Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[CH3:14][O:15][C:16]([NH:18][C@@H:19]([C:27]([O-:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17].OS([O-])(=O)=O.[K+].[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[C:40]([Cl:44])=[CH:39][C:38]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[C:40]([Cl:44])=[CH:39][C:38]=1[O:28][C:27](=[O:29])[C@@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:18][C:16]([O:15][CH3:14])=[O:17]
Reactant: COC(=O)N[C@H](Cc1ccccc1)C(=O)[O-]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 8 h

Procedure:
11.3 g (28 mmol) of methoxycarbonyl-3-phenyl-D-alanine dicyclohexylammonium salt (Synthesis 2, Step A) is distributed between 75 ml of ethyl acetate and 30.5 ml of 1M KHSO4. The phases are separated, the organic phase is washed neutral with water, dried over anhydrous sodium sulphate and concentrated at a pressure of 2.0-2.5 kPa to a volume of 15 ml. To the cooled (approx. 0° C.) residue 5.5 g (28 mmol) of 2,4,5-trichlorophenol and 5,75 g (28 mmol) of dicyclohexyl carbodiimide are added and the reaction mixture is allowed to stand overnight. The separated dicyclohexylurea is filtered off, and the filtrate evaporated. The oily residue is crystallised from ethanol. The crystals are filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3](=[O:37])[C@@H:4]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)[C@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[CH2:9]1)=[O:7].[OH:39]O.[OH-].[Na+].Cl>C1COCC1.O>[C:17]([O:16][C:15](=[O:21])[NH:14][C@H:5]([C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[CH2:9]1)=[O:7])[C@H:4]([C:22]1[CH:27]=[CH:26][C:25]([OH:39])=[CH:24][CH:23]=1)[C:3]([N:2]([CH3:1])[CH3:38])=[O:37])([CH3:19])([CH3:18])[CH3:20]
Reactant: OO
Reactant: CN(C)C(=O)[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the material from Step A (0.5 g, 0.94 mmol) in THF (10 mL) at 0° C. was added sequentially 30% hydrogen peroxide (0.16 mL, 1.4 mmol) and 3N aqueous sodium hydroxide (0.31 g, 0.94 mmol). After 1.5 h at this temperature, the mixture was allowed to warm to ambient temperature, and then water (50 mL) was added, and the resulting solution was adjusted to pH 5 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with 10% aqueous sodium thiosulfate until the organic phase showed a negative peroxide test. The combined organics were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% methanol in ethyl acetate) to give the title compound as a white foam. LC/MS 424.3 (M+1).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH:3]2[O:8][CH2:7][CH2:6][NH:5][CH2:4]2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Product: CN1CCN(CC2CNCCO2)CC1

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and N-methylpiperazine, the reactin is similarly carried out as Reference example 2 to give 2-(4-methyl-1-piperazinylmethyl) morpholine.trihydrochloride as white crystals, melting at 210°-212° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(C2CCNCC2)cc1

Procedure:
A solution of 2.4 g of 1-tert.butyloxycarbonyl-4-(4-cyanophenyl)-piperidine in 20 ml of dioxane and 20 ml of ethereal hydrochloric acid is stirred for 16 hours at ambient temperature. The crystalline precipitate is suction filtered, washed with ether and dried. Yield: 1.85 g (99% of theory), Melting point: 284°-288° C. Rf value: 0.79 (silica gel; methylene chloride/methanol/conc. ammonia=4:1:0.25)
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25](OC)=[O:26])[N:4]=1)#[N:2].[NH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25]([NH:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:26])[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O

