Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([O:14][C@@H:15]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]2)=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>C(OCC)(=O)C>[CH:12]([O-:14])=[O:13].[C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([O:14][C@@H:15]2[CH:20]3[CH2:19][CH2:18][N+:17]([CH2:30][C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([CH2:22][CH2:21]3)[CH2:16]2)=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)c1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
(R)-Quinuclidin-3-yl 2-(3-acetylphenylamino)-2-phenylacetate (C53) (134 mg, 0.35 mmol) and 2-bromo-1-phenylethanone (85.0 mg, 0.42 mmol) are dissolved in ethyl acetate (5 mL) and stirred at RT for 2 hours. EtOAc is evaporated and the resulting crude oil is first purified by flash chromatography (DCM/MeOH=95/5) and then by preparative HPLC. The fractions containing the product are combined and concentrated under vacuum to remove the organic solvent. The resulting aqueous solution is freeze-dried obtaining the title compound as a white-foam (77.7 mg, 40% yield, formate salt, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].O>C1COCC1>[CH3:9][C:10]([S@@:13](/[N:15]=[CH:7]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: Cn1cc(C=O)cn1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(/C=N/[S@@](=O)C(C)(C)C)cn1
Temperature: 65 °C
Yield: 97.2 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (3.0 g, 27 mmol) in THF (100 mL) was added (S)-2-methylpropane-2-sulfinamide (6.6 g, 54 mmol) and Ti(OEt)4 (22.3 g, 98.0 mmol). The reaction mixture was heated at 65° C. for 12 h. After cooling, the mixture was poured into water. The solid was filtered, and the filtrate was extracted with EtOAc (3×100 mL). The organic layer was washed with water (3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) to afford 5.6 g (98%) of (S,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide 40 as colorless oil. LCMS (ESI) m/z: 214.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12](C(OC(C)(C)C)=O)[CH:11]=[C:10]3[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:24]=2)=[N:4][N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:32]1[CH2:31][CH2:30][N:29]([C:25]2[N:24]=[C:23]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:5]5[S:6][C:2]([NH2:1])=[N:3][N:4]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N)s3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)s1
Yield: 22.6 %

Procedure:
A solution of tert-butyl 5-(5-amino-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (212 mg, 0.443 mmol) in DCM/TFA (1:1, 4 mL) was stirred at RT for 1 h, then the solvent was removed. The residue was diluted with DCM and washed with sat. NaHCO3. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 0.5-4.5% MeOH in DCM) to give 5-(3-(6-morpholinopyridin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (38.0 mg, 0.100 mmol, 22.7%) as a light brown solid. MS (ESI, pos. ion) m/z: 379 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, d, J=2.2 Hz), 8.82 (1H, d, J=1.6 Hz), 8.11 (1H, d, J=2.5 Hz), 7.74 (1H, dd, J=8.6, 1.8 Hz), 7.53-7.62 (1H, m), 7.48 (1H, d, J=8.6 Hz), 7.30 (1H, s), 7.22 (1H, d, J=7.4 Hz), 6.64 (1H, d, J=8.4 Hz), 3.79-3.93 (4H, m), 3.55-3.67 (4H, m).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.Cl.[CH3:11][O:12][NH2:13].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][NH:13][CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1cccnc1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CONCc1cccnc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 18.1 %

Procedure:
In 200 ml of acetonitrile was suspended 6.6 g (0.04 mole) of 3-pyridylmethyl chloride hydrochloride, followed by addition of 10 g (0.12 mole) of O-methylhydroxylamine hydrochloride and 16.2 g (0.16 mole) of triethylamine. The mixture was stirred at 50° C. for 15 hours. The insoluble matter was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, using EtOH-CHCl3 (1:10) as an eluent. The procedure gave 1.0 g of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.FC1C=CC2[B:22](O)[O:21]CC=2C=1>>[OH:21][B:22]1[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[CH2:9][O:10]1
Reactant: COCOCc1cc(C)ccc1Br
Reactant: OB1OCc2cc(F)ccc21
Product: Cc1ccc2c(c1)COB2O

