Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[N:22]1([C:28](=[S:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:29]=[C:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[S:30][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)N1CCCCC1
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2sc(N3CCCCC3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.462 g, 1.24 mmol) (Example 26, Step 2) in ethanol (10 mL) in a 25 mL round bottom flask was added piperidine thiocarboxamide (0.198 g, 1.37 mmol) and the solution was heated to reflux for 14 hours. The reaction was cooled to room temperature and concentrated in vacuo yielding a foam. This foam was dissolved in methylene chloride and washed successively with NaHCO3 saturated solution (3 portions) and brine, dried over Na2SO4, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-piperidinyl)-thiazole (0.371 g, 72%) as a yellow-green fluffy solid: mp 173°-175° C., 1H NMR (CDCl3) 400 mHz δ7.77 (d, J=8.56 Hz, 2H), 7.46 (dd, J=5.60, 8.80), 7.38 (d, J=8.56 Hz, 2H), 6.99 (t, J=8.80 Hz, 2H), 3.53 (s (broad), 4H), 3.05 (s, 3H), 1.70 (s (broad), 6H). MS (EI): m/z 417 (MH+). HRMS Δ=-1.5 mmu.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>>[CH2:19]([O:18][C:4]1[CH:3]=[C:2]([NH:1][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=3)=[CH:38][CH:37]=2)[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Product: O=C(OCc1ccccc1)c1ccc(NCc2ccc(-c3ccc(Br)cc3)cc2)cc1OCc1ccccc1
Yield: 70 %

Procedure:
Primary aniline 1 was coupled to 4′-bromo-[1,1′-biphenyl]-4-carbaldehyde on a 3.7 mmol scale via General Procedure A to furnish 5 (1.52 g, 70%): δH (400 MHz, CDCl3) 4.39 (s, 2H, CH2), 4.59 (br s, 1H, NH), 5.10 (s, 2H, CH2), 5.31 (s, 2H, CH2), 6.20 (d, J=2.0 Hz, 1H, CH), 6.24 (d of d, J=8.6 and 2.0 Hz, 1H, CH), 7.25-7.36 (m, 6H, CH), 7.37-7.49 (m, 8H, CH), 7.53 (d, J=8.4 Hz, 2H, CH), 7.57 (d, J=8.4 Hz, 2H, CH) 7.85 (d, J=8.6 Hz, 1H, CH); δC (100 MHz, CDCl3) 47.3, 65.7, 70.3, 97.4, 104.9, 108.7, 121.5, 126.8, 127.1, 127.5, 127.6, 127.8, 127.9, 128.3, 128.3, 128.5, 131.8, 134.3, 136.6, 136.7, 137.6, 139.1, 139.4, 152.6, 160.8, 165.6.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[N:12]=[CH:13][C:14]4[C:19](=[O:20])[N:18]5[N:21]=[CH:22][CH:23]=[C:17]5[NH:16][C:15]=4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][CH2:26][CH2:27]Br>>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][C:14]4[C:19](=[O:20])[N:18]5[N:21]=[CH:22][CH:23]=[C:17]5[N:16]([CH2:27][CH2:26][O:25][CH3:24])[C:15]=4[C:10]=3[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2cnc3c(cnn3-c3ccccc3)c2[nH]c2ccnn12
Reactant: COCCBr
Product: COCCn1c2c(cnc3c2cnn3-c2ccccc2)c(=O)n2nccc12

