Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:5][C@@H:4]1[CH2:6]O.NO.S(Cl)(Cl)=O.[OH-].[Na+]>C(OC(C)C)(=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([C@@:3]23[CH2:5][C@@H:4]2[CH2:6][NH:1][CH2:2]3)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: NC[C@]1(c2ccc(Cl)c(Cl)c2)C[C@@H]1CO
Agent: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O=S(Cl)Cl
Product: Clc1ccc([C@]23CNC[C@H]2C3)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
Title compound 487 (4.63 g, 18.81 mmol) was dissolved in isopropyl acetate (24.5 mL). The above crude amino alcohol solution in isopropyl acetate was slowly subsurface-added to a solution of thionyl chloride (1.61 ml, 22.06 mmol) in isopropyl acetate (17.5 mL) at ambient temperature over 2 hours. After aging additional 1-5 h, 5.0 N sodium hydroxide (16.4 mL) was added over 1 hour while the batch temperature was maintained at <30° C. with external cooling. The two-phase reaction mixture was stirred for 1 hour at ambient temperature to allow pH to stabilize (usually to 8.5-9.0) with sodium hydroxide pH titration. The organic phase was washed with 40% aqueous isopropanol (21 mL) followed by water (10.5 mL). Concentrated HCl (1.69 mL) was added. The aqueous isopropyl acetate was azeotropically concentrated in vacuum to ca. 24.5 mL. Methylcyclohexane (17.5 mL) was added dropwise over 2 hours. Compound did not crystallize out. The pH was adjusted to neutral and organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by ISCO (EtOAc to 60% MeOH in EtOAc, 40 g silica column) to afford title compound 488 (1.8 g, 42%) as a thick yellow oil. 1H NMR (CD3OD) δ (ppm): 7.44 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.4, 2.2 Hz, 1H), 3.31-3.30 (m, 2H), 3.23-3.17 (m, 2H), 1.97-1.93 (m, 1H), 1.20-1.04 (m, 2H). MS (m/z)=228.15 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at about 0° C. After 10 minutes, (S)-methyl 2-amino-3-methylbutanoate hydrochloride (0.720, 8.64 mmol) and Et3N (1.2 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.440 g; Yield: 85.9%; 1H NMR (300 MHz, CDCl3): δ 5.62 (d, 1H, J=8.4 Hz), 4.77 (d, 111, J=8.4 Hz), 4.70-4.60 (m, 1H), 4.89-4.71 (m, 1H), 3.72 (s, 3H), 2.46-2.21 (m, 2H), 2.18-1.99 (m, 1H), 1.70-1.50 (m, 1H), 1.42 (s, 9H), 1.31 (s, 3H), 0.94-0.90 (s, 9H); Mass: The related mass peak was not observed; IR (KBr, cm−1): 3345, 3314, 2960, 1753, 1690, 1664, 1529, 1456, 1366, 1271, 1172, 1049, 1028, 986, 873.
Reaction SMILES: BrBr.[CH3:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[C:5]=1[CH:12]=[O:13].[Cl-].[NH4+].O1C[CH2:19][CH2:18][CH2:17]1>>[CH3:3][C:4]1[CH:5]([CH:12]([OH:13])/[CH:17]=[CH:18]\[CH3:19])[C:6]([CH3:10])([CH3:11])[CH2:7][CH2:8][CH:9]=1
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: C1CCOC1
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Product: C/C=C\C(O)C1C(C)=CCCC1(C)C
Reaction time: 1 h

