Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:10]([S-:12])#[N:11].[K+]>C1(C)C=CC=CC=1>[O:9]=[C:3]([CH2:2][S:12][C:10]#[N:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)CCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)CSC#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of methyl 4-chloro-3-oxobutanoate (10 g, 66 mmol) in toluene (100 ml) was added a vessel containing KSCN (9.6 g, 99 mmol), the reaction mixture was stirred at rt for 24 h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, the residue was purified by a standard method to give the desired product. LC-MS: m/z (M+H)=174.3
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:15][C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[CH3:15][C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)=[O:27])=[CH:24][CH:23]=1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)cc1
Yield: 77.6 %

Procedure:
By reaction and treatment in the same manner as in Example 52 and using 4-(p-tolyloxy)piperidine (1 g) and (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1.2 g) described in Preparation Example 37, the title compound (1.6 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:13](=[O:22])[CH:12]=[C:11]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>CN(C=O)C.C(NCC)C.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:13](=[O:22])[CH:12]=[C:11]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(I)c1)cc(=O)n2CC1CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of 6-(4chloro-benzoyl)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one (4.0 g, 7.41 mmol) in DMF/diethylamine (1:1, 80 mL) was treated with palladium (II) bis(triphenyl)phosphine chloride (0.26 9, 0.37 mmol), trimethylsilylacetylene (1.09 g, 11.1 mmol), and copper (I) iodide (0.21 g, 1.09 mmol). The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo, poured into H2O (450 mL), and filtered to give a crude brown foam. Purification by flash column chromatography (silica, ether:petroleum ether 1:1) gave 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.47 g, 92%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:25])=[C:17]([C:20]3[NH:21][CH:22]=[CH:23][N:24]=3)[CH:18]=2)[C:13](=[O:26])[N:12]([CH2:27][C:28]([O:30]CC)=[O:29])[C:11]1=[O:33].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:25])=[C:17]([C:20]3[NH:24][CH:23]=[CH:22][N:21]=3)[CH:18]=2)[C:13](=[O:26])[N:12]([CH2:27][C:28]([OH:30])=[O:29])[C:11]1=[O:33]
Reactant: CCOC(=O)Cn1c(=O)c2cc(F)c(-c3ncc[nH]3)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cn1c(=O)c2cc(F)c(-c3ncc[nH]3)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 49.3 %

Procedure:
Into 50 ml of ethanol were dissolved 2.0 g of ethyl 1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-6-fluoro-7-imidazolyl-3(2H)-quinazolineacetate, and, after added 4.5 ml of 1N aqueous solution of sodium hydroxide, the mixture was refluxed for 1.5 hours. Ethanol was distilled off, water was added, pH was made to be 5 with 3N hydrochloric acid, and the deposits were collected by filtration. They were recrystallized from dioxane to obtain 930 mg of title compound. m.p. 188°-189° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1I

Procedure:
In a 5 liter 3 necked flask, 2-iodo-5-nitro-benzoic acid (100 grams) was dissolved in methanol (3000 ml). The flask was fitted with a reflux condenser and 50 ml of concentrated sulfuric acid was added carefully with cooling. After the completion of the addition, the contents were refluxed for 3 days until completion of the reaction. The reaction was followed by TLC. After the completion of the reaction, the reaction mixture was concentrated to 1000 ml and allowed to cool. The product crystalized as a light yellow colored powder. The solid material was filtered and washed with water and methanol and air-dried. The yield was 90 grams.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]([O:9][C@H:10]1[CH2:29][C@@:28]2([CH3:30])[C@@H:21]([CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[C@H:20]2[C@H:11]1[C@:12]1([CH3:32])[C@@H:17]([CH2:18][CH2:19]2)[CH2:16][C@@H:15]2[O:31][C@@H:14]2[CH2:13]1)=[O:8])[CH2:4][CH3:5])[CH3:2].C(=O)(O)[O-].[Na+].[ClH:38]>>[Cl:38][C@H:14]1[CH2:13][C@@:12]2([CH3:32])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:11]2[C@@H:10]([O:9][C:7](=[O:8])[CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:29][C@@:28]2([CH3:30])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:25](=[O:27])[CH3:26])[CH2:16][C@@H:15]1[OH:31]
Reactant: Cl
Reactant: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@@H]4O[C@@H]4C[C@]3(C)[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)[C@@H](Cl)C[C@]3(C)[C@H]21

