Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][CH:26]([CH2:29][C:30]3[O:34][C:33](=[O:35])[NH:32][N:31]=3)[CH2:25][CH2:24]2)[CH:3]=1.FC(F)(F)C([O-])=O.[Br:43]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][CH:26]([CH2:29][C:30]3[O:34][C:33](=[O:35])[NH:32][N:31]=3)[CH2:27][CH2:28]2)[C:3]=1[Br:43]
Reactant: Nc1cc(C2CCC(Cc3n[nH]c(=O)o3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: Nc1c(Br)c(C2CCC(Cc3n[nH]c(=O)o3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 20 mL scintillation vial was charged 5-((4-(7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)methyl)-1,3,4-oxadiazol-2(3H)-one as a trifluoroacetate salt (0.035 mmol, 20 mg), MeCN (2 mL) and N-bromosuccinimide (0.035 mmol, 6.3 mg). The resulting solution was stirred at room temperature for 1 hour. After 1 hour, the solvent was removed in vacuo and the resulting residue was purified via reverse-phase HPLC to yield 5-((4-(7-amino-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)methyl)-1,3,4-oxadiazol-2(3H)-one (m+H=546.57, retention time=4.07 min).
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:11]=1)([CH3:9])=[O:8])=O)C.[O-]CC.[Na+]>>[CH:29]([NH:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([O:17][CH2:16][C:12]3[CH:11]=[C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])[CH:15]=[CH:14][CH:13]=3)=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1)([CH3:31])[CH3:30]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2ccc3c(NC(C)C)ncnc3c2)c1
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)Nc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)ccc12
Yield: 51 %

Procedure:
According to GWP 6, (RS)-N-(ethoxycarbonyl)-S-[3-({[4(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]-S-methylsulphoximide (68 mg, 0.16 mmol) is reacted with sodium ethoxide (46 mg, 0.68 mmol) at 80° C. for 2 hours. The reaction mixture is concentrated to dryness. The residue is taken up in ethyl acetate and water. The organic phase is separated off, dried over sodium sulphate and subsequently concentrated. The residue is triturated a number of times with diethyl ether and the solvent is subsequently decanted off. The residue is dissolved in dichloromethane and concentrated again. The desired product is obtained in 51% yield (30 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>O1CCOCC1>[C:19]([CH:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:20]
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CC(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
There were gradually added to a cooled and stirred solution of 190 grams of 2,6-dichloro-3-nitropyridine and 117 grams of benzyl cyanide in 2 liters of dioxane under a nitrogen atmosphere 64 grams of sodium hydride (80% in white oil). The reaction mixture immediately turned a deep dark blue color, gradually a finely divided precipitate began to separate out, the temperature rose (with cooling with ice water) to 30° C. After 3 hours the mixture was treated with about 20 ml of ethyl alcohol, stirred for another 20 minutes, then filtered with suction. The deep blue sodium salt was dissolved in 1 liter of water, treated with dilute acetic acid until the color changed. The 2-(α-cyanobenzyl)-3-nitro-6-chloropyridine formed crystallized out in pure form. M.P. 165° C; Yield 146 grams.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CCCCCC>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Product: CCOP(=O)(Cc1c2ccccc2cc2ccccc12)OCC
Temperature: 140 °C

