Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:6](=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH2:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](O)[CH2:23]CC>>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:6](=[CH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH2:7])[CH2:2][CH2:22][CH3:23]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)c1cc([N+](=O)[O-])ccc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
210 parts of 5-nitroanthranilic acid ethyl ester, 210 parts of n-butanol and 10 parts of potassium carbonate are refluxed for half an hour. The thus formed ethanol is then distilled off over a column. Distillation is continued until the boiling point of n-butanol is reached. 450 parts of cyclohexane are then added, and after addition of 4 parts each of bleaching earth and active charcoal the hot mixture is filtered, followed by cooling to 0° C. The reaction lasts for about 4 hours. The precipitate is filtered off, washed with about 100 parts of cyclohexane and dried in vacuo at 60° C. There are obtained 222 parts of 5-nitroanthranilic acid-n-butyl ester, melting point 91°-93° C. The yield is approximately 93% of the theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:7]([C:8]2[CH:9]=[N:10][C:11]([CH3:17])=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)=[CH:6][CH2:5][NH:4][CH2:3]1.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:21][N:4]1[CH2:5][CH:6]=[C:7]([C:8]2[CH:9]=[N:10][C:11]([CH3:17])=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[C:2]([CH3:18])([CH3:1])[CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ncc(C2=CCNCC2(C)C)cc1[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(C2=CCN(C)CC2(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3′,3′,6-trimethyl-5-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine [HCl] (1.12 g, 3.50 mmol) in DCM (55 mL) were added formaldehyde (37% in water, 4.0 mL) and sodium triacetoxyborohydride (4.45 g, 21.0 mmol). The reaction mixture was allowed to stir for 2 h at rt. The mixture was quenched by the addition of sat. aq. sodium bicarbonate (40 mL). After stirring for 10 min, the aqueous solution was extracted with DCM. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 1′,3′,3′,6-tetramethyl-5-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (0.914 g, 100%). LCMS (FA): Rt=0.85 min, m/z=262.4 (M+H).
Reaction SMILES: C(C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)#N.[NH3:20]>O1CCCC1>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH2:20])=[O:4])=[CH:11]1
Reactant: N#CCOC(=O)CCCCc1c[nH]c2ccccc12
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)CCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
A solution of 5-(1H-indol-3-yl)pentanoic acid cyanomethyl ester (4.5 g, 17.5 mmol) in tetrahydrofuran (110 ml) was added to a 25 percent strength ammonia solution (80 ml) and the mixture was stirred at room temperature for 3 d. Working up of the mixture was carried out by phase separation and extraction of the aqueous phase with tetrahydrofuran (2×30 ml). The organic phases were combined, washed with saturated sodium chloride solution (50 ml), dried and concentrated. The residue was washed with water (2×10 ml) and ether (2×10 ml) and dried. The product remained as a colourless solid in a yield of 68% (2.56 g) with an m.p. of 134-139° C.