Procedure:
When the addition of the bromine derivative was completed, the mixture was refluxed for 45 minutes; then cooled to -10°, at which temperature 110 g. of β-cyclocitral dissolved in 410 ml. of tetrahydrofuran were introduced dropwise within 45 minutes. Stirring was continued for 1 hour at -5°, then overnight at room temperature under nitrogen. The reaction mixture was poured into a suspension of 0.5 kg. of crushed ice in 1.5 l. of a saturated ammonium chloride solution. It was extracted 3 times with ether, the extracts were combined and washed 3 times with water and then with a concentrated NaCl solution. After drying over anhydrous Na2SO4 the volatile portions were evaporated and the residue distilled. There were thus obtained 91 g. (65.2%) of cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene. B.p. 64°-68°/0.01 Torr. By replacing in the above procedure the β-cyclocitral by its analogue α, cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]2-cyclohexene was obtained. 1700 ml. of absolute pyridine were cooled to 0°-5° and 154 g. of CrO3 were added portionwise within 30 minutes while stirring vigorously. Stirring was continued for 10 minutes at 5° and then 95 g. of cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene dissolved in 300 ml. of pyridine were added dropwise within 20 minutes, while maintaining the temperature below 10°. When the addition was completed stirring was continued for 20 minutes, then the mixture was allowed to stand for 15 hours at room temperature. The reaction mixture was diluted with 5 l. of water and extracted with 6 portions of 800 ml. of ether each. The extracts were combined and successively washed with: 4 portions of water, 8 portions of 10% HCl at 0°, 3 portions of water, 2 portions of 5% Na2CO3, 2 portions of water. Moreover, each washing portion was extracted with ether before being discarded, and the extract was added to the main extract after washing. The ethereal solution was dried over anhydrous Na2SO4, concentrated in vacuo and the residue distilled. There were thus obtained 57 g. of a liquid fraction, b.p. 75°-85°/0.001 Torr, which fraction was redistilled by means of a spinning band column and yielded 24 g. (25.5%) of pure trans-2,6,6-trimethyl-1-crotonoyl-1-cyclohexene.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:7][C:6]=1[CH2:29][NH:30][CH2:31][CH2:32][CH3:33]>C(O)C>[NH2:1][C:2]1[N:30]([CH2:31][CH2:32][CH3:33])[CH2:29][C:6]2[C:5](=[CH:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:7]=2)[N:4]=1
Reactant: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CCCN1Cc2cc(-c3ccccc3CCNS(=O)(=O)c3ccccc3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanogen bromide (0.00034 mol) was added to a mixture of N-[2-(4′-amino-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide (0.00031 mol) in ethanol (1 mL) in a Fast-tube, and then the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by high-performance liquid chromatography. The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]([C:14]([F:17])([F:16])[F:15])[OH:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:20][C:21]1[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]([O:13][C:24]3[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=3)[C:14]([F:17])([F:15])[F:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccnc2cc(Cl)ccc12)C(F)(F)F
Reactant: CS(=O)(=O)c1ncc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cnc(OC(c2ccnc3cc(Cl)ccc23)C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
7-Chloro-α-(trifluoromethyl)-4-quinolinemethanol (0.25 g, 0.96 mmol) was dissolved in 5 ml of tetrahydrofuran in a oven dried, nitrogen swept 25 ml round bottomed flask and the resulting solution was cooled to 0° C. under nitrogen. With stirring, NaH (0.042 g, 1.1 mmol, 60% dispersion in mineral oil) was added all at once. After 15 minutes, 5-fluoro-2-(methylsulfonyl) pyrimidine (0.17 g, 0.96 mmol) was added dropwise via syringe as a solution in tetrahydrofuran (2.5 ml) over 5 minutes. An additional 2 ml of tetrahydrofuran was used to rinse the flask containing the sulfone and the syringe. The milky solution was allowed to warm to room temperature and stir for 15 hours by which time thin layer chromatography (hexanes:ethyl acetate/1:1) indicated complete consumption of the starting materials. The reaction mixture was partitioned between water and ethyl acetate, the layers separated and the aqueous layer extracted with an additional portion of ethyl acetate. The combined organic layers were dried (MgSO4) filtered and concentrated to dryness. Purification by flash silica gel chromatography (hexanes:ethyl acetate/2:1) provided 7-chloro-4-[2,2,2-trifluoro-1-[(5-fluoro-2-pyrimidinyl) oxy]ethyl]quinoline (0.32 g, 94%) as a white solid. An analytical sample was prepared by recrystallization from hexane. (mp 92° C.).
Reaction SMILES: C[Si](C)(C)[O-].[K+].C([O:9][C:10](=[O:45])[CH2:11][N:12]([CH3:44])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[O:34])=[CH:28][CH:27]=3)[C:21]2=[O:43])=[CH:15][CH:14]=1)C.Cl>O1CCCC1.C(OCC)C>[CH3:44][N:12]([CH2:11][C:10]([OH:45])=[O:9])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[O:34])=[CH:28][CH:27]=3)[C:21]2=[O:43])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CN(C)c1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(-c2cccn(Cc3ccc(N(C)CC(=O)O)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium trimethylsilanolate (0.035 g, 0.25 mmol) was added to a solution of [methyl-(4-{2-oxo-3-[4-(3-o-tolyl-ureido)phenyl]-2H-pyridin-1-ylmethyl}phenyl)amino]acetic acid ethyl ester (0.90 g, 0.17 mmol) in tetrahydrofuran (5 mL) and the mixture stirred at room temperature for 2 hours. A solution of hydrochloric acid in diethyl ether (1 M, 1 mL) was added and solvent evaporated. The residue was triturated with diethyl ether, filtered and dried to give the title compound as a solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C1COCC1.Cl[C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:15])=[CH:12][C:11]=1[N+:24]([O-:26])=[O:25]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:13]1[CH:22]=[CH:23][C:10]([NH:3][CH2:1][CH3:2])=[C:11]([N+:24]([O-:26])=[O:25])[CH:12]=1
Reactant: CCN
Reactant: CN(C)CCNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCNc1ccc(C(=O)NCCN(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 73 %