Procedure:
By treating the product of Example 23 with methoxyethyl bromide instead of 1-bromo-3-methylbutane according to the procedure of Example 2,3-phenyl-3,11-dihydro-11-methoxyethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:9][O:10][C:11]1C=C[C:14]2[C:24]3[C:19](=[C:20]([CH3:25])[N:21]=[CH:22][CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1)(C)(C)C.[C:31](O)([C:33](F)(F)F)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]2[C:24]3[C:19](=[C:20]([CH3:25])[N:21]=[CH:22][CH:23]=3)[C:18](=[O:17])[O:32][C:31]=2[CH:33]=1
Reactant: Cc1nccc2c1COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nccc2c1c(=O)oc1cc(OC[C@@H](N)CC(C)C)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A solution of (S)-tert-butyl(4-methyl-1-((4-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (35 mg, 0.085 mmol) in DCM (3 mL) was cooled to 0° C. and then TFA (0.033 mL, 0.424 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then neutralized with saturated NaHCO3 and extracted with EtOAc (3×5 mL). Organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude which was purified by column chromatography on silica gel to afford material which air oxidized during purification to afford (S)-8-((2-amino-4-methylpentyl)oxy)-4-methyl-5H-chromeno[3,4-c]pyridin-5-one (3 mg, 9.19 umol, 10% yield) as yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=5.6 Hz, 1H) 8.19-8.23 (m, 1H) 8.02-8.06 (d, J=5.6 Hz, 1H) 7.06-7.10 (m, 1H) 6.98 (s, 1H), 4.08-4.14 (m, 1H), 3.91-3.97 (m, 1H), 3.28-3.30 (m, 1H), 3.01 (s, 3H), 1.80-1.88 (m, 1H), 1.41-1.48 (m, 2H), 0.97-1.03 (m, 6H); LCMS (ESI) m/e 327.2 [(M+H)+, calcd for C19H23N2O3 327.2]; LC/MS retention time (Method G): tR=0.82 min; HPLC retention time (method A): tR=8.47 min; HPLC retention time (method B): tR=8.90 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>O>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=[N:11]2)=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: O
Product: Clc1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
Piperazine (65.2 g) was melted by heating at 120° C., and 4,7-dichloroquinoline (15.0 g) was added thereto. The mixture was stirred at 120° C. for 2.5 hr and the reaction mixture was added to water. The mixture was extracted with chloroform and concentrated under reduced pressure to give 1-(7-chloro-4-quinolyl)piperazine (7.72 g).
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[Cl:14][C:15]1[C:16]([OH:37])=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:18]([OH:24])=[C:19]([CH:22]=[O:23])[C:20]=1[CH3:21].[CH3:38][C:39](O)([CH3:41])[CH3:40].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[C:16]([OH:37])=[C:17]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][C:39]([CH3:41])([CH3:40])[CH3:38])=[O:35])[C:18]([OH:24])=[C:19]([CH:22]=[O:23])[C:20]=1[CH3:21]
Reactant: CC(C)(C)O
Reactant: Cc1c(Cl)c(O)c(CCCCCCCCCC(=O)O)c(O)c1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(Cl)c(O)c(CCCCCCCCCC(=O)OC(C)(C)C)c(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
TFAA (0.20 ml, 1.4 mmol) was added to a suspension of Compound 215-11-COOH (144 mg, 0.403 mmol) in toluene (5 ml) at 0° C., and the mixture was allowed to warm to room temperature with stirring for 30 minutes. After checking for complete dissolution of the raw material, the mixture was again cooled to 0° C. tBuOH (0.40 ml, 4.2 mmol) was added to the cooled mixture, which was allowed to warm to room temperature with stirring for 15 hours. A saturated aqueous NaHCO3 solution was added to the reaction solution, which was extracted with EtOAc twice after stirring for 5 minutes. The combined organic layer was washed with a saturated aqueous NaCl solution, and was dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (Hexane:EtOAc=7:1 to 4:1) followed by PTLC (Hexane:EtOAc=7:1) to yield the target product (28 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[C:4]([NH:13][C:14]([O:16]CC)=O)[CH:3]=1.[NH2:19][CH2:20][CH2:21][OH:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:19]([CH2:20][CH2:21][OH:22])[C:14](=[O:16])[NH:13]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C(=O)OCC
Reactant: NCCO
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1CCO
Yield: 64 %

Procedure:
A mixture of 40 parts of ethyl 4-chloro-2-[(ethoxycarbonyl)amino]benzoate and 10 parts of 2-aminoethanol is stirred and heated to 160°-170° C. while the formed ethanol is distilled off. After stirring for about 30 minutes, the mixture is cooled and 2-propanol is added. The solid product is filtered off and dried, yielding 23 parts (64%) of 7-chloro-3-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:2]3[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1cc(Br)c2c(N)ncnn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 80 °C
Yield: 48 %