Reaction SMILES: [OH-].[K+].CC1C=CC(S([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([F:23])=[CH:16][C:15]=2[Cl:24])(=O)=O)=CC=1[N+]([O-])=O>O.O1CCOCC1>[Cl:24][C:15]1[CH:16]=[C:17]([F:23])[C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[OH:13]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc([N+](=O)[O-])c(F)cc2Cl)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Yield: 81.1 %

Procedure:
A solution of 12.84 g (0.195 mole) of potassium hydroxide in 200 mL of water was added to a vigorously stirred solution of 34.0 g (0.097 mole) of 2-chloro-4-fluoro-5-nitrophenyl 4-methyl-3-nitrophenylsulfonate in 190 mL of p-dioxane. The resultant mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was filtered and the filtrate acidified with concentrated hydrochloric acid. The acidic solution was extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure to leave a solid. The solid was washed with petroleum ether to yield 15.07 g of 2-chloro-4-fluoro-5-nitrophenol.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)[C:9](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.N1C=CC=CC=1.C(N(C(C)C)C(C)C)C.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH2:53][C:54](Cl)=[O:55])[CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:52][O:51][C:47]1[CH:46]=[C:45]([CH2:53][C:54]([C:7]2[NH:8][C:9](=[CH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[CH:12][CH:11]=3)=[O:55])[CH:44]=[C:43]([O:42][CH3:41])[C:48]=1[O:49][CH3:50]
Reactant: COc1cc(CC(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(C=C2NCCc3cc(OC)c(OC)cc32)cc1OC
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C=C2NC(C(=O)Cc3cc(OC)c(OC)c(OC)c3)=Cc3ccccc32)cc1OC

Procedure:
To a suspension of 12 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methylene]isoquinoline in 50 parts of pyridine and 5 parts of N-ethyl-N-(1-methylethyl)-2-propanamine is added a solution of 10 parts of 3,4,5-trimethoxybenzeneacetyl chloride in 45 parts of benzene. The resultant mixture is heated at the boiling point under reflux for 1 hour, then cooled and thereupon diluted with 500 parts of chloroform. The resultant solution is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and ether to give (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzeneacetyl-1-[(3,4-dimethoxyphenyl)-methylene]isoquinoline melting at 164°-170°.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12])C.[OH:16][C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22]CC(N(OC)C)=O)[CH2:18]1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH:12]=[C:14]([CH2:15][CH2:22][N:19]1[CH2:20][CH2:21][C@@H:17]([OH:16])[CH2:18]1)[NH:3][C:4]2=[O:13]
Reactant: CON(C)C(=O)CCN1CC[C@@H](O)C1
Reactant: CCN(CC)C(=O)c1cccc(F)c1C
Product: O=c1[nH]c(CCN2CC[C@@H](O)C2)cc2c(F)cccc12
Yield: 26 %

Procedure:
In the same manner as in Example 16b and using N,N-diethyl-3-fluoro-2-methylbenzamide (3.46 g) and (R)-3-(3-hydroxypyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (3.36 g), (R)-5-fluoro-3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one (1.19 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][N:5]2[C:6]3[CH:19]=[CH:18][N:17]=[CH:16][C:7]=3[C:8](=O)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.C(O)COCCO.[OH-].[K+].O.NN>CS(C)=O>[CH3:1][N:2]1[CH2:21][CH2:20][N:5]2[C:6]3[CH:19]=[CH:18][N:17]=[CH:16][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: CN1CCN2c3ccncc3C(=O)c3ccccc3C2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN2c3ccncc3Cc3ccccc3C2C1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
800 mg (0.00285 mol) 2-methyl-10-oxo-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[1,2-a]pyrido[3,4-f]azepine is added to a well-stirred suspension consisting of 4 ml di-ethylene glycol, 1 ml DMSO, 0.4 g KOH and 1 ml 80% hydrazine hydrate. The reaction is exothermic; the temperature of the reaction mixture is adjusted to 120° C and held there for 30 minutes. During this period hydrazine/water (0.8 ml) is distilled off, and the reaction temperature is then raised to 160° C for 2 hours. The reaction mixture is subsequently cooled, poured into water, and extracted with ether. After drying, and removing the solvent by evaporation, 685 mg (90%) 2-methyl-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[1,2-a]pyrido[3,4-f]azepine is obtained as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(Nc1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 48e, using 5-(4-chloro-phenyl)-6-cyclobutoxy-pyridin-3-ylamine (example 78 d) and nicotinoyl chloride hydrochloride as starting materials; MS (EI) 380.2(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH2:11][C:12]4[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[N:17][N:16](COCC[Si](C)(C)C)[C:13]=4[C:14]=3[CH:15]=2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH2:11][C:12]4[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[N:17][NH:16][C:13]=4[C:14]=3[CH:15]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(F)cc4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(F)cc4)cc2-3)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.62 g, 0.12 mmol) was dissolved in MeOH and treated with concentrated HCl (0.37 mL, 1.2 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a ]pentalene (0.26 g, 0.09 mmol) as brown solid in 75% yield.