Procedure:
After a mixture of 28.5g of 9-chloromethylanthracene and 62.3g of triethyl phosphite was heated at a temperature of 140° C for 2 hours with stirring, the mixture was cooled to a room temperature to obtain light yellowish needle-like crystalline product. The crystalline product was filtered off and washed with petroleum ether, and then dried. A crude product was obtained in a yield of 34.4g (83.8%). A pure crystalline product of diethyl 9-anthrylmethylphosphonate (m.p. 103.5° C - 104° C) was obtained by the recrystallization of the crude product from n-hexane in a yield of 31.2g.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:19]([O:20][CH3:21])[CH3:18])=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CNOC
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CON(C)C(=O)c1cc2c(O)cccc2s1
Yield: 89.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)-benzo(b)thiophene-2-carboxylic acid (4.5 g), N,O-dimethylhydroxylamine hydrochloride (2.1 g) and diethyl cyanophosphate (3.2 g), 4-hydroxy-N-methoxy-N-methylbenzo(b)-thiophene-2-carboxamide (4.0 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.0 g), the title compound (1.1 g) was obtained as brown crystals.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: COc1ccccc1N
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1OC
Yield: 33.6 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (4.95 g, 20mmol), 2-methoxyaniline (4.51 ml, 40mmol) and tetrahydrofuran (20 ml) were stirred at room temperature overnight. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethyl acetate/petroleum ether to give 3-butyryl-4-(2-methoxyphenylamino)-8-methylquinoline (2.25 g), m.p. 135°-137°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH2:19])[CH2:8][CH2:7]1)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH:19][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2ccc(Cl)cc2N)CC1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of 0.710 g (2.39 mmol) of [1-(2-amino-4-chloro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester in acetonitrile (25 mL) is added 0.37 mL (2.9 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue is treated with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.590 g (56.7%) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[C:9](=[O:15])[CH:10]=[C:11]=[CH:12][CH2:13][CH:14]=1)=[O:6])C.[NH2:17][NH2:18]>C(O)C>[O:15]=[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[C:8]1[NH:7][C:5](=[O:6])[C:4]([NH:17][NH2:18])=[O:3]
Reactant: NN
Reactant: CCOC(=O)C(=O)NC1=CCC=C=CC1=O
Solvent: CCO
Product: NNC(=O)C(=O)Nc1cccccc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of [(2-oxo-3,4,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester (1.2 g, described in Example 1) and anhydrous hydrazine in anhydrous ethanol (25 ml) is stirred at 25° C. for 5 hr. The precipitate is collected on a filter and crystallized from methanol to give crystals of the title compound, mp 193° C.
Reaction SMILES: [C:1](CC(N)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18]>>[C:17]([N:19]=[C:1]([NH:15][CH:16]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:17]([NH:19][C:20]1([C:30]#[N:31])[CH2:24][CH2:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:21]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:16]
Reactant: CCC(CC)N1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)C1
Reactant: NC(=O)CC(=S)c1ccccc1
Agent: Cl
Product: CCC(CC)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=NC(C)=O)c2ccccc2)C1

Procedure:
The title compound was prepared starting from thiobenzoyl acetamide and 2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 1, step b, except that the compound was purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to 90% acetonitrile in water. MS, m/z 480=M+1.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH3:10])[C:7]3[O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:6]=3[C:5]=2[CH:17]=O)[CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH:1]1([C:4]2[C:5]([CH2:17][NH:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:6]3[CH2:14][O:13][C:12]([CH3:15])([CH3:16])[O:11][C:7]3=[C:8]([CH3:10])[N:9]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1nc(C2CC2)c(C=O)c2c1OC(C)(C)OC2
Product: Cc1nc(C2CC2)c(CNc2ccc(C#N)cc2)c2c1OC(C)(C)OC2
Yield: 51.4 %

Procedure:
The reductive amination of 6-cyclopropyl-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (168) (5.11 g, 20.6 mmol) and 4-aminobenzonitrile (2.9 g, 24.7 mmol), as described in Example 21, gave give 4-[(6-cyclopropyl-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-benzonitrile (169) (3.7 g, 51% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)([O-:18])=[O:17].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:14][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]([CH3:11])[CH3:10])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)N(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Subsequently, to a solution of (N-t-butoxycarbonyl-N-isopropyl-amino)-acetic acid (2.05 g, 9.44 mmol) and p-nitrobenzyl alcohol (2.89 g, 18.9 mmol) in methylene chloride (100 ml) were added WSC (3.62 g, 18.9 mmol) and 4-dimethylaminopyridine (120 mg, 0.98 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:2) as the eluant to afford (N-t-butoxycarbonyl-N-isopropyl-amino)acetic acid p-nitrobenzyl ester (1.93 g, yield 58%) as a pale yellow transparent syrup.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][NH:6][C:7](=[O:35])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:16][CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>CO>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH:15]([O:14][C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[O:35])=[CH:13][CH:12]=3)[CH2:16][CH3:17])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Oc1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 3-{4-[1-(4′-trifluoromethyl-biphenyl-4-ylmethyl)-propoxy]-benzoylamino}-propionic acid methyl ester (0.012 g, 0.02 mmol) in methanol (1 mL) is added sodium hydroxide (5.0N, 0.02 mL, 0.12 mmol) and stirred for three hours. The mixture is acidified with 1.0 N HCl and extracted with ethyl acetate three times. Organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure provided 0.009 g (0.019 mmol, 77%) of title compound. MS (ESI) m/z 486.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH3:24]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ncccc1C(=O)O
Product: CCN1CCCC1CNC(=O)c1cccnc1OCC=C(C)C
Yield: 92 %