Procedure:
A solution of 11β-diethylaminoacetoxy-2α,3α-epoxy-5α-pregnan-20-one (800 mg) in concentrated hydrochloric acid (6 ml) was kept at room temperature for 15 minutes and then diluted with a large excess of sodium bicarbonate solution. The precipitated solid (767 mg) was collected by filtration and purified by preparative TLC (ethylacetate) and crystallization from petroleum ether to afford title compound, (305 mg). m.p. 182°-187°, [α]D +101.4°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a mixture of 1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (160 mg, 0.319 mmol) and EtOH (3.2 mL) was added 4M HCl in dioxane (3.21 mL, 12.8 mmol). The mixture stirred for 18 h at 23° C. The reaction mixture was concentrated and the resulting residue was triturated in Et2O. The suspension was filtered and washed with Et2O to yield the titled compound (0.125 g, 95%) MS (ESI/CI): mass calcd. for C20H17ClN4O2S, 412.1; m/z found, 413.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6); 13.53 (d, J=12.3 Hz, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 7.78 (s, 0.5H), 7.65 (s, 0.5H), 7.55 (s, 0.5H), 7.44 (s, 0.5H), 7.38 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (s, 1H), 4.32-4.26 (m, 4H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]2[N:21]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=3)[N:22]=[CH:23][C:16]=12.Cl>C1COCC1>[Cl:30][C:29]1[C:24]([N:21]2[C:17]3=[N:18][CH:19]=[N:20][C:15]([O:3][C@@H:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[C:5]([O:7][CH3:8])=[O:6])=[C:16]3[CH:23]=[N:22]2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COC(=O)[C@@H](O)COC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Sodium hydride (1.84 g, 45.9 mmol) was added to a stirred solution of (S)-methyl 2-hydroxy-3-isopropoxypropanoate (Intermediate C7a) (6.0 g, 30.6 mmol) in anhydrous THF (200 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (8.14 g, 30.59 mmol) in dry THF (50 mL) was added dropwise, maintaining the temperature below 5° C. The reaction mixture was stirred at 0° C. for 10 minutes. Then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M HCl. The majority of the THF was evaporated in vacuo and then EtOAc (100 mL) was added. The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 70% EtOAc in isohexane to afford (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (7.76 g, 64.8%), ee 53%. A sample of this (1.48 g) was purified by preparative chiral-HPLC on a 50 mm 20um chiralcel OJ column, eluting with 30% isopropanol in isohexane (modified with 0.1% TEA), to give (2S)-methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoate (1.03 g, 99% ee). 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.14 (6H, m), 3.68-3.75 (4H, m), 3.98-4.00 (2H, m), 5.80-5.82 (1H, m), 7.74-7.77 (1H, m), 8.33-8.35 (1H, d), 8.59 (1H, s), 8.64 (1H, s), 8.67-8.68 (1H, m); m/z (ESI+) (M+H)+=392; HPLC tR=2.13 min.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][CH:8]=[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][C:10]2=[O:20])=[CH:4][CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>N1C=CC=CC=1.CN(C)C=O>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[CH:8][NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=2)[C:10](=[O:20])[NH:11]1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a suspension of 4-[(4-Amino-benzylamino)-methylene]-4H-isoquinoline-1,3-dione (29.3 mg, 0.1 mmol) in pyridine (250 μL) is added isovaleryl chloride (26 μL, 0.2 mmol). The reaction mixture is shaken at room temperature for 1 hour. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (37.2 mg).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.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>O1CCCC1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH:37]1[CH2:41][N:40]([CH2:42][CH3:43])[N:39]([CH2:44][CH3:45])[CH2:38]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:44]([N:39]1[CH2:38][CH:37]([NH:36][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=2)[CH2:41][N:40]1[CH2:42][CH3:43])[CH3:45]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: CCN1CC(N)CN1CC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 4- geranyloxybenzoic acid (1.10 g) in chloroform (20 ml), triethylamine (1.11 ml) and a solution of diphenylphosphinic chloride (0.95 g) in chloroform (5 ml) were successively added. After the reaction solution was stirred for 30 minutes, 4-amino-1,2-diethylpyrazolidine (0.57 g) was added and then the mixture was stirred at room temperature for one night. The reaction solution was washed with aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) and then recrystallized from n-hexane, thereby yielding 1.39 g (87%) of the aimed compound.
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]1([CH2:17][S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:16])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1

