Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[C:6]=1[O:23][CH3:24])=[O:4].[OH-].[Na+].O>CO>[CH3:24][O:23][C:6]1[C:7]2[N:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[O:16][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c3ccccc3n(-c3ccccc3)c2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)oc2c3ccccc3n(-c3ccccc3)c12
Yield: 45 %

Procedure:
A suspension of 13.5 g (0.042 mole) of 3-methoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic acid methyl ester in 75 ml of methanol was treated with 70.6 ml of 1.0N aqueous sodium hydroxide. The mixture was stirred at reflux for 17 hours, then added to 1.4 l of water. The insoluble material was filtered, added to 1.0 l of water, and acidified with acetic acid while cooling in an ice bath. The crude acid product was recovered by filtration. The original filtrate from the reaction mixture and 1.4 l of water was also cooled in ice and acidified with acetic acid. The crude product obtained was filtered and combined with the earlier crop. The combined crude products were stirred in 400 ml of water, filtered, and recrystallized from methanol. There are obtained 5.8 g (45% yield) of analytically pure acid, mp 154°-155° C.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1.[C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)([OH:27])[CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Brc1cccc(I)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cccc(Br)c2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 7.6 mL, 19.0 mmol) was added over 10 min to a solution of 1-bromo-3-iodobenzene (5.37 g, 19.0 mmol) in THF (100 mL) at −78° C. After 15 min, a solution of 1-boc-3-piperidone (3.44 g, 17.3 mmol) in THF (10 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then warmed to 0° C. and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was allowed to warm to ambient temperature and partitioned between ethyl acetate (400 mL) and water (150 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless gum (1.99 g, 33%). 1H NMR (CDCl3, 300 MHz): 7.70-7.67 (m, 1H); 7.46-7.40 (m, 2H); 7.24-7.20 (m, 1H); 4.15-3.88 (m, 2H); 3.21-3.08 (m, 1H); 2.93-2.79 (m, 1H); 2.03-1.82 (m, 2H); 1.75-1.51 (m, 2H); 1.48 (s, 9H). LCMS (Method B): RT=3.88 min, M-[Boc-18]+238.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[F:22])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:23]>CO.C1(OC)C=CC=CC=1.C(OCC)C>[ClH:23].[ClH:23].[ClH:23].[F:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2F)CC1
Agent: Cl
Solvent: COc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: Fc1cnccc1CCN1CCNCC1
Reaction time: 1 h
Yield: 84 %