Procedure:
In a manner identical to Example 15, 2-prenyloxynicotinic acid (1.00 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.63 g), thereby yielding 1.41 g (92%) of the aimed compound.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C1CNCCO1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
In a 500-mL round-bottom flask, 2-benzyl 4-tert-butyl morpholine-2,4-dicarboxylate (7.94 g, 25 mmol) was dissolved in DCM (200 mL). It was then cooled to 0° C. TFA (15 ml, 198 mmol) was added via pipet, and the solution was allowed to warm naturally to ambient temperature in the ice bath, whereupon it was stirred for 14 h. The mixture was concentrated to afford the title compound (50% by weight with the remainder assumed to be TFA, 10.86 g, 24 mmol). MS m/z 222 (M+1).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH:8]=[N:9][OH:10])[CH:5]=[CH:4][N:3]=1>C(O)(C)C>[N:3]1[CH:4]=[CH:5][C:6]([CH:8]=[N:9][OH:10])=[CH:7][CH:2]=1
Reactant: ON=Cc1ccnc(O)c1
Solvent: CC(C)O
Product: ON=Cc1ccncc1

Procedure:
One hundred mL of isopropanol was added to the resulting broth containing 0.27 g of 2-hydroxy-4-pyridinaldoxime obtained from the reaction with 4-pyridinaldoxime as a substance. After shaking for 30 minutes, the solid contents were removed by filtration. After an addition of 100 mL of water to the filtrate, the whole was concentrated under a reduced pressure, whereby isopropanol was removed to precipitate the crystals. The precipitated crystals were separated by filtration to obtain 0.20 g of crude crystals. The resulting crystals were washed by water, and then were separated by filtration to obtain 0.15 g of white crystals of 2-hydroxy-4-pyridinaldoxime (rate of isolated yield=53%). The structure of the crystals was identified by IR analysis, proton NMR analysis and MS analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([OH:25])=O)=[C:11]2[CH2:10][N:9]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:32]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][C:22]([C:23]([NH2:32])=[O:25])=[C:11]2[CH2:10][N:9]=1
Reactant: O=C(O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1ncn2c1CN=C(c1ccccc1Br)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g (7.5 mmol) of 6-(2-bromophenyl)-8-fluoro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 300 mL of methylene chloride and 2.25 g (10.8 mmol) of phosphorus pentachloride was stirred at room temperature for 2 hours. Ammonia gas was then introduced until the mixture was basic. After layering with 20 mL of concentrated aqueous ammonia, the mixture was stirred for 15 minutes. The methylene chloride was washed with water, dried and evaporated. The residue was crystallized from ethanol/water to yield 2.4 g of product having the above formula. A second crop of 0.4 g was obtained from the mother liquor for a total yield of 2.8 g. For analysis, a sample of the product was recrystallized from methylene chloride/ethanol and had m.p. 298°-299° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][OH:27])[N:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@:10]3([CH2:25][CH:24]3[CH:26]=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CO)c1nnc(C)n1-2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(CC1C=O)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-yl)methanol (Compound 210; 75 mg, 0.188 mmol) in DCM (2 mL) at 0° C. was added Dess-Martin periodinane (96 mg, 0.226 mmol). After 1 h at 0° C., extra Dess-Martin periodinane (96 mg, 0.226 mmol) was added, and the reaction was warmed to rt for 2 h. Then the reaction was diluted with diethylether and filtered. The filtrate was concentrated to dryness under vacuum, and the residue was used without purification in the next step. LRMS (M+H)+: 397 m/z.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[C:14]([F:20])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][C:22]1[C:27](I)=[CH:26][CH:25]=[CH:24][C:23]=1[C:29](=[O:31])[CH3:30]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15](/[CH:16]=[CH:17]/[C:27]3[C:22]([OH:21])=[C:23]([C:29](=[O:31])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[C:14]([F:20])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc(OCCCCc2ccccc2)cc1F
Reactant: CC(=O)c1cccc(I)c1O
Product: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2F)c1O
Yield: 67 %