Procedure:
Methyl 1-cyano-4-hydroxy-7-(naphthalen-1-yloxy)isoquinoline-3-carboxylate (15 mg, 0.04 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (24 mg, 0.16 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 16 mg. MS: (−) m/z 482.30 (M−1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH3:24])[CH2:22][CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CC#N.CCOC(C)=O>[CH3:24][C@@H:23]1[N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[C@H:20]([C:25]([O:27][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])=[O:26])[CH2:21][CH2:22]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N1C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
To a solution of 2-bromo-1-(4-bromophenyl)ethanone (505 mg, 1.82 mmol) in MeCN (18 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (500 mg, 2.18 mmol) and triethyl amine (0.27 mL, 2.0 mmol). After stirring for 15 h, the solution was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 40% EtOAc/hexanes) to afford (2S,5S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (640 mg, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19](O)=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH2:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([NH:30][CH3:29])=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to methylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 36.4 mg of 131. MS (Q1) 395.2 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25](=[O:30])[C:26]([OH:29])([CH3:28])[CH3:27].[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>C(#N)C.C(Cl)Cl>[C:31]([O:34][CH2:35][C:36]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25](=[O:30])[C:26]([OH:29])([CH3:27])[CH3:28])=[O:37])(=[O:33])[CH3:32]
Reactant: CC(C)(O)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
To a solution of 4.0 g of the product of Example 100 in 25 mL of acetonitrile was added 7.5 mL acetoxy acetylchloride and the reaction mixture was stirred at room temperature. After 50 min the reaction mixture was diluted with CH2Cl2 and washed two times with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate then concentrated. The residue was suspended in 150 mL of methanol at 60–65° C. After cooling to room temperature the methanol was decanted away and the solid rinsed three times with fresh methanol. The solids were then dried in vacuo to afford the title compound. HPLC/MS: 540.9 (M+1), 542.8 (M+3); Rt=4.07 min.
Reaction SMILES: [NH2:1][C:2]1C=CNN=1.COC(=O)C1C=CC(OCC2CC2)=C(Cl)C=1.CO[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[O:26]>>[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:2]#[N:1]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccccn1
Agent: COC(=O)c1ccc(OCC2CC2)c(Cl)c1
Product: N#CC(=O)c1ccccn1
Yield: 69 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from pyridine-2-carboxylic acid methyl ester (3.0 g, 21.9 mmol, 1.0 eq). The crude was precipitated from HCl to give the title product as a solid (2.2 g, yield: 69%) which was used directly for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCCC(=O)NCCNC(=O)OC(C)(C)C)cc1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CCCCNCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of {2-[4-(4-methoxy-phenyl)-butyrylamino]-ethyl}-carbamic acid tert-butyl ester (6 g, 17.88 mmol) in dry THF (60 ml) under an inert atmosphere of Argon is treated carefully with borane.THF complex (53.88 ml, 1M Borane in THF). The reaction mixture is heated at reflux for 2 hours and then allowed to cool to room temperature overnight. The mixture is quenched by addition of MeOH and then heated to 70° C. for a further 2 hours. After cooling to room temperature, the solvent is removed in vacuo to afford {2-[4-(4-Methoxy-phenyl)-butylamino]-ethyl}-carbamic acid tert-butyl ester as a viscous oil; [M+H]+ 323
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.[Cl:12][C:13]1[C:19]([CH2:20][O:21][CH2:22][CH3:23])=[CH:18][C:16]([NH2:17])=[C:15]([F:24])[CH:14]=1>>[Cl:12][C:13]1[C:19]([CH2:20][O:21][CH2:22][CH3:23])=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:24])[CH:14]=1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CCOCc1cc(N)c(F)cc1Cl
Product: CCOCc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl

Procedure:
Tetrahydrophthalic anhydride (0.58 g, 0.0039 mole), and 4-chloro-5-ethoxymethyl-2-fluoroaniline in glacial acetic acid from Step C was heated at 100° C. overnight. Acetic acid was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed successively with a saturated aqueous solution of sodium bicarbonate (5×50 ml) and a 10% aqueous solution of hydrochloric acid. The dried (magnesium sulfate) organic layer was concentrated under reduced pressure. The residue was passed through a column of silica gel eluting with ethyl acetate:heptane (3:17). Appropriate fractions were combined and concentrated under reduced pressure yielding N-[4-chloro-2-fluoro-5-ethoxymethylphenyl]-3,4,5,6-tetrahydrophthalimide as an amber solid, m.p. 89°-91° C. The nmr spectrum was consistent for the proposed structure.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:28](=[O:29])[CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: COc1ccccc1CC(=O)O
Reactant: C[C@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CC(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 27.4 g of (4R,5R)-4-methyl-5-phenyl-2-oxazolidinone in 200 cm3 of dry tetrahydrofuran are added, at -78° C., 100 cm3 of a 1.6M butyllithium solution in hexane, followed by addition of 33.12 g of a solution of 2-methoxyphenylacetic acid in 30 cm3 of tetrahydrofuran. The mixture is stirred for 30 minutes at this temperature and then allowed to return to room temperature. 200 cm3 of saturated aqueous ammonium chloride solution are subsequently poured in, followed by 200 cm3 of ethyl acetate. The organic phase is washed three times with 300 cm3 of water, and then with 300 cm3 of saturated aqueous sodium chloride solution, and dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of diethyl ether. 35.5 g of (4R,5R)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]-2-oxazolidinone are obtained, in the form of white crystals melting at 126° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:9]
Reactant: O=C(O)Cc1cccs1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NCCCSc1ccncc1
Yield: 86.3 %