Procedure:
To a stirred suspension of 5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (3.00 g, 7.51 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (3.77 g, 11.3 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) dichloromethane adduct (550 mg, 0.75 mmol) in degassed DME (50 mL) was added aqueous Na2CO3 solution (2 M, 11.3 mL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (75 mL) and water (75 mL) and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×75 mL). The combined organics were filtered to remove a fine precipitate, dried (Na2SO4), and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes to afford 1.9 g (48%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1 H), 7.85 (s, 1 H), 7.77 (dd, 1 H), 7.57-7.54 (m, 1 H), 7.35-7.25 (m, 5 H), 7.11 (dd, 1 H), 6.55 (s, 1 H), 5.63 (s, 2 H), 3.59 (t, 2 H), 2.88 (t, 2 H), 1.79-1.68 (m, 2 H), 1.58-1.48 (m, 2 H), 0.83 (s, 9 H), 0.00 (s, 6 H); ES-MS m/z 527.3 [M+H]+, HPLC RT (min) 3.62.
Reaction SMILES: [Cl-].C[Zn+].[Cl:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](Cl)=[O:8].Cl.[CH2:19](Cl)Cl>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](=[O:8])[CH3:19]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: ClCCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn+]
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2 M solution of methylzinc chloride in tetra-hydrofuran (5.00 mL, 10.1 mmol) is treated dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) in tetrahydrofuran, treated with tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.350 mmol), stirred at room temperature for one hour, and poured into 3 N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark liquid. Flash column chromatography of the liquid using silica gel and a methylene chloride in hexanes solution (6:4) gives the title product as an off-white solid (mp 66-68° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[Cl:19][C:20]1[CH:54]=[CH:53][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:42]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[C:8]([C:24]([C:23]2[CH:53]=[CH:54][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:51])([CH3:52])[CH3:50])[CH:42]=2)=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccnc1[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyl)-1-methyl-1H-imidazole (1.71 g, 8.7 mmol) in THF (40 mL) at −78° C. was treated with sec-butyllithium (1.3 M in cyclohexane, 8.4 mL, 10.9 mmol). The reaction mixture was warmed to 0° C., stirred for 3 hours, and cooled to −78° C. A solution of 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.47 g, 6.8 mmol) (2.87 g, 6.4 mmol) in THF (20 mL) was cannulated into the reaction mixture, slowly warmed to room temperature, and stirred overnight. The reaction mixture was quenched with ammonium chloride (12 mL), diluted with ether (200 mL), and washed with H2O (200 mL) and brine (200 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give 6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2one (4.50 g) as a yellow foam. The crude material was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCN(C)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCNC
Yield: 63 %

Procedure:
A solution of ethyl 3-(benzyl(methyl)amino)propanoate (3 g, 13.56 mmol) in ethanol (67.8 mL) was added palladium, 10 wt. % on carbon (0.3 g, 0.282 mmol) and hydrogenated (double-walled balloon pressure) at room temperature for 3 h. The reaction mixture was filtered via a pad of Celite, and the filtrate was concentrated in vacuo to give ethyl 3-(methylamino)propanoate (1.12 g, 63.0% yield) as a light golden yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:15])[NH:1][C@@H:2]([CH3:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of L-alaninol (2.00 g, 26.6 mmol) in methylene chloride (60 ml) were added chloroformic acid benzyl ester (4.57 ml, 32.0 mmol) and triethylamine (4.48 ml, 32.0 mmol) in an ice bath. 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 hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford [(1S)-2-hydroxy-1-methylethyl]carbamic acid benzyl ester (4.61 g, yield 83%) as white crystals.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([F:31])[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)(=O)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:31][C:9]1[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][S:33]([CH3:32])(=[O:35])=[O:34])[N:8]=1
Reactant: CC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Using the same procedure as for the starting material of Example 29 but using methanesulphonyl chloride in place of acetyl chloride, there was obtained 2-fluoro-4-(2-methanesulphonylaminoethyl)-1-triphenylmethylimidazole, which was used without further characterisation.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[O:14]([CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[CH3:34])[Si](C(C)(C)C)(C)C.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.CN(C=O)C.CO.[Pd]>[NH2:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:29]([C:28]1[CH:31]=[C:32]([CH3:33])[C:25]([O:24][CH2:23][CH2:22][OH:14])=[C:26]([CH3:34])[CH:27]=1)[NH:6][C:4]2=[O:5]
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(-c2nc3ccc(N)cc3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 150 °C
Reaction time: 4 h
Yield: 15.6 %