Procedure:
Following the process described in example 20 (point D), starting from 4-(4-phenylbutoxy)-2-fluorostyrene and 2'-hydroxy-3'-iodoacetophenone, the title compound was prepared, which was purified by flash chromatography through a column, eluting with petroleum ether:ethyl acetate, 95:5 (67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([C:14]#N)[CH2:11][CH:10]2[CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C([OH:18])C.[OH-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:11][C@H:10]2[CH2:12][O:13][C:14]3=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCO
Reactant: N#C[C@@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1OC[C@@H]2C[C@]12c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
(1S)-1-(3,4-dichloro-phenyl)-2-hydroxymethyl cyclopropanecarbonitrile (10 g, 4.13 mmol), ethanol (20 mL) and 25N sodium hydroxide solution (10 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (10 mL) was added to the reaction mass followed by concentrated hydrochloric acid drop wise to adjust the pH of the reaction mass to 1-2 and stirred for overnight at room temperature. The aqueous layer was extracted with dichloromethane (100 mL). The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 4.5 g (45%) of product. 1H NMR δ(300 MHz,CDCl3): 1.41-1.43 (1H,t, J=4.9 Hz), 1.58-1.63 (1H,dd, J=7.79,4.94 Hz), 2.56-2.62 (1H,m), 4.28-4.31 (1H,d, J=9.3 Hz), 4.44-4.48 (1H,dd, J=9.34,4.58 Hz), 7.26-7.30 (1H,dd, J=8.2,2.0 Hz), 7.40-7.43 (1H,d, J=8.2 Hz), 7.52-7.53 (1H,d, J=2 Hz).
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>Br>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1COC1CCCCC1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@@H]2CCN[C@@H](COC3CCCCC3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.9 %

Procedure:
Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (121 mg, 0.36 mmol) was dissolved in hydrogen bromide (33% in acetic acid, (2.75 mL, 15.69 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(cyclohexyloxymethyl)piperidin-4-yl)isoxazol-3(2H)-one (15 mg, 15%). 1H NMR (600 MHz, dmso) δ 1.09-1.25 (m, 5H), 1.38-1.53 (m, 2H), 1.55-1.65 (m, 2H), 1.65-1.83 (m, 5H), 2.55-2.63 (m, 1H), 2.69-2.80 (m, 2H), 3.02-3.88 (m, 4H), 5.76 (s, 1H). HRMS Calculated for [C15H24N2O3+H]+: 281.1865. Found: 281.1879
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cc(O)cc(Cl)c2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of Intermediate 62b (615 mg, 2.31 mmol) and imidazole (189 mg, 2.78 mmol) in DMF (4.5 mL) was added tert-butyl dimethylchlorosilane (384 mg, 2.55 mmol). The solution was stirred for 2 h then added tert-butyl dimethylchlorosilane (192 mg, 1.28 mmol). After 1.5 h, the solution was diluted with water and extracted with EtOAc. The combined organics were dried and concentrated in vacuo to give the title compound (831 mg, 94%). LCMS (Method 3): Rt 5.21 min, m/z 380 [MH+].