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:16](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH:12]([CH2:14][CH3:15])[CH3:13])([CH:8]([CH2:10][CH3:11])[CH3:9])=[S:7])C.Br.[CH3:30]COCC>C(O)(=O)C>[CH2:16]([N:4]([CH2:5][P:6]([CH:12]([CH2:14][CH3:15])[CH3:13])([CH:8]([CH2:10][CH3:11])[CH3:9])=[S:7])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCC(C(=O)O)N(CP(=S)(C(C)CC)C(C)CC)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCC(C)P(=S)(CN(CC)CC(=O)O)C(C)CC
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(di-sec-butylthiophosphinylmethyl)glycine (1 g., 0.0023 mole) was dissolved in 5 ml. of 30% hydrogen bromide in glacial acetic acid at 0° C. The mixture was stirred for one hour. Ether was added and the oily precipitate isolated by decanting the ether layer. The oil was washed twice with ether and then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(di-sec-butylthiophosphinylmethyl)-glycine (0.04 g., 0.001 mole) as an oil, ND25 =1.3450.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=1.Cl.[NH2:19][OH:20]>CO>[OH:20][NH:19][C:14](=[NH:15])[CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(OCC#N)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCC(=N)NO)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Add sodium acetate (5.1 g, 62 mmol) to 4-methoxyphenoxyacetonitrile (5.0 g, 31 mmol) and hydroxylamine hydrochloride (4.3 g, 62 mmol) in methanol (100 mL). Stir the resulting mixture at room temperature for 20 hours. Filter the resulting mixture through Celite, concentrate, stir in chloroform for 18 hours and filter. Concentrate the resulting solution to the title compound (5.1 g). LC-MS (m/e): 197 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A stirred solution of the t-butyl piperidin-4-ylcarbamate (1 equiv.), 4-fluoronitrobenzene (1 equiv.), and potassium carbonate (1 equiv.) in ethanol was heated at reflux temperature under nitrogen for 18 h, cooled, diluted with water and extracted with CH2Cl2. The combined extracts were dried over MgSO4 and concentrated in vacuo to give a solid residue. The solid was triturated with 20:80 ethyl acetate:hexanes and filtered. The filtercake was air-dried to afford t-butyl 1-(4-nitrophenyl)piperidin-4-ylcarbamate.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].CC1C=CC(S(O[CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of 60% sodium hydride (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) dropwisely. The solution was added with 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 2.10 g, 21.8 mmol) dropwisely. The reaction was stirred at 65° C. for 16 h. The solution was cooled to room temperature, poured into icy H2O, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly for the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Sodium hydride, 80% dispersion in oil (0.14 g, 4.8 mmoI) was added to a solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (1.0 g, 4.8 mmol) [prepared from 4-hydroxypiperidine and di-tert-butyl dicarbonate] in dimethylformamide (30 ml) and the mixture stirred for 30 minutes. Benzyl bromide (0.68 ml, 5.7 mmol) was added and the reaction mixture stirred overnight. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with water and brine, dried (MgSO4) and the residue after evaporation purified by flash chromatography eluting with 0-20% ethyl acetate in hexane to give 1-(tert-butoxycarbonyl)-4-benzyloxypiperidine (1.1 g, 94% ); δH (CDCl3) 1.39 (9H, s, C(CH3)3), 1.82 (2H, m, piperidinyl. H), 3.04 (2H, m, piperidinyl H), 3.59 (3H, m, piperidinyl H), 4.51 (2H, s, OCH2Ph), 7.24-7.39 (5H, m, PhH).