Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([N:27]2[CH:31]=[C:30]([CH:32]=O)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[N:28][N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:31]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnn(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cnn(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1-phenyl-1H-pyrazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 392.03 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:17](=[O:18])[C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:5]=3[C:4]=2[C:3]1=[O:26].[H-].[Na+].[Cl-].[CH2:30]([N+:32]1([CH2:37][CH3:38])[CH2:35][CH:34]([OH:36])[CH2:33]1)[CH3:31].C(OC(C)C)(C)C>CN(C)C=O>[CH2:30]([N:32]([CH2:37][CH3:38])[CH2:33][CH:34]([OH:36])[CH2:35][N:19]1[C:6]2[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]3[C:17](=[O:18])[N:2]([CH3:1])[C:3](=[O:26])[C:4]=3[C:5]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:31]
Reactant: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O
Reactant: CC[N+]1(CC)CC(O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)N(C)C3=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
The starting material is prepared in the following manner: 1 g (2.95 mmol) 6,7,12,13-Tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole (precursor for Example 5) is dissolved in 15 ml dry dimethylformamide and added dropwise, under an atmosphere of argon, to a suspension of 100 mg (3.3 mmol) sodium hydride (80% in paraffin oil) in 25 ml dimethyl formamide. After stirring for 1 hour at 20° C., 915 mg (5.9 mmol) 1,1-diethyl-3-hydroxyazetidinium chloride are added thereto and the reaction mixture is stirred for 3 days at 20° C. The reaction mixture is evaporated in a vacuum, the residue is taken up in 150 ml of water and 500 ml ethyl acetate and the organic phase is separated off and dried over anhydrous sodium sulphate. After filtration, the filtrate is evaporated and the residue is chromatographed on silica gel with dichloro-methane/methanol (99:1 v/v). The fraction with the Rf 0.2 in dichloromethane/methanol (95:5 v/v) is isolated, stirred with 20 ml diisopropyl ether and the crystals obtained are filtered off. (±)-12-(3-Diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole is obtained in the form of yellow crystals; decomposition point 220°-228° C.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH:21]1([N:19]([CH3:20])[C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: CN(c1cnc2c(n1)OCCN(Cc1ccccc1)C2)C1CCC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1cnc2c(n1)OCCNC2)C1CCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of 8-benzyl-N-cyclobutyl-N-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.48 g) in methanol (10 mL) was added 20% Pd(OH)2/C (90 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (400 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (257 mg, 65%) as a colorless powder.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@@H:38]([C:52](O)=[O:53])[CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@H:38]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)[C:52]([N:4]3[CH2:3][CH2:2][N:1]([CH:7]4[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]4)[CH2:6][CH2:5]3)=[O:53])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
283 mg (1.00 mmol) ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butyrate (Example A16b) were added to a mixture of 500 mg (0.90 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 321 mg (1.00 mmol) TBTU and 0.14 mL (1.00 mmol) triethylamine in 10 mL DMF and the reaction mixture was stirred for 2 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined, evaporated down i. vac., the residue was stirred with saturated NaHCO3 solution, filtered and dried.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[C:9]([O:27][C:28]([F:31])([F:30])[F:29])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:14]1([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[O:27][C:28]([F:30])([F:31])[F:29])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2OC(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(N2CCOCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A 50 mL round-bottom flask was charged with a solution of tert-butyl 4-[[4-(morpholin-4-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate (590 mg, 1.32 mmol, 1.00 equiv) in dichloromethane (15 mL). Trifluoroacetic acid (262 mg, 2.30 mmol, 1.74 equiv) was added dropwise at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to provide 445 mg (crude) of 4-[4-(piperazin-1-ylmethyl)-3-(trifluoromethoxy)phenyl]morpholine as light yellow oil. LCMS (ESI, m/z): 346 [M+H]+.
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:40]=1)[C:35]([OH:37])=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)cc(OC(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-chloro-5-(trifluoromethoxy)benzoic acid (228 mg, 947 μmol, CAS RN 433926-46-6) after a reaction time of 19.5 hours. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (47%). MS (ESI): m/z=455.08 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C)ccc1F
Yield: 82.1 %