Procedure:
This compound was made from 18e in the same manner as compound 19b: mp 124-128° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 2.33 (s, 3H), 4.91 (s, 2H), 7.13 (d, J=7.2 Hz, 1H), 7.18 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 9.05 (s, 1H); ESI-MS m/z 147 (M−H)−; HPLC purity 99.0%; Anal (C8HgBO2) C, H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 80.3 %

Procedure:
2,48 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylate were treated with 0.8 g of potassium hydroxide in 2 ml of water and 50 ml of methanol at 20° C. Methanol was removed from the mixture by evaporation and the residue was taken up in water. After washing with diethyl ether, the aqueous alkaline solution was acidified with 2N hydrochloric acid and extracted with diethyl ether. The ethereal extract was dried over magnesium sulfate and evaporated to give 1.9 g of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]-isoxazole-7-carboxylic acid of melting point 215°-217° C. (from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]([O:13]C)=O.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([OH:13])[NH:18][N:17]=1
Reactant: NN
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
970 g of methyl 3-(2,4-dichlorophenyl)-3-oxopropionate were initially charged in 4000 ml of ethanol. Over a period of 15 min, 201 g of hydrazine hydrate were added dropwise, the mixture was stirred at room temperature overnight, the precipitated solid was filtered off and the filtrate was concentrated to ⅓ of its original volume. The filtrate was stirred for another two nights, the resulting solid was filtered off with suction and the filtrate was again concentrated to ⅓ of its original volume. This gave a total of 714.2 g (79.4%) of 3-(2,4-dichlorophenyl)-5-hydroxy-1H-pyrazole as a colorless solid. M.p.: 198° C.
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[CH3:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([C:7]([OH:8])([CH:2]([CH3:3])[CH2:4][CH3:5])[CH3:6])[CH2:14]1
Reactant: CCC(C)Br
Reactant: CC(=O)C1CCCC(C)(C)C1
Product: CCC(C)C(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 2-bromobutane replacing bromoethane, and herbac replacing dehydroherbac.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:33]C1C=CC=CC=1CCN>>[Cl:33][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][CH2:1][NH:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1
Reactant: NCCc1ccccc1Cl
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2Cl)n1

Procedure:
Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.22 g, 0.6 mmol) was displaced with 2-(2-chlorophenyl)ethylamine (0.25 mL, 1.8 mmol) to give the title compound as a yellow solid. MS m/e 458 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC>C1(C)C=CC=CC=1.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:16]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C#N)c(F)c1
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
A mixture of 4-bromo-2-fluorobenzonitrile (10.6 g, 52.8 mmol), tributyl(1-ethoxyvinyl)tin (21 g, 58.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (371 mg, 0.53 mmol) in 190 mL of dry toluene were refluxed for 2 h and then quenched with 5% HCl and stirred for 30 min. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.5 g of crude product. Purification of the product on silica gel using 5% ethyl acetate:hexane gave 4-acetyl-2-fluorobenzonitrile (1.0 g, 11%), MS (ES) m/z 164 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].Cl>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Cl)c3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1NCc1cccc(Cl)c1
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a solution of t-butyl 4-(3-(3-chlorobenzylamino)-4-nitrophenyl)piperazine-1-carboxylate (104 mg, 0.23 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (35.0 mg, 39% yield after recrystallization). 1H NMR (400 MHz, CD3OD): δ 8.07 (d, 1H), 7.42 (s, 1H), 7.33 (m, 2H), 7.28 (m, 1H), 6.40 (d, 1H), 6.03 (s, 1H), 4.61 (s, 1H), 3.56 (m, 4H), 3.27 (m, 4H); MS (ESI) m/z: Calculated for C17H20ClN4O2: 347.13; Observed: 347.5 (M++1) [corresponding to the free base].
Reaction SMILES: P.II.C([O:6][C:7](=[O:22])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=O)=O)=[CH:12][C:11]=1[CH2:20][CH3:21])C.O>C(O)(=O)C>[CH2:20]([C:11]1[CH:12]=[C:13]([SH:16])[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][C:7]([OH:22])=[O:6])[CH3:21]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Agent: II
Agent: P
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(S)ccc1OCC(=O)O