Procedure:
To 2.0 M solution of ethylamine in THF (8 mL, 16 mmol) slowly added 4-chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide (0.40 g, 1.5 mmol). After heating at 65° C. for 16 h, the reaction mixture was cooled, concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to afford the title compound (0.30 g, 73%) as a yellow solid. 1H-NMR (CD30D): δ 8.75 (1H, d), 8.32 (1H, br s), 7.98 (1H, dd), 7.08 (1H, d), 3.58-3.64 (3H, m), 3.43-3.51 (2H, m), 2.94 (2H, br t), 2.62 (6H, s), 1.35 (3H, t).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[Mg]Br>C1COCC1>[OH:2][CH:1]([C:19]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)c2cnccc2-c2cccc(C#N)c2)c(C)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 2,4,6-trimethylphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2,4,6-trimethyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [NH2:1][C:2]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO.O>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])[C:3]=1[C:7]#[N:8]
Reactant: CCCN(CCC)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: O
Solvent: CCO
Product: CCCN(CCC)c1nsc(N)c1C#N
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 9.6 g of 3-amino-2-cyano-3-(dipropylamino)propenethioamide in 50 ml of ethanol was heated to reflux temperature and 5 ml of 30% hydrogen peroxide (1.4 g H2O2) were added at such a rate as to maintain reflux. After complete addition the reaction mixture was heated under reflux during 10 minutes. To the reaction mixture was added 40 ml of water, which was then allowed to cool to ambient temperature. The solid precipitate was collected by filtration, and recrystallized from acetonitrile-water, to give 7.0 g of 5-amino-4-cyano-3-(dipropylamino)isothiazole; m.p. 136°-138°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][C:9]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)CCC.I[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:34]([C:31]1[CH:32]=[C:33]([C:6]2[O:10][C:9]([P:11]([O:12][CH2:13][CH3:14])(=[O:15])[O:16][CH2:17][CH3:18])=[CH:8][CH:7]=2)[CH:28]=[C:29]([N+:37]([O-:39])=[O:38])[CH:30]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc(I)c([N+](=O)[O-])c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)o1
Temperature: 80 °C

Procedure:
A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1 mmol), 1-iodo-2,4-dinitrobenzene (1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 mmol) in 6 mL of dioxane was heated at 80° C. for 16 h. Evaporation of solvent and chromatography provided diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate as solid foam.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.C(#N)C>[Cl:3][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([CH3:17])=[CH:9][N:8]=1
Reactant: Cc1cnc(CO)c(C)c1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cnc(CCl)c(C)c1[N+](=O)[O-]
Temperature: 12.5 °C

Procedure:
8.0 ml (0.11 mole) of thionyl chloride in 20.0 ml of methylenechloride was added to a solution of 20.0 gms 2-hydroxymethyl-3,5dimethyl-4-nitropyridine, of formula-II obtained in step-(a), at temperature of 10-15° C. over a period of 1 hr. The reaction is maintained at 10-15° C. for further 30 min. Aqueous 10% solution of sodium carbonate was slowly added to the reaction mixture at 10-15° C. and pH adjusted to 8.0 to 8.5. The organic base (compound) is over anhydrous sodium sulfate and solvent was removed under vacuum to obtain crude product. (purity 85%) Pure compound is isolated by re-crystallization from acetonitrile.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH2:25]O)[CH2:20]2.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH:19]([CH2:25][N:31]1[C:30](=[O:32])[C:29]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]3[C:27]1=[O:37])[CH2:20]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cccc2c1CCC(CO)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc2c1CCC(CN1C(=O)c3ccccc3C1=O)C2
Reaction time: 24 h
Yield: 55.3 %