Procedure:
Heat a mixture of 2-fluoro-5-methyl-benzoic acid (1.0 g, 6.48 mmol), iodomethane (1.38 g, 9.73 mmol), and potassium carbonate (2.68 g, 19.44 mmol) in acetone (20 mL) at reflux overnight. Cool the reaction and filter through Celite®. Concentrate the filtrate under reduced pressure to provide the title compound as a colorless gum (0.895 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 2.32 (s, 3H), 3.89 (s, 3H), 6.95-7.10 (m, 1H), 7.20-7.30 (m 1H), 7.75-7.80 (m, 1H); TLC Rf=0.45 (2:1 Hexanes/Ethyl Acetate).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:15][C:14]2[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[C:19]([CH3:20])[C:13]=2[C@H:12]([CH2:23][Br:24])[O:11]1)C1C=CC=CC=1.[H][H]>[Pt].CO.C(OCC)(=O)C>[Br:24][CH2:23][C@H:12]1[C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([O:21][CH3:22])[C:14]=2[CH2:15][C@@H:10]([CH2:9][OH:8])[O:11]1
Reactant: [H][H]
Reactant: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CBr
Reaction time: 8 h

Procedure:
5% Platinum on carbon (1.0 g) is added to a solution of [1R,3S] 3-benzyloxymethyl-1-bromomethyl-3,4-dihydro-5-methoxy-8-methyl-1H-2-benzopyran (3.42 g, 8.7 mmol), from Step 2, in 150 mL of methanol and 5 mL of ethyl acetate. The reaction mixture is sealed under 4 atmospheres of hydrogen and shaken overnight. The reaction mixture is filtered to remove the catalyst and concentrated. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@H:19]1[CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CCCCOc1nc(N)c2c(n1)N(CCCN[C@H]1CCCO1)C(OC)N2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN[C@H]3CCCO3)c2n1
Yield: 97.1 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-{3-[(2R)-tetrahydro-2-furanylamino]propyl}-8,9-dihydro-7H-purin-6-amine (3 mg, 8.23 μmol) was stirred with 4M HCl in 1,4 dioxane (0.05 ml, 0.2 mmol) in methanol (2 ml) at 40° C. for 3 hours. The solvent was stripped using the Radleys blowdown apparatus under a stream of nitrogen. The sample was loaded in methanol and purified by SPE (2 g) on an aminopropyl (NH2) cartridge using methanol. The appropriate fractions were combined and dried under a stream of nitrogen to give the title compound as a white solid (2.8 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2)#N.C(O)=[O:15]>[Ni]>[O:13]=[C:7]1[CH2:6][CH2:5][C:4]2[C:3]([CH:1]=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1
Reactant: O=CO
Reactant: N#Cc1cccc2c1CCC(=O)N2
Agent: [Ni]
Product: O=Cc1cccc2c1CCC(=O)N2
Yield: 76 %