Procedure:
To a refluxing solution of PH3 (4.3 g, 126.5 mmol) and I2 (0.7 g, 2.6 mmol) in glacial acetic acid (30 ml) was added slowly a solution of (4-chlorosulfonyl-2-ethyl-phenoxy)-acetic acid ethyl ester (15 g, 48.9 mmol) in glacial acetic acid (20 ml). The reaction mixture was refluxed for 24 h. Water (10 ml) was added carefully and the mixture was refluxed for further 1 h after cooling, the reaction mixture was filtered and the filtrate diluted with water (100 ml). The mixture was extracted with dichloromethane (3×100 ml), and the organic phases were washed with water. After drying the dichloromethane phase was evaporated to give crude (2-ethyl-4-mercapto-phenoxy)-acetic acid in 10 g (96%) yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[C:10]([N:13]1[CH2:17][C:16](=O)[N:15]=[CH:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CCc1cc(N)n(C)n1
Reactant: CC(=O)N1C=NC(=O)C1
Product: CCc1cc(NC2=NCCN2C(C)=O)n(C)n1

Procedure:
5-Amino-3-ethyl-1-methyl pyrazole (British Patent 863,060) (35.2 g.) and 1-acetyl-2-imidazolinone (43.2 g.) were reacted as described in Example I to give 1-acetyl -2-(3-ethyl-1-methyl-5-pyrazolyl) amino-2-imidazoline which was de-acetylated without purification by the method of Example II giving 39.3 g. product. mp 160°-162°
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[O:9]1[CH:13]=[CH:12][CH2:11][CH2:10]1.[CH2:14]([OH:17])[C:15]#[CH:16].O>C(Cl)Cl>[CH2:14]([O:17][C@H:13]1[C@H:12]([I:1])[CH2:11][CH2:10][O:9]1)[C:15]#[CH:16]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCO
Reactant: C1=COCC1
Solvent: ClCCl
Solvent: O
Product: C#CCO[C@@H]1OCC[C@H]1I
Temperature: 24 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred, ice cold suspension of 15 g (66.6 mmol) of N-iodosuccinimide in 150 mL of CH2Cl2 was added a mixture of dihydrofuran (66.6 mmol, 4.67 g, 5.1 mL) and propargyl alcohol (100 mmol, 5.0 g, 5.2 mL) in 50 mL of CH2Cl2 over 20 min. After warming to 24° C. with stirring over 2 hours, 200 mL of water was added and the stirring was continued for 1 hour. The layers were separated and the aqueous layer extracted with 2×100 mL of CH2Cl2. The combined organic extracts were washed with a brine solution containing a small amount of sodium thiosulfate (Na2S2O3) (70 mg), dried over anhydrous Na2SO4, filtered, and concentrated. Chromatography over silica gel using 30% EtOAc in hexane yielded (15.4 g, 92%) of iodoether 10 as an oil. 1H-NMR (CDCl3): δ 5.4 (br s, 1H), 4.0–4.3 (m, 5H), 2.7 (m, 1H), 2.48 (br s, 1H), 2.25 (m, 1H); IR (neat), 2956, 2180, 1621, 1440 cm−1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>O>[OH:12][C:3]1[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[N:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)nc1O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a mixture of 0.80 g of 3-amino-2-hydroxy-6-trifluoromethylpyridine, 1.14 g of triethylamine and 10 ml of DMF, 0.88 g of isonicotinic acid chloride hydrochloride was added while ice-cooling. The reaction mixture was stirred at room temperature for one hour and further stirred while heating at 50° C. for one hour. To the reaction mixture, 0.88 g of isonicotinic acid chloride hydrochloride and 1.1 g of triethylamine were added, and the reaction mixture was stirred while heating at 50° C. for further 1.5 hours. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture. Precipitated crystals were collected by filtration. The resultant solid was dissolved in ethyl acetate, then washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.91 g of N-[2-hydroxy-6-(trifluoromethyl)pyridin-3-yl]-isonicotinamide.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:10]2[CH2:9][N:8]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[OH-:28].[K+]>C(O)C.O>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:9]1[CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:7][N:8]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:28])=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(NCCCCN2CC3CCCC3C2)cc1
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(NCCCCN2CC3CCCC3C2)cc1

