Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]OC(OC)OC.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:17]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:25]=[N:16][C:14]2=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: NC(=O)C1(NCC2CCCCC2)CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1N=CN(CC2CCCCC2)C12CCN(Cc1ccccc1)CC2
Yield: 76.5 %

Procedure:
A stirred mixture of 1-benzyl-4-(cyclohexylmethylamino)piperidine-4-carboxamide (8 g, 24.32 mmol), 8 ml of trimethoxymethane, 2 ml of acetic acid and 65 ml of toluene was refluxed for 48 hours. The mixture was concentrated. The residue was dissolved in water, made alkaline with aqueous ammonia, and the mixture was extracted with chloroform. The extracts were dried (MgSO4) and concentrated. Recrystallization of the residue from ethyl acetate gave 6.3 g (76.5%) of crystals, mp 117°-118° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:13][NH2:14])(=[O:12])[CH3:11]>C(O)C>[C:10]([NH:13][NH:14][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9])(=[O:12])[CH3:11]
Reactant: S=C=Nc1ccccc1
Reactant: CC(=O)NN
Solvent: CCO
Product: CC(=O)NNC(=S)Nc1ccccc1

Procedure:
By reacting 27 g of phenyl isothiocyanate and 15 g of acetylhydrazine in ethanol at room temperature, 1-acetyl-4-phenylthiosemicarbazide was formed, which was collected by filtration and refluxed in ethanol in the presence of sodium ethylate to provide 3-mercapto-5-methyl-4-phenyl-1,2,4-triazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH2:9][Br:18])=[CH:6][C:7]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(Br)c(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)nc(C)c1Br
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 3-bromo-2,4,6-trimethylpyridine (15.6 g), NBS (13.9 g) and benzoyl peroxide (567 mg) was heated under reflux in a carbon tetrachloride solvent (300 mL) for two hours. The reaction mixture was cooled to room temperature and then filtered, and the filtration residue was washed with carbon tetrachloride. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (8.00 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH3:14][O-:15].[Na+]>CO>[CH:8]([NH:7][C:5](=[O:6])[C:4]1[CH:11]=[CH:12][N:13]=[C:2]([O:15][CH3:14])[CH:3]=1)([CH3:10])[CH3:9]
Reactant: C[O-]
Reactant: CC(C)NC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)NC(C)C)ccn1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
To a stirred solution of 19.44 g 2-chloro-N-isopropyl-isonicotinamide (97.86 mmol) as obtainable from example 12, in 165 mL methanol were added 27.82 g NaOMe (489.3 mmol, 5.0 eq) in four equal portions over 60 min. The solution was then heated to 80° C. and the reaction was monitored by HPLC. After 23 h (<2% area starting material 2-chloro-N-isopropyl-isonicotinamide), the mixture was cooled to room temperature and quenched by addition of 200 mL saturated aqueous NH4Cl. The product was extracted three times with 150 mL, in total 450 mL dichloromethane. The combined organic phases were dried over 40 g Na2SO4 (30 min) and filtered. The filter cake was washed with 80 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 22 mbar), the crude product (15.856 g, 83% w/w, HPLC purity 93.7% area) was obtained as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])O.[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: O=C1C=CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
In 300 ml of dichloromethane was dissolved 10 g of 4-hydroxy-2-cyclopentenone. To the solution were added 25.7 g of dihydropyran and 0.5 g of p-toluenesulfonic acid, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was poured into an aqueous solution of sodium hydrogencarbonate. The organic layer was separated. The aqueous layer was further extracted with dichloromethane. The organic layers were combined, washed with a saturated aqueous saline solution, then dried (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane--ethyl acetate (7:3) to give 17.4 g of 4-(2-tetrahydropyranyl)oxy-2-cyclopentenone as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N+:8]([O-])[CH:7]=[CH:6]2.C(OC(=O)C)(=[O:16])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:16])[NH:8][CH:7]=[CH:6]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c[n+]([O-])ccc2c1
Product: COc1ccc2c(=O)[nH]ccc2c1
Temperature: 100 °C