Procedure:
1-Boc-4-[2-(3-fluoropyridin-4-yl)ethyl]piperazine (6.0 g, 19.4 mmol) was dissolved in methanol (20 mL) and anisole (6 mL). To this solution, concentrated hydrochloric acid (15 mL) was added and the mixture stirred for 1 h. The solvents were removed under vacuum to provide a yellow solid. The residue was suspended in diethyl ether and sonicated for 1 h. The product was recovered by vacuum filtration, and the solid dried under vacuum to provide 1-[2-(3-fluoropyridin-4-yl)ethyl]piperazine trihydrochloride (5.2 g, 84%) as an off white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[CH:25][CH2:26][O:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:28][O:27][CH2:26][CH:25]=[CH:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:29]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=CCOC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
The product (220) and KOH (1.0 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. After the filtration, the obtained brown solid is purified by HPLC to give pure product (221) as white solid (200 mg, 62%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(C(C)C)cc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccc(C(C)C)cc1
Yield: 91.4 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (15.8 g), which is the product of Reference example 5(h), and palladium on carbon (5%, 1.60 g) and the reaction mixture was treated to afford the title compound (13.5 g) as a syrup.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.C([O:17][CH:18](O)[C:19]([F:22])([F:21])[F:20])C.C(O)(=O)C>C1C=CC=CC=1>[CH3:7][O:6][C:4]([CH:3]1[CH:18]([C:19]([F:22])([F:21])[F:20])[O:17][CH:2]=[N:1]1)=[O:5]
Reactant: CCOC(O)C(F)(F)F
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1N=COC1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of methyl isocyanoacetate (4.55 ml) and triethylamine (7.0 ml) in benzene (45 ml) was added trifluoroacetaldehyde ethyl hemiacetal (8 ml) at 0° C. The mixture was stirred at room temperature for an hour and then heated with reflux for 2 hours. The resulting mixture was neutrized with acetic acid, evaporated, diluted with ethyl acetate and washed successively with water (2 times), 10% aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was distilled (60° C. /4 mmHg) to give 4-methoxycarbonyl-5-trifluoromethyl-2-oxazoline (5 g).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:6]=2[CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.[Zn]>[NH2:21][C:18]1[CH:19]=[CH:20][C:5]([S:4][CH:1]2[CH2:3][CH2:2]2)=[C:6]([CH:17]=1)[CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1SC1CC1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CN(Cc1cc(N)ccc1SC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
Zinc (1.063 g, 16.25 mmol) was added to a mixture of Intermediate 6B (1 g, 2.95 mmol) and ammonium chloride (3.16 g, 59.1 mmol) in ethanol (10 mL). The mixture was stirred for 3 h at rt and concentrated. Na2CO3 (sat'd, 50 mL) and EtOAc (50 mL) was added and stirred for 1 h. The phases were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 30 min using a 40 g silica gel cartridge) to yield Intermediate 6C (600 mg, 1.945 mmol, 65.8% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.35 (1H, d, J=8.35 Hz), 6.58 (1H, dd, J=8.13, 2.42 Hz), 6.52 (1H, d, J=30.32 Hz), 4.45-4.61 (2H, m), 3.68 (2H, br. s.), 2.75-2.91 (3H, m), 2.03-2.15 (1H, m), 1.41-1.55 (9H, m), 0.83-0.97 (2H, m), 0.64 (2H, q, J=4.54 Hz).
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)[CH3:8])(C)(C)C.C(O)(=O)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C([BH3-])#N.[Na+]>C(O)C>[CH3:8][NH:7][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:29]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: CN1CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
In 2 mL of ethanol, 40 mg (0.07 mmol) of (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester was dissolved, and 15 μL of acetic acid and 20 mg (0.20 mmol) of 1-methylpiperazine were added thereto, and the mixture solution was stirred at room temperature for 30 minutes. To the reaction solution, 10 mg (0.26 mmol) of sodium cyanoborohydride was further added and the resulting solution was stirred at room temperature for one hour. The reaction solution was concentrated and partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, concentrated under reduced pressure and purified by a silica gel column (ethyl acetate:methanol=4:1). The obtained intermediate was dissolved in 1 mL of trifluoroacetic acid and stirred for one hour. The reaction solution was concentrated and partitioned between a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution, concentrated under reduced pressure, and purified by trituration with ethyl acetate to obtain 27.4 mg (70%) of a target product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]=[O:12].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[O:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=1)[CH3:10]
Reactant: C=O
Reactant: CN(C)CCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CCc1ccc(CO)o1