Procedure:
To a solution of 913 mg (6.42 mmol) of 2-thienylacetic acid and 961 mg (8.35 mmol) of N-hydroxysuccinimide in 65 ml of methylene chloride, 1.48 g (7.70 mmol) of 1-ethyl-3 (3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.08 g (6.42 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.62 g of the desired compound Lyield: 86.3%, pale yellow powder).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([CH:34]=O)[CH2:30][CH2:29]1)[CH2:25][CH3:26]>CCOCC>[CH3:2][O:3][CH:4]=[CH:34][C@H:31]1[CH2:30][CH2:29][C@H:28]([O:27][CH2:24][CH2:25][CH3:26])[CH2:33][CH2:32]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCO[C@H]1CC[C@H](C=O)CC1
Agent: [Cl-]
Solvent: CCOCC
Product: CCCO[C@H]1CC[C@H](C=COC)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 94.6 g. of (methoxymethyl)triphenylphosphonium chloride in 1000 ml. of dry ether is treated with 33.0 g. of potassium tert.butylate. After stirring for 45 minutes, a solution of 31.4 g. of trans-4-n-propyloxycyclohexane carboxaldehyde in 200 ml. of ether is added dropwise. The mixture is stirred for a further 2.5 hours and then poured into 1.2 liters of ice-water. The organic phase is separated, washed neutral with water, dried over sodium sulfate and evaporated. The crude trans-2-(4-n-propyloxycyclohexyl)vinyl methyl ether obtained is distilled at 82°-85° C./0.6 mmHg in order to separate the residual triphenylphosphine.
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[CH2:5][CH2:6][C:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[OH-].[K+].C([OH:33])C>O>[CH:23]([N:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:17][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:26]([CH3:28])[CH3:27])([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:8]([NH2:9])=[O:33])([CH3:25])[CH3:24]
Reactant: CCO
Reactant: Cc1ccc(C(C#N)(CCN(C(C)C)C(C)C)CCN(C(C)C)C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(CCN(C(C)C)C(C)C)(CCN(C(C)C)C(C)C)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 10 parts of the preceding acetonitrile, 20 parts of potassium hydroxide, 2 parts by volume of water and 50 parts by volume of ethanol is refluxed for 22 hours. The mixture is then cooled to room temperature, poured into water and extracted with ether. The ether extract is dried over calcium sulfate and stripped of solvent to afford an oil which solidifies upon standing. The crude solid is crystallized from pentane to afford α,α-bis[2-(diisopropylamino)ethyl]-α-(p-tolyl)acetamide, melting at about 97°-100° C. This compound is represented by the following structural formula ##STR17##
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=2)[O:6]C(C)(C)[N:4]1[C:20](=[O:24])[CH2:21][C:22]#[N:23].Br[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:30][CH:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.FC(F)(F)C(O)=O>CN(C)C=O.O.C(Cl)Cl.C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:22]([CH2:21][C:20]([NH:4][C@H:3]([CH2:2][F:1])[C@H:7]([OH:6])[C:8]1[CH:9]=[CH:10][C:11]([C:26]2[CH:31]=[N:30][C:29]([CH2:32][NH:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:28][CH:27]=2)=[CH:12][CH:13]=1)=[O:24])#[N:23]
Reactant: CS(=O)(=O)NCc1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc([Sn](C)(C)C)cc2)[C@@H](CF)N1C(=O)CC#N
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)CC#N)cc2)cn1
Temperature: 70 °C
Yield: 2.8 %

Procedure:
A mixture of 3-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(trimethylstannyl)-phenyl)oxazolidin-3-yl)-3-oxopropanenitrile (150 mg, 0.342 mmol), N-((5-bromopyridin-2-yl)methyl) methanesulfonamide (90 mg, 0.342 mmol), tris(2-furyl)phosphine (16 mg, 0.068 mmol) and tris(dibenzylideneacetone) dipalladium(0) (32 mg, 0.034 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 4 h under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product m/z (CI) M+H 461. Obtained product is dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (0.5 mL) for 3 hours at room temperature. Reaction is diluted with toluene (10 mL) and concentrated to syrup. Obtained crude product dissolved in dimethylformamide (2 mL) and purified using HPLC to give the title product (4 mg): m/z (CI) M+H 421.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.[OH-].[Li+]>C1COCC1.CO>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
220 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate (Example 23A; 0.524 mmol, 1 equivalent) were dissolved in 7 ml of THF/methanol 1:1, 2.6 ml of 1 N aqueous lithium hydroxide solution (2.6 mmol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure and the residue was acidified with 1N hydrochloric acid. The solid was triturated, filtered off, washed with water and dried under reduced pressure. This gave 120 mg of the title compound (60% of theory).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][CH2:27][CH:28]=1)CCC>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3[O:24][CH2:25][CH2:26][CH2:27][CH:28]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Product: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)OCCC1

Procedure:
Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and tributyl-(5,6-dihydro-4H-pyran-2-yl)-stannane. Orange oil. MS (m/e): 292.1 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=O)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[O:8]1.C([O-])(=O)C.[K+]>C(O)(=O)C.C(OCC)(=O)C>[O:8]=[C:7]1[C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:16])[N:1]1[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-aminopropanoic acid (20 g, 224.48 mmol, 1.00 equiv) and 1,3-dihydro-2-benzofuran-1,3-dione (33.28 g, 224.69 mmol, 1.00 equiv) in acetic acid (1,200 mL). This was followed by the addition of potassium acetate (66.0 g, 672.49 mmol, 3.00 equiv) in several batches at 0° C. The resulting solution was stirred for 3 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 150 mL of water. The solids were collected by filtration. This resulted in 40 g (81%) of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid as a white solid. Rf: 0.15 (in ethyl acetate:petroleum ether=1:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)=[N:9][C:10]=2[C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([N:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C@H:28]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:26][CH:27]=2)[N:9]=1)(=[O:37])[CH:35]=[CH2:36]
Reactant: N#Cc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2)c1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3cc(C#N)ccn3)cc2)c2c(N)nccn12
Yield: 10.4 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-cyanopyridin-2-yl)benzamide (intermediate 24) and acryloylchloride, to afford the title compound (4.8 mg, 10.4%). Data: UPLC(C) Rt: 2.31 min.