Procedure:
A solution of diethyl azodicarboxylate (871 mg) in tetrahydrofuran (4 ml) was added slowly to a stirred solution of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methanol (961 mg), phthalimide (736 mg), and triphenylphosphine (1.31 g) in tetrahydrofuran (10 ml) at room temperature and the resulting mixture was stirred at the same temperature for 24 hours. The reactIon mixture was evaporated in vacuo and the residue was chromatographed (toluene) over silica gel. The eluate was evaporated in vacuo and the residue was triturated with n-hexane to afford N-[(1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl]phthalimide (888 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:34]O)[CH2:33][CH2:32]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][C:31]1([CH2:34][O:24][C:23]([C:18]2([C:20]([O:22][CH2:30][C:31]3([CH3:34])[CH2:33][CH2:32]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:33][CH2:32]1
Reactant: CC1(CO)CC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1(C)CC1)(C(=O)OCC1(C)CC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclopropyl-methanol according to the procedure of Example 30 as a white solid (HCl salt); 1H NMR (CDCl3) δ 0.39 (m, 4H), 0.52 (m, 4H), 1.10, (s, 6H), 1.32 (d, J=6.5 Hz, 3H), 2.80 (m, 1H), 3.19 (m, 2H), 3.48 (m, 2H), 4.10 (s, 4H), 5.50 (bd, 1H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1763 cm-1 (C=O); MS (ES) m/z 558 (MH+); [α]D25 -25° (c, 1.0, CHCl3). Anal. Calcd. for C30H36ClNO7 ·HCl: C, 60.61; H, 6.10; N, 2.36; Cl, 11.94. Found: C, 60.02; H, 6.58; N, 2.17; Cl, 11.20.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.Cl.[NH2:17][CH2:18][C:19]([NH2:21])=[O:20].[OH-].[K+]>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:17][CH2:18][C:19]([NH2:21])=[O:20]
Reactant: NCC(N)=O
Reactant: CN(C)CCCOc1ccccc1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=NCC(N)=O
Yield: 93.9 %

Procedure:
Fifteen grams of 2-(3-dimethylaminopropoxy)benzaldehyde and 8.1 g of glycinamide, hydrochloride are reacted in 300 ml of ethanol in the presence of 4.8 g of 85% potassium hydroxide as described in Example 1 to give 20 g of a crude semi-solid product. The crude product is triturated with 100 ml of isopropyl ether and cooled to yield 17.9 g of solid; melting point 71°-73° C. (sintering at 60° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:22][C:21]([CH3:23])=[N:20][N:19]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][C:21]1[NH:22][C:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:12][CH:13]=2)=[N:19][N:20]=1
Reactant: Cc1nnc(Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(Cc2ccc(OCCN)cc2)[nH]1
Yield: 45.3 %

Procedure:
To a solution of tert-butyl-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethyl}-carbamate (380 mg, 1.14 mmol) in methylene chloride (10 ml) was added trifluoroacetic acid (1.7 ml). The resulting mixture was stirred for about thirty minutes and was then concentrated in vacuo. The resulting crude oil was then dissolved in ethyl acetate and brought to pH 10 with aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 120 mg (45% yield) of the amine product. LRMS ([M+H]+)=233.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH:5]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)Nc1ccc(N2CCN(c3cc([N+](=O)[O-])ccn3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N2CCN(c3cc(N)ccn3)CC2)cc1
Yield: 59.7 %

Procedure:
A solution of N-{4-[4-(4-nitropyrid-2-yl)piperazin-1-yl]phenyl}methanesulphonamide (100 mg) in methanol (40 ml) was hydrogenated at 3 bar and 22° C. in the presence of 5% palladium on carbon (20 mg) until no more hydrogen was taken up. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallised from aqueous methanol to give the title compound (55 mg), m.p. 225°-227° C. Found: C,55.50; H,6.04; N,19.66. C16H21N5O2S requires: C,55.31; H,6.09; N,20.16%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 2.5 °C
Yield: 100 %

Procedure:
A solution of 4-trifluoromethoxyaniline (XII) (14.66 mL, 108 mmol) in dry tetrahydrofuran (THF; 120 mL) was added, dropwise, to a cold (0-5° C.) stirred suspension of cyanuric chloride (II) (20.0 g, 108 mmol) and potassium carbonate (15 g, 108 mmol) in dry THF (400 mL). The reaction mixture was stirred for 3 h while slowly warming to ambient temperature. After stirring for 14 h at ambient temperature, the reaction mixture was diluted with ethyl acetate (400 mL) and then acidified with 1 N aqueous hydrochloric acid. The organic phase was separated, rinsed successively with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue, an off white solid, was recrystallized from hot hexanes to afford (4,6-dichloro-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIII) (35.1 g, 99% yield): m.p. 119-122° C.; 1H NMR (CDCl3) δ 7.62 (d, J=3.3 Hz, 2H), 7.58 (d, J=2.2 Hz, 2H); ESI/MS 325 (M+H), 323 (M−H); Anal. Calcd. For C10H5Cl2F3N4O: C, 36.95; H, 1.55; N, 17.53. Found: C, 36.80; H, 1.53; N, 16.98.