Procedure:
N,N-Dimethyl-2-furanethanamine (9.8 g), 30% aqueous formaldehyde (17.5 g) and glacial acetic acid (18 ml) were heated at 70° for 5 hr. The reaction was cooled, basified with sodium hydroxide and extracted with ether. The organic extracts were distilled to give an oil b.p. 90°-100° (0.5 mm). Found: C, 64.0; H, 8.9; N, 8.0. C9H15NO2 requires: C, 63.9; H, 8.9; N, 8.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[NH:10])=[CH:4][CH:3]=1.Cl[C:20](=[CH2:23])[C:21]#[N:22].C(N(CC)C(C)C)(C)C.N#N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:23][CH:20]([C:21]#[N:22])[N:10]=[C:9]2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Part A: A magnetically stirred mixture of N-(4-chlorophenyl)-2,4-dichlorobenzenecarboxamidine (10.0 gram, 0.033 mol), 2-chloroacrylonitrile (5.7 gram, 0.065 mol) and N,N-diisopropylethylamine (DIPEA) (12.5 ml, 0.069 mol) in tetrahydrofuran (150 ml) is heated at reflux temperature for 40 hours (N2 atmosphere). After cooling to room temperature the mixture is concentrated in vacuo. The residue is dissolved in a mixture of dichloromethane and water (200 ml/200 ml). The dichloromethane layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallised from ethanol/water to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4,5-dihydro-1H-imidazole-4-carbonitrile (11.23 gram, 97% yield). 1H-NMR (400 MHz, CDCl3): δ 4.28 (dd, J=10 and 8 Hz, 1H), 4.36 (t, J=10 Hz, 1H), 5.07 (dd, J=10 and 8 Hz, 1H), 6.68 (br d, J=8 Hz, 2H), 7.16 (br d, J=8 Hz, 2H), 7.32–7.36 (m, 2H), 7.45 (d, J=8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[CH2:10][O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH:22][CH:23]=[O:24])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd].O>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH:22][CH:23]=[O:24])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/CON=C(C(=O)O)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCON=C(C(=O)O)c1csc(NC=O)n1
Reaction time: 4 h
Yield: 22.4 %

Procedure:
To a solution of 2-(trans-3-tert-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (8.0 g) in ethyl acetate (60 ml) and ethanol (60 ml) was added 10% palladium on carbon (4.0 g) moistened in water (3 ml) in a stream of nitrogen atmosphere, followed by subjecting to catalytic reduction under atmospheric pressure for 4 hours. After the catalyst was removed by filtration, the filtrate was evaporated. To the residue were added water and ethyl acetate, followed by adjusting to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated aqueous layer was washed with ethyl acetate, and thereto was added ethyl acetate, followed by adjusting to pH 2.0 with 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was crystallized from n-hexane and collected by filtration to obtain 2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.80 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[F:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][C@H:38]2[CH2:43][NH:42][CH2:41][CH2:40][NH:39]2)[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][C@@H:38]2[NH:39][CH2:40][CH2:41][N:42]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:43]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Fc1cccc(CC[C@H]2CNCCN2)c1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Product: Fc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)c1
Yield: 52.9 %

Procedure:
Following a method similar as described in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to formed the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine and then (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.62 g, 3.0 mmol), followed by two chromatographic purifications, the first with a pre-packed silica gel column, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane); and the second with a pre-packed cation exchange column, loading with methanol, and then eluting the product with increasing concentrations of 2M ammonia in methanol, in dichloromethane gives the title compound (0.754 g): mass spectrum (APCI+, m/e): 476 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.45 (s, 1H), 7.33–7.23 (m, 1H), 7.05–6.80 (m, 6H), 6.74–6.68 (m, 1H), 4.06–3.80 (br. m, 2.94–2.76 (m, 2H), 2.74–2.52 (m, 5H), 2.35 (br. s, 1H), 1.67–1.49 (m, 2H).
Reaction SMILES: CC1C=CC(S([NH:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])(=O)=O)=CC=1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[F:22][C:13]1[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]([F:18])=[CH:17][C:12]=1[NH2:11]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(F)c([N+](=O)[O-])cc2F)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 120 h
Yield: 95.5 %

Procedure:
To a stirred mixture of 12.2 g (0.0370 mole) of N-(4-methylphenylsulfonyl)-2,5-difluoro-4-nitroaniline in 20 ml of water was added 70 ml of concentrated sulfuric acid. This mixture was heated at 90° C. for 15 minutes and then was allowed to cool and stir at room temperature for five days. The reaction mixture was poured into ice-water, and the aqueous mixture was neutralized with concentrated ammonium hydroxide. The resulting solid was collected by filtration. The filter cake was washed with water and was dried under reduced pressure to yield 6.15 g of 2,5-difluoro-4-nitroaniline. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[CH3:17])(OC(C)(C)C)=O.Cl>O1CCOCC1>[CH:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:17])[CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1CCN[C@@H](C)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To crude (S)-1-Boc-2-methyl-4-isopropylpiperazine in 1,4-dioxane (10 mL) was added HCl (5 mL of a 4M solution in 1,4-dioxane). The reaction mixture was stirred at room temperature for 28 h then concentrated. The resulting solid was suspended in diethyl ether, concentrated and dried on high vacuum for 1 d. The resulting solid was taken up in aq. 2N NaOH and the solution extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the free base of the product which was used without further purification. LCMS-ESI+: calc'd for C8H18N2 (M+H+): 143.1; Found: 143.7 (M+H+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=O)=O.O>C(O)(=O)C.Cl>[SH:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)cc1S