Procedure:
5.2 g of 6-Methoxy-isoquinoline 2-oxide (58) was heated in 120 mL of acetic anhydride at 100° C. for 3 h. The reaction mixture was evaporated and the residue was taken up in 2 M NaOH and heated at 100° C. for another hour. The mixture was allowed to cool down and the pH was adjusted by addition of 2N HCl to 6. The aqueous layer was extracted several times with methyl-tert.butyl ether, the combined organic layer was dried over sodium sulphate and evaporated. The crude material was purified by silica gel chromatography to yield 3.26 g of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:14]3)[NH:12][C:11](=[O:28])[C:10]=2[CH:29]=1.[OH-].[Na+]>O.O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][C:13]3([NH:12][C:11](=[O:28])[C:10]4[CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=[CH:8][C:9]=4[O:27]3)[CH2:14]2)=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2

Procedure:
A solution of (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (300 mg, 0.73 mmol) in water (2.5 ml) and dioxane (5 ml) was treated with 1 M NaOH (0.95 ml) as described in Example 30, Step A to give (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid as a white solid [LC-MS: (ES+) MH+: 397]. The obtained acrylic acid was suspended in DCM (5 ml), treated with TEA (0.15 ml, 1.1 mmol) and then with EDC (208 mg, 1.09 mmol), HOBt (147 mg, 1.09 mmol) and NH2OTHP (102 mg, 0.87 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{t-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (60 mg) as a light yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>>[O:18]1[CH2:17][CH:16]1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][CH:11]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C2CCOCC2)cc1
Product: c1cc(C2CCOCC2)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-(tetrahydropyran-4-yl)-phenol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7].Cl>CO>[Br:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:7]
Reactant: O=C(CCBr)c1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCBr)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
NaBH4 (1.5 g, 39.7 mmol) was added by portions to a solution of 3-bromo-1-(4-bromophenyl)propan-1-one (11.7 g, 40 mmol) (Preparation 5) in MeOH while keeping the temperature below 10° C. After 1 h at RT, 1N aqueous hydrochloric acid was added at 5° C. to pH=1 and the mixture was concentrated in vacuum. The residue was dissolved in water and extracted three times with DCM. The organic layer was dried over Na2SO4 and concentrated to yield 3-bromo-1-(4-bromophenyl)propan-1-ol as a yellow oil (11.1 g). 1H NMR (CDCl3): 7.47 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 4.87 (1H, br s), 3.50-3.62 (1H, m), 3.31-3.42 (1H, m), 2.35 (1H, OH, br s), 2-2.31 (2H, m).
Reaction SMILES: CO.C[O-].[Na+].[SH:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11].[CH3:16][C:17]([CH3:35])=[CH:18][CH2:19][C@H:20]1[O:22][C@@:21]1([C@@H:24]1[C@:29]2([O:31][CH2:30]2)[CH2:28][CH2:27][C@@H:26]([OH:32])[C@H:25]1[O:33][CH3:34])[CH3:23]>O>[O:22]1[CH:20]([CH2:19][CH:18]=[C:17]([CH3:35])[CH3:16])[C:21]1([CH:24]1[CH:25]([O:33][CH3:34])[CH:26]([OH:32])[CH2:27][CH2:28][C:29]1([CH2:30][S:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11])[OH:31])[CH3:23]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: OCc1ccccc1CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To an about 14% methanol solution (6 ml) of sodium methoxide were added, under ice-cooling, 2-mercaptomethylbenzylalcohol (655 mg) and fumagillol (1.00 g). The mixture was stirred for one hour at room temperature, to which was added water to suspend the reaction. The product was extracted with ethyl acetate, The extract solution was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent : ethyl acetate - hexane=2:1) to give 2-(1,2-epoxy-1,5-dimethy-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (1.43 g : yield 92%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH2:26]O)[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.S(Cl)([Cl:35])=O>>[Cl:35][CH2:26][C:24]1[NH:23][C:17]2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=[C:15]([C:6]3[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=3[F:1])[C:16]=2[CH:25]=1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(CO)[nH]c2c1=O
Reactant: O=S(Cl)Cl
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(CCl)[nH]c2c1=O

