give the product (2.4 g) as amber oil in 67% yield. 1H NMR (300 MHz, CDCl3): 8.027 (d, 1H), 7.673 (d, 1H), 5.201 (dd, 1H), 4.202 (q, 2H), 3.464 (dd, 1H), 3.248 (dd, 1H), 1.223 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1)([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:24][C:22]([F:25])([F:23])[C:19]1[CH:20]=[CH:21][C:16]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:8][CH:7]=2)=[C:10]2[CH2:15][CH2:14][N:13]([CH2:37][C:34]3[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)[CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CN2CCC(=C(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 3.8 grams (0.010 mole) of 4-{bis[4-(trifluoromethyl)phenyl]methylene}piperidine, 2.2 grams (0.010 mole) of 4-nitrophenylmethyl bromide, and 1.7 grams (0.012 mole) of potassium carbonate in about 20 mL of ethanol was warmed to 75° C., where it stirred for about 18 hours. After this time, an additional 0.2 gram (0.001 mole) of 4-nitrophenylmethyl bromide and an additional 0.2 gram (0.001 mole) of potassium carbonate was added to the reaction mixture. The reaction mixture was again heated to 75° C., where it stirred for about eight hours. After this time, the reaction mixture was cooled and filtered to remove excess potassium carbonate. The reaction mixture was then taken up in acetic acid, and 0.2 gram (catalyst) of 5% platinum on carbon was added to the mixture in preparation for the following hydrogenation step. A quantitative yield of the subject compound was assumed.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)[N:17]=2)=[CH:9][CH:8]=[C:7]([F:26])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[N:17]=2)=[CH:9][CH:8]=[C:7]([F:26])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cccc(-c2csc(COc3ccc(F)c(C(N)=O)c3F)n2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3cccc(O)c3)cs2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
A solution of 2,6-Difluoro-3-[4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-benzamide (0.20 g, 0.53 mmol) in 15 ml of DCM was cooled to −78° C. followed by addition of BBr3 (0.20 ml, 2.14 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.065 g, 33%). 1H NMR (DMSO-d6, 400 MHz): δ 5.60 (s, 2H), 6.74 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.37-7.45 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.17 (br s, 1H) and 9.55 (s, 1H). MS ES+ (362.99), HPLC (method II) Rt=14.95 min.
Reaction SMILES: [C@H:1]1([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]4[C:25](=[O:31])[N:26]5[C@H:30]([C:23]=4[N:22]=[C:21]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[C:20]=3[C:41](OCC)=[O:42])[CH2:29][CH2:28][CH2:27]5)=[C:15]([N+:46]([O-])=O)[CH:14]=2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O>[C@H:1]1([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]3[C:19]4[C:24]5[C:25](=[O:31])[N:26]6[C@H:30]([C:23]=5[N:22]=[C:21]([CH2:32][CH2:33][C:34]5[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=5)[C:20]=4[C:41](=[O:42])[NH:46][C:15]=3[CH:14]=2)[CH2:29][CH2:28][CH2:27]6)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)N[C@@H]3CCc4ccccc43)cc1[N+](=O)[O-])C(=O)N1CCC[C@@H]21
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(N[C@@H]1CCc2ccccc21)c1ccc2c(c1)[nH]c(=O)c1c(CCc3ccc(F)cc3)nc3c(c12)C(=O)N1CCC[C@@H]31
Reaction time: 12 h

Procedure:
A solution of ethyl (9aS)-4-(4-{[(1R)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}-2-nitrophenyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate Example 53 (0.068 g, 0.11 mmol, 1 equiv) in a 1:1 mixture of ethanol and H2O (4.0 mL) was treated with sodium dithionite (0.057 g, 0.33 mmol, 3 equiv). After 12 h, the reaction was acidified with 1 N HCl to ca. pH 5. Extraction with EtOAc (3×3 mL) was followed by drying (Na2SO4), and concentration. Trituration with acetone gave 0.048 g (80%) of analytically pure title compound as a light brown solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.80 (s, 1H); low resolution MS (ES+) m/e 573 (MH+); RP-HPLC (Dynamax C-18 25 cm×4.1 mm; 50–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=11.39 min, 97% purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:16][SH:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7].[N+]([O-])(O)=O.[C:22](C1C(C)=NNC=1C)(=[NH:24])[NH2:23].C(N(CC)CC)C>CN(C)C=O>[NH:1]([CH2:2][CH2:3][CH2:4][CH:5]([CH2:16][SH:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])[C:22]([NH2:24])=[NH:23]
Reactant: Cc1n[nH]c(C)c1C(=N)N
Reactant: NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: N=C(N)NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-amino-2-mercaptomethylpentanoyl)-L-proline (2.3 g), guanyl-3,5-dimethylpyrazole nitrate (2.41 g) and triethylamine (3.36 ml) in dimethylformamide (20 ml) is stored at room temperature under a blanket of argon for sixteen hours. The solvents are removed in vacuo, the residue is dissolved in 0.1 N hydrochloric acid (10 ml) and zinc dust (500 mg) is added. The suspension is stirred at room temperature for two hours. After filtering, the filtrate is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. The column is washed with water until no more acid is eluted and 1-(5-guanidino-2-mercaptomethylpentanoyl)-L-proline is then eluted with a pyridine-acetate buffer at pH 6.5.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1>CO.[Pd]>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][O:4][C:3]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:2]=1[Br:1]
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Br)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCc2cccc(F)c2)c(Br)c1

Procedure:
A solution of (1-((2-bromo-4-nitrophenoxy)methyl)-3-fluorobenzene (3.26 g) in methanol (50 mL) with palladium on carbon (10%, 300 mg) was hydrogenated on a Parr shaker for 24 hours at 60 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure to give a white crystalline solid, which was used without further purification. LCMS ESI(+) m/z: 297 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O.[F-].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:37][C:38]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cccc(F)c1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3F)ccc2c1
Yield: 83.6 %

Procedure:
Using the procedure demonstrated in Example 9, react trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (800 mg, 1.52 mmol), 2,3-difluorobenzene boronic acid (720 mg, 4.57 mmol), cesium fluoride (2.1 g, 13.7 mmol), palladium(II)acetate (34 mg, 0.15 mmol) and tricyclohexylphosphine (64 mg, 0.23 mmol) to obtain 622 mg (84%) of the title compound: mass spectrum (ion spray) 490.4 (M+H).