Procedure:
A stirred solution of 3-chlorosulfonyl-4-methoxybenzoic acid (58 g; that is prepared as described in Reference Example 44) in glacial acetic acid (250 mL) at 40° C. is treated during 15 minutes with a solution of stannous chloride (107 g) in concentrated hydrochloric acid. The mixture is heated at reflux for 2 hours and the hot mixture is then poured into water (2 L) with vigorous stirring. The resulting solid is filtered off and dried, to give crude 3-mercapto-4-methoxybenzoic acid (34 g).
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[OH:8][C@H:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:10][N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[CH:23][CH:22]=1)C(=O)OC(C)(C)C>>[ClH:7].[ClH:7].[OH:8][C@H:9]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:10][NH:11][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)c2ccccn2)cc1)C[C@H](O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CCNC[C@H](O)c2ccccc2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4N hydrogen chloride-ethyl acetate solution (10 ml) was added to 10 ml of an ethanolic solution of 458 mg of tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-pyridinecarbonyl)amino]phenyl]ethyl]carbamate. The reaction solution was stirred at room temperature for three hours, and the solvent was then evaporated in vacuo. The obtained crude crystals were recrystallized from methanol-ethanol-ethyl acetate to give 289 mg of (R)-4′-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]-2-pyridinecarboxanilide dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:5]=[C:4]([OH:15])[CH:3]=1.O[C:17]([C:20]1[CH2:25][CH:24]=[C:23]([O:26][CH3:27])[CH2:22][CH:21]=1)([CH3:19])[CH3:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:27][O:26][C:23]12[CH2:22][CH:21]([C:20](=[C:17]([CH3:18])[CH3:19])[CH2:25][CH2:24]1)[C:3]1=[C:4]([OH:15])[CH:5]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:7]=[C:2]1[O:1]2
Reactant: COC1=CCC(C(C)(C)O)=CC1
Reactant: COCCCC(C)c1cc(O)cc(O)c1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCCCC(C)c1cc(O)c2c(c1)OC1(OC)CCC(=C(C)C)C2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.05 g. of 1,3-dihydroxy-5-(5-methoxy-2-pentyl)- benzene and 1.06 g. (6 mmoles) of 1-(2-hydroxy-2-propyl)- 4methoxy-1,4-cyclohexadiene [R.A. Archer et. al. J. Org. Chem., 42, 2277 (1977)]are dissolved in 25 ml. of abs. benzene. 0.5 ml. (3.4 mmoles) of borontrifluoride etherate are added and the mixture is stirred at room temperature for 5 hours. Further 0.40 g. (2.4 mmoles) diene are added and the mixture is stirred overnight. The solution is poured off from the precipitated gum and extracted with 3 ×10 ml. of 1 N sodium hydroxide. The benzene solution is dried, evaporated and the residue is chromatographed on a column with a 8.1 mixture of benzene: ethyl acetate. The product is a colorless resin.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([O:51][CH2:52][CH3:53])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=5)=[C:38]([O:51][CH2:52][CH3:53])[CH:37]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: CCOc1cc(N)ccc1C(O)c1cc(C)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(OCC)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 64.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.7 g), (4-amino-2-ethoxyphenyl)(4-methylpyridin-2-yl)methanol (0.45 g) and 1-hydroxybenzotriazole (0.34 g) were dissolved in N,N-dimethylformamide (15 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g), triethylamine (0.61 ml) and 4-dimethylaminopyridine (catalytic amout) at room temperature under ice-cooling, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.68 g) as colorless amorphous.