Procedure:
436 mg of the compound of Example 18 are dissolved in 4 ml of ethanol. 86 mg of potassium hydroxide (1 eq.) are dissolved in 1.5 ml of water before being added to the alcohol solution. The mixture is heated at reflux for 1.5 hours and then evaporated to dryness. The residue is taken up in dichloromethane. The resulting solution is washed with water, dried over magnesium sulphate and then concentrated in vacuo. The product is crystallised in oxalate form.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1.[NH3:25].CC(O)C>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:25])[C:5]2=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:3]=1
Reactant: Clc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C

Procedure:
3-Bromo-8-chloro-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazine (2.05 g, 5.0 mmol) and NH3 in iPrOH (9 M, 20 mL, 180 mmol) in a bomb apparatus were heated at 110° C. for 24 h. Cooled to rt., and evaporated. The residue was dissolved in EtOAc (20 mL), washed with water (10 mL) and dried (Na2SO4). Evaporation of solvent gave a residue, which was triturated with diisopropyl ether (30 mL). 1H NMR (DMSO-d6, 400 MHz), δ 6.23 (bs, 2H), 7.09-7.19 (m, 6H), 7.39-7.43 (m, 3H), 7.58 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)[O:4][N:3]=1.C([NH2:23])(C)C.[CH:24](O)([CH3:26])[CH3:25]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH:18]([NH2:23])[CH:24]([CH3:26])[CH3:25])[O:4][N:3]=1
Reactant: CC(C)O
Reactant: CC(C)N
Reactant: Cc1cc(C=Cc2ccccc2OCC2CO2)on1
Product: Cc1cc(C=Cc2ccccc2OCC(O)C(N)C(C)C)on1

Procedure:
3.4 g (0.013 mole) of 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 2.3 g (0.039 mole) of isopropylamine in 50 ml of isopropanol are refluxed for 8 hours. When the reaction solution has cooled, it is filtered, and concentrated on a rotary evaporator. 3.8 g of solid residue are obtained and are recrystallized from toluene, giving 2.4 g (58% of theory) of colorless crystals, melting point 106°-108° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
Using the procedure of Example 100A but replacing 4-(2-propyl)-oxazolidine-2-one with 4-benzyloxazolidine-2-one and replacing 4-methylpentanoyl chloride with isovaleryl chloride provided the desired compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:35][CH2:36][C@H:37]([OH:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:35][CH2:36][C@H:37]([OH:39])[CH3:38])=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (580 mg, 1.24 mmol) synthesized in Example (66g) was dissolved in dichloromethane (15 mL), and (R)-(−)-1-amino-2-propanol (196 μL, 2.48 mmol), WSCI•HCl (366 mg, 1.91 mmol) and 4-dimethylaminopyridine (228 mg, 1.87 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. To the reaction solution, 0.25N hydrochloric acid (100 mL) was added, and extraction was carried out with ethyl acetate (100 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=3%-9%) to afford the desired compound (486 mg, yield 75%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH3:17])[C:13]([CH3:23])([C:18]([O:20]CC)=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH3:17])[C:13]([CH3:23])([C:18]([OH:20])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC1CN(C(=O)OCc2ccccc2)CC1(C)C(=O)O
Temperature: 40 °C
Reaction time: 17.5 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 1-benzyloxycarbonyl-4-methoxy-3-methylpyrrolidine-3-carboxylate (0.38 g, 1.18 mmol) in ethanol (4 mL) was added 1N aqueous solution of sodium hydroxide (4 mL), and the mixture was stirred at 40° C. for 17.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (10 mL×2). To the aqueous layer was added 1N hydrochloric acid (10 mL), and the mixture was extracted by chloroform (20 mL×3). The extract was washed with saturated aqueous solution of sodium chloride (20 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.31 g (89%) of the title compound as a colorless oily product.