Procedure:
A mixture of Example 276 (0.50 g, 1.09 mmol) and thionyl chloride (5.0 mL, 69 mmol) was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was dried under vacuo for 1 hour to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]([NH2:6])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25](=[O:32])[CH2:26][C:27](OCC)=[O:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][C:10]2[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]([NH:6][C:27](=[O:28])[CH2:26][C:25]([C:24]([F:34])([F:33])[F:23])=[O:32])=[C:4]([F:22])[CH:3]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COC(=O)COc1ncccc1Oc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 100.5 %

Procedure:
A mixture of 0.5 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline, 0.28 g of ethyl trifluoroacetoacetate, and 10 ml of toluene was azeotropically distilled for 3 hours, while passing through molecular sieves 5A to remove ethanol. After cooling, the reaction mixture was concentrated to give 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]1[NH:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>[Pd].C(O)C>[NH2:19][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:18]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N1CCNC1C1OCCO1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(N)cc1-n1ccnc1C1OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a par bottle, 2-(2-[1,3]dioxolan-2-yl-imidazolidin-1-yl)-4-nitro-benzonitrile (8.20 g), ethanol (50 mL) and 10% Pd/C (0.50 g) were added. The reaction mixture was evacuated and charged with hydrogen 3 times. The reaction was shaken at room temperature on the par at 45 psi for 4 hours. The solid was filtered and washed with ethanol. The solvent was concentrated to give 4-amino-2-(2-[1,3]dioxolan-2-yl-imidazol-1-yl)-benzonitrile as an off white solid. 1H-NMR (DMSO-D6, 400 MHz): δ 7.52 (d, 1H), 7.40 (s, 1H), 7.03 (s, 1H), 6.68 (d, 1H), 6.60 (s, 1H), 6.45 (bs, 2H), 5.75 (s, 1H), 3.80 (bs, 2H), 3.62 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:27])=[O:26])=[CH:19][CH:20]=4)[C:15](=O)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:38][OH:39]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][C:18]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=5)(=[O:26])=[O:27])=[CH:19][CH:20]=4)[C:15](=[N:38][OH:39])[C:14]=3[CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1cccc(NS(=O)(=O)c2ccc3c(c2)C(=NO)c2cc(S(=O)(=O)Nc4cccc(O)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
The product from Example 7A (134 mg, 0.257 mmol) in pyridine (3 mL) was treated with hydroxylamine hydrochloride (20 mg, 0.283 mmol) and stirred at ambient temperature. After 3 hours, the mixture was partitioned between ethyl acetate and 1N HCl. The separated organic phase was washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate and CH2Cl2 was added to effect precipitation. The solid was collected by filtration and dried under reduced pressure to provide the title compound as a white solid (123 mg, 89% yield). 1H NMR (300 MHz, DMSO-d6) δ 13.43 (bs, 1H), 10.17-10.35 (m, 1H), 9.96-10.13 (m, 1H), 9.46 (d, 1H), 8.76 (d, 1H), 8.02-8.18 (m, 3H), 7.8-7.93 (m, 2H), 6.98 (m, 1H), 6.81 (m, 1H), 6.5-6.6 (m, 2H), 6.32-6.44 (m, 2H), 6.16-6.28 (m, 2H), 5.1 (bs, 2H); MS (ESI) 535 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[S:19][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:26]N1C(=O)CCC1=O>C(Cl)Cl>[Br:26][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([NH:10][C:11]3[C:12]4[S:19][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Solvent: ClCCl
Product: Brc1c[nH]c2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
To a solution of (1H-Indol-5-yl)-(6-phenyl-thieno[3,2-d]pyrimidin-4-yl)-amine (150 mg, 0.438 mmol) in methylene chloride was added N-bromosuccinimide (86 mg, 0.482 mmol). The reaction mixture was stirred for 2 days at room temperature and then concentrated in vacuo. The orange residue was chromatographed by preparative reverse-phase HPLC using a 200 nM acetate buffer and acetonitrile gradient to afford pure product (17% yield). RP18-HPLC RT: 6.377 minutes; API MS: 371.2 (M+1); MP: 201-203° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.COC(C1N=NC(NCC2[C:40]([C:45]3[CH:50]=[CH:49]C=CC=3)=[N:41]OC=2C)=CC=1)=O>>[CH:45]1([CH2:40][NH:41][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:50][CH2:49]1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NCC2CC2)nn1
Yield: 91 %