Procedure:
To a solution of 2-amino-5-nitro-benzamide (680 mg, 3.75 mmol) and 4-[2-(tert-butyldimethylsilanoxy) ethoxy]-3,5-dimethylbenzaldehyde (1.16 g, 3.75 mmol) in N,N-dimethyl acetamide (35 mL), NaHSO3 (736 mg, 4.14 mmol) and p-TSA (71 mg, 0.375 mmol) were added and the reaction mixture was heated at 150° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with water and the solids were filtered off to give crude product (590 mg, 44%). To a solution of above crude product (490 mg, 1.38 mmol) in DMF (20 mL) and MeOH (20 mL), Pd—C (100 mg, 10%) was added and the reaction mixture was hydrogenated for 4 h at room temperature at 30 psi H2. The reaction mixture was filtered and the solvent was evaporated to give crude product. The crude was purified by column chromatography (silica gel 230-400 mesh; 4% methanol in CH2Cl2 as eluent) to give 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one (190 mg, 42% yield). To a solution of 6-amino-2-(4-(2-hydroxy ethoxy)-3,5-dimethyl phenyl)-3H-quinazolin-4-one (95 mg, 0.29 mmol) in pyridine (5 mL), acetic anhydride (108 mg, 0.73 mmol) was added and the mixture was stirred for 16 h at room temperature. The solvent was removed and the solids were dissolved in a mixture of MeOH (10 mL) and THF (10 mL) (compound was partially soluble). Then K2CO3 (100 mg, 0.73 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The solvent was removed and the crude was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:14][N:13]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]1)[CH2:10][C:9]2=[O:27].[OH-].[Na+]>>[C:15]([N:13]1[CH2:14][C:11]2([CH2:10][C:9](=[O:27])[C:8]3[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=3)[O:23]2)[CH2:12]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Yield: 60.5 %

Procedure:
(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (380 mg, 1.0 mmol) was hydrolyzed with 1 M NaOH following the procedure described in Example 30, Step A, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (220 mg, hydrochloride salt) as a light brown solid.
Reaction SMILES: [ClH:1].CC1ON=C(C2C=CC(C3OCCNCC3)=CC=2)N=1.[CH3:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[O:39][CH2:38][CH2:37][N:36]([C@@H](C4C=CC=CC=4)C)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[O:24][N:23]=1>>[ClH:1].[CH3:21][C:22]1[N:26]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([CH:33]3[O:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[O:24][N:23]=1
Reactant: Cc1noc(-c2ccc(C3CCN([C@H](C)c4ccccc4)CCO3)cc2)n1
Agent: Cc1nc(-c2ccc(C3CCNCCO3)cc2)no1
Agent: Cl
Product: Cc1noc(-c2ccc(C3CCNCCO3)cc2)n1

Procedure:
Optically active 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride was prepared by the same procedure as that of optically active 7-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-[1,4]oxazepane hydrochloride except for utilizing 7-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-4-((R)-1-phenyl-ethyl)-[1,4]oxazepane instead of 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-4-(1-phenyl-ethyl)-[1,4]oxazepane. Optically active 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride was obtained as white solid (0.16 g, 0.54 mmol, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:7]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:6]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[C@@H:7]([C:22]([OH:24])=[O:23])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)O)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred, cold (0° C.) solution of (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester (4.4 g, 10.6 mmol) in 30 mL of methylene chloride was added 10 mL of trifluoroacetic acid dropwise. The mixture was stirred for 1 hour at 0° C. and for 8 hours at ambient temperature. Concentration provided (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 4-methyl ester, which was used in the subsequent step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9](=O)[C:10]3[CH:15]=[CH:14][S:13][C:11]=3[N:12]=2)[CH:2]=1.N.O.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:9]1[C:10]2[CH:15]=[CH:14][S:13][C:11]=2[N:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2cccnc2)nc2sccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: Clc1nc(-c2cccnc2)nc2sccc12
Temperature: 120 °C
Reaction time: 10 h

Procedure:
The suspension of 2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4(3H)-one (6.0 g, containing salts) in POCl3 (30 ml.) was stirred at 120° C. for 10 h. After the reaction was completed, the mixture was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NH3.H2O at 0° C., then a precipitate formed. The solid was collected and 540 mg of 4-chloro-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine was obtained as a brown solid, LCMS m/z=247.9, 250.0 (M+1) (Method B) (retention time=1.85 min).