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:36]([N:38]([CH2:54][CH3:55])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=1)[CH3:37]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.O.COCCOC>[CH2:54]([N:38]([CH2:36][CH3:37])[C:39]1[CH:40]=[C:41]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[C:4]([NH:15][C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:23]=3)=[O:17])[CH:3]=2)[CH:42]=[CH:43][CH:44]=1)[CH3:55]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: CCN(CC)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CCN(CC)c1cccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.11 g), sodium carbonate (64 mg), water (0.30 mL), and bis(triphenylphosphine)palladium(II) dichloride (3.5 mg) were added to an ethylene glycol dimethyl ether (1.0 mL) solution of N,N-diethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (83 mg), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 40 minutes. The reaction mixture was cooled to room temperature, and then water and chloroform were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-70% hexane/ethyl acetate] to obtain 0.12 g of tert-butyl 4-(3-(diethylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH:11]O>C(O)(=O)C>[CH2:1]([S:5]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCSc1nc[nH]n1
Solvent: CC(=O)O
Product: CCCCS(=O)c1nc[nH]n1
Reaction time: 24 h

Procedure:
To a solution of 15.7 g. 3-butylthio-1,2,4-triazole in 60 ml. glacial acetic acid was added 100 vol. hydrogen peroxide solution (11.4 ml., 1 molecular proportion). The reaction mixture was cooled occasionally during 1 hour to maintain the reaction temperature at 25° - 30° C., and then kept at room temperature for 24 hours. The resulting solution was distilled under reduced pressure to produce a solid residue which was recrystallized from ethyl acetate to give 3-n-butylsulphinyl-1,2,4-triazole, m.p. 82° - 83° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:34]([CH3:36])[CH3:35])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:37][CH3:38])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:34]([CH3:35])[CH3:36])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:24]=[CH:25][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:27][CH:28]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:37][CH3:38])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CC[C@@H]3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (235 mg, 0.431 mmol from Example 100) was purified using chiral SFC to afford 29.2 mg of peak A (Example 100A) and 29.2 mg of peak B (Example 100B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 11 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=3.7 min, tR (peak B) 8.4 min. The absolute stereochemistry of individual enantiomers (Examples 100A and 100B) was not determined. LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 100).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:2]2[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cc1ncc[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Product: CCOC(=O)Cc1nccn1Cc1ccc(Cl)cc1
Yield: 47.9 %

Procedure:
1.07 g of ethyl imidazol-2-ylaceate hydrochloride and 1.69 g of 4-chlorobenzyl bromide were subjected to an alkylation reaction to obtain 0.75 g of ethyl 1-(4-chlorobenzyl)imidazol-2-ylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25]Br)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:34]([NH2:37])(=S)[CH3:35].O.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:37]/[C:34](/[CH3:35])=[CH:25]\[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:27]
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)CBr)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(N)=C/C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
To a solution (44 ml) of 6-bromo-3-(2-bromoacetyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (4.41 g) in DMF was added thioacetamide (1.1 g) and the mixture was stirred at 70° C. for 24 hrs. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were washed with methanol and recrystallized (ethyl acetate) to give the title compound (1.31 g).
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:20]=[C:19]([Cl:29])[C:18]=1[Cl:30].CCN(CC)CC.CC(=O)OCC>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([C:23]2([C:25]([F:28])([F:27])[F:26])[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=3)[CH2:24]2)[CH:20]=[C:19]([Cl:29])[C:18]=1[Cl:30]
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1C
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
To a solution of methyl 4-(chloro(hydroxyimino)methyl)-2-methylbenzoate (12.6 mmol) in DMF (30 mL) at 0° C. was added 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (4.2 g, 15.1 mmol) followed by Et3N (2.55 g, 25.2 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water (30 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1) to give methyl 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-2-methylbenzoate (4.1 g; yield 70% over 3 steps) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.5 Hz, 1H), 7.66 (s, 2H), 7.55 (s, 2H), 4.13 (d, J=17.5 Hz, 1H), 3.93 (s, 3H), 3.73 (d, J=17.5 Hz, 1H), 2.64 (s, 3H) ppm; MS: m/z=465.9 (M+1, ESI+).