Procedure:
As described for example 73c, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, instead of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester, to the title compound (87 mg, 91%) which was obtained as an off white foam. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>C(#N)C>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:11]=1[C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:16])=[O:13]
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
An 0.4 g. portion of 5-bromo-2-aminopyridine was dissolved in 20 ml. of acetonitrile, and was reacted with 0.5 g. of 2-chloro-6-fluorobenzoyl isocyanate as described in Example 1. The yield was 0.5 g. of the desired product, m.p. 207°-213° C. Elemental analysis gave the following results:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2ccccc2c1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2ccccc12
Yield: 74 %

Procedure:
Naphthalene (13.62 g), Zn2+ montmorillonite (0.25 g) and CCl4 were stirred in 50 ml two-necked round-bottomed flask equipped with Dean-Stark apparatus. Fuming nitric acid (5 ml) was added dropwise into the reaction mixture. The reaction mixture was heated to reflux where upon the required amount of liberated water is collected in the Dean-Stark apparatus which usually takes 1 hr. Later on, the catalyst was filtered and the organic layer is concentrated to obtain 1-nitronaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21](O)=[C:20]([Cl:26])[C:19]=1[OH:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:20]([Cl:26])[C:19]=1[OH:27]
Reactant: CC(C)(C)OC(=O)CNCCCCO
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(OCCCCNCC(=O)OC(C)(C)C)c(Cl)c1O
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a solution of 4-tert-butoxycarbonylmethylamino-1-butanol (3 g) and known 3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (3.85 g) in THF (80 ml) were added triphenylphosphine (4.26 g) and diisopropyl azodicarboxylate (3.2 ml) under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (5.2 g, yield 83%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:18])[N:3]=1
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(Oc1nc(N)nc(-c2ccco2)c1C#N)c1ccccn1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (RS)-alpha-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), 4-aminothiophenol (8.8 g, 68 mmol) and K2CO3 (11.8 g, 85 mmol) in DMF (150 mL) was heated at 90° C. for 1.5 hours, cooled to room temperature, and then poured into H2O (450 mL) under stirring. The aqueous mixture was extracted with AcOEt (400 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give the crude product as orange crystal. The crude product was suspended in 150 mL of i-Pr2O and stirred at room temperature for 1 hour. The crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. for 3 days under reduced pressure to give purified title compound as orange crystal (18.6 g, 90%).
Reaction SMILES: [ClH:1].C1(C2C=CC([C:14]3[S:15][C:16](N)=[C:17]([C:19]4[CH:20]=[C:21]([C:26]([NH2:28])=[NH:27])[S:22][C:23]=4[S:24][CH3:25])[N:18]=3)=CC=2)CCCCC1.Br.[CH:31]1([C:37]2[CH:42]=[CH:41][C:40]([NH:43]C3SC=C(C4C=C(C(OC)=S)SC=4C)N=3)=[CH:39][CH:38]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:1].[CH:31]1([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:14]3[S:15][CH:16]=[C:17]([C:19]4[CH:20]=[C:21]([C:26]([NH2:28])=[NH:27])[S:22][C:23]=4[S:24][CH3:25])[N:18]=3)=[CH:41][CH:42]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=S)c1cc(-c2csc(Nc3ccc(C4CCCCC4)cc3)n2)c(C)s1
Reactant: CSc1sc(C(=N)N)cc1-c1nc(-c2ccc(C3CCCCC3)cc2)sc1N
Agent: Br
Agent: Cl
Product: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(C3CCCCC3)cc2)n1
Yield: 47 %

Procedure:
4-{2-(4-Cyclohexylphenyl)amino(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide (31.1 mg, 0.059 mmol) was treated as described in Example 154, step (b) to give 12.8 mg (47% yield) of 4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) δ 1.33-1.40 (m, 5H), 1.68-1.79 (m, 5H), 2.44 (m, 1H), 2.73 (s, 3H), 7.12 (s, 1H), 7.18 (d, 2H, J=8.7 Hz), 7.68 (d, 2H, J=8.7 Hz), 8.47 (s, 1H), 8.85 (bs, 2H), 9.32 (bs, 2H), 10.28 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C21H24N4S3, 428.64 (M+H), found 429.2.