Procedure:
Starting materials: (E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-acrylic acid tert-butylester (compound C2) (1.45 g), CH2Cl2 (80 ml), TFA (8 ml). Reaction conditions: room temperature, 2 hours.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2>>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[CH:22]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Reactant: Nc1ccc2[nH]ncc2c1
Product: CN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 5-aminoindazole (Aldrich), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1](N(CC)CC)C.[C:8]([C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])(=O)[NH2:9].ClC(OC)=O>ClCCl>[C:8]([C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:12]=1[C:13]([O:15][CH3:1])=[O:14])#[N:9]
Reactant: CCN(CC)CC
Reactant: NC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Cl)cc1C#N
Temperature: 25 °C
Yield: 97.9 %

Procedure:
Triethylamine (25.4 mL, 0.182 mol) was added dropwise over a 20 minute period to a cold (0°-5° C.), stirred suspension of 2-carbamoyl-4,5-dichlorobenzoic acid (21.3 g, 91.0 mmol) in dichloromethane (110 mL). Methyl chloroformate (15.5 mL, 0.2 mol) was then added dropwise over a 30 minute period. The reaction mixture was then warmed to room temperature and stirred overnight. The solvents were removed and water (200 mL) was added. The water phase was filtered and the precipitate was washed with water and dried in vacuo to provide the product (20.5 g, 97%) as a tan solid, m.p. 120°-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[C:22]([C:27](O)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:22]3[C:21]([C:20]([F:31])([F:19])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncccc1C(F)(F)F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3C(F)(F)F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=433.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[CH3:25][CH:26]1[O:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)C.C(OCC)(=O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[C:10]([C:21]([F:24])([F:23])[F:22])=[N:9][N:5]2[C:6]([OH:8])=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][O:31][CH:26]([CH3:25])[CH2:27]3)=[N:3][C:4]=12
Reactant: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Reactant: CC1CNCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CN(c2cc(O)n3nc(C(F)(F)F)c(Cc4cccc(Cl)c4Cl)c3n2)CCO1

Procedure:
To a solution of 5-chloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol (79 mg, 0.2 mmol), prepared as described in Example 7 step b, in ethanol (2 mL) was added 2-methylmorpholine (101 mg, 1.0 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 150° C. for seven hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% HCl solution (5 mL). Organic layer was dried, filtered, and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (17 mg, 18%); LC/MS: MS (ES+) m/e 461 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=6.32 Hz, 3H) 2.68 (m, 1H) 2.96 (m, 1H) 3.56 (m, 2H) 3.71 (m, 2H) 3.88 (m, 1H) 4.20 (s, 2H) 5.23 (s, 1H) 6.85 (s, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.53 (d, J=7.58 Hz, 1H) 11.24 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:4][N:3]=1.C(SCCSCCSC1N=C2N(N=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=N2)CCCCC>>[CH2:12]([S:11][CH2:10][CH2:9][CH2:8][S:7][C:5]1[N:6]=[C:2]2[N:3]([N:4]=1)[C:36]([OH:39])=[CH:35][C:34]([CH3:40])=[N:1]2)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCSCCSCCSc1nc2nc(C)cc(O)n2n1
Reactant: CCCCCSCCCSc1nc(N)n[nH]1
Product: CCCCCSCCCSc1nc2nc(C)cc(O)n2n1

Procedure:
Compound 18 was prepared from Compound 9, using a procedure analogous to that described previously for Compound 20. The crude product was recrystallized from ethyl acetate to give a 24% yield of white solid, m.p. 121°-123° C. Analysis: Calculated for C14H22N4OS2 : C, 51.50; H, 6.79; N, 17.16. Found: C, 61.30; H, 6.69; N, 16.97.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][NH:14][CH2:15][CH2:16][OH:17].O>CS(C)=O>[OH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CNCCO
Solvent: CS(C)=O
Solvent: O
Product: CN(CCO)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.3 %

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol) in DMSO (3.5 mL) was added with 2-methylaminoethanol (0.52 mL, 6.5 mmol) and stirred at 100° C. for 5.0 hours. The reaction mixture was added with water and was washed with hexane/ethyl acetate (4/1) to remove impurities. After removing the impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4-[N-(2-hydroxyethyl) methylamino]-2-nitrobenzaldehyde (0.20 g, 75%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28](O)=[O:29])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:11])[F:13])=[O:29])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 5-(3-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=444.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([N:1]=[CH:26][C:24]2[O:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Product: O=[N+]([O-])c1ccc(-c2ccc(C=Nc3cc([N+](=O)[O-])ccc3O)o2)cc1

Procedure:
Using 2-amino-4-nitrophenol and 5-(4-nitrophenyl)furan-2-carbaldehyde, 4.10 g of 4-nitro-2-{[5-(4-nitrophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 97%).