Procedure:
5-Cyano-3,4-dihydro-1H-quinolin-2-one (100 mg) and Raney nickel (100 mg) were suspended in formic acid (10 ml), and the suspension was heated under reflux for 2 hours. An additional 100 mg of Raney nickel was added, followed by heating under reflux for 1 hour. The reaction mixture was filtered to remove the insoluble matter, and the filtrate was concentrated. Ethyl acetate and water were added to the residue, and after stirring, the mixture was filtered through Celite. The filtrate was separated into layers, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 77 mg (yield: 76%) of 2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:22][CH3:23].Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:28]([Cl:44])=[CH:27][N:26]=1>>[Cl:44][C:28]1[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38](=[O:40])(=[O:39])[N:41]([CH3:42])[CH3:43])=[N:30][C:25]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:22][CH3:23])=[N:26][CH:27]=1
Reactant: CCN1C(=O)C(NC(=O)C2CC2)CCc2c1ccc(N)c2OC
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)C2CC2)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113 Cyclopropanecarboxylic acid (7-amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-amide (45 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide was converted to the title compound (48 mgs). 1H NMR (400 MHz, (CD3)2SO) δ 9.41 (s, 1H), 8.70 (s, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 4.19-4.30 (m, 2H), 3.69 (s, 3H), 3.48 (m, 1H), 3.04 (dd, J=13.7 Hz, J=5.4 Hz, 1H), 2.65 (s, 6H), 2.33-2.41 (m, 1H), 2.04-2.12 (m, 2H), 1.67 (m, 1H), 1.02 (t, J=6.8 Hz, 3H), 0.56-0.67 (m, 4H). LCMS: found 629.11 (m+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.60 g), methyl 3-(2-hydroxyphenyl)propionate (0.345 g), anhydrous potassium carbonate (0.529 g) and N,N-dimethylformamide (7 mL) was stirred at room temperature for 18 hrs., and further at 70° C. for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (0.61 g, 70%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1([OH:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][C:14]([OH:20])([CH3:13])[CH2:15][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1(O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(O)CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
A 50 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.57 g, 3.33 mmol), 4-methylpiperidin-4-ol (0.46 g, 3.99 mmol) and 4 Å molecular sieves (3.34 g) in DCE (20 mL) The reaction mixture was stirred for 6 h at room temperature. Sodium triacetoxyborohydride (1.41 g, 6.66 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the solution was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, 0:100 to 100:0) to give 3-(4-Hydroxy-4-methylpiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.49 g, 55%). 1H NMR (CDCl3, 400 MHz) δ 3.93 (dd, J=8.7, 7.17 Hz, 2H); 3.82 (dd, J=8.7, 5.5 Hz, 2H); 3.15-3.07 (m, 1H); 2.58-2.44 (m, 2H); 2.27 (td, J=11.0, 3.5 Hz, 2H); 1.77-1.54 (m, 4H); 1.42 (s, 9H); 1.26 (t, J=6.7 Hz, 3H).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](Br)=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O:27][B:28](OC)[O:29]C.Cl>CCCCCC.C(OCC)C>[Br:6][C:7]1[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][C:10]([B:28]([OH:29])[OH:27])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1
Reactant: COB(OC)OC
Reactant: Brc1cc(-c2ccccc2)c(Br)cc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(-c2ccccc2)c(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-2,5-diphenylbenzeneboronic acid is prepared as follows: A solution of n-butyllithium (1.6M, 15 ml) in hexane is added slowly to a cooled (-40° C.) solution of 1,4-di-bromo-2,5-diphenylbenzene (25 mmol) in diethylether (100 ml). This mixture is allowed to warm to room temperature an is stirred for 2 hours. This solution is transferred into a dropping funnel and added to a cooled (-60° C.) solution of trimethylborate (74 mmol) in ether (200 ml). It is then stirred for 8 hours at room temperature. After hydrolysis with aqueous HCl (2M, 150 ml), the layers are separated and the aqueous layer is extracted with ether (100 ml). The solvent is then removed from the combined organic layers and water (5 ml) and petroleum ether (100) are added. The precipitate is recovered by filtration, and recrystallized from toluene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:8](=[C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]=1[CH3:11])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:5]2.[Cl:28]S([N:32]=[C:33]=[O:34])(=O)=O.Cl.O>C(Cl)Cl>[ClH:28].[CH3:27][C:3]1[C:2]([NH:1][C:33]([NH2:32])=[O:34])=[C:10]([CH3:11])[C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCN1CCc2c(C)c(N)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCN1CCc2c(C)c(NC(N)=O)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 3 h

Procedure:
N-(5-Amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide (500 mg) was dissolved in methylene chloride (5.0 mL), and chlorosulfonyl isocyanate (0.14 mL) was added dropwise at −60° C. The mixture was stirred at the same temperature for 3 hr and 6M hydrochloric acid (0.45 mL) was added. The mixture was stirred at room temperature for 30 min. Water (50 mL) was added to the reaction solution and the mixture was extracted with chloroform (100 mL). The chloroform layer was washed with saturated brine and dried over sodium sulfate. Chloroform was evaporated under reduced pressure and the obtained crystalline residue was recrystallized from a mixture of chloroform-diisopropyl ether to give the title compound as crystals (407 mg).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:12]1([C:15]([O:17]CC)=O)[CH2:14][CH2:13]1)[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>[Ni]>[CH2:1]([NH:8][CH:9]1[C:12]2([CH2:14][CH2:13]2)[C:15](=[O:17])[NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(C#N)NCc2ccccc2)CC1
Agent: [Ni]
Agent: N
Product: O=C1NCC(NCc2ccccc2)C12CC2

Procedure:
An autoclave was charged with 61.3 mg of 1-(1-benzylamino-1-cyanomethyl)-1-ethoxycarbonylcyclopropane, 0.2 ml of Raney nickel and 2.0 ml of ammonia-saturated ethanol, and the contents were stirred at room temperature for 2 hours in an atmosphere of hydrogen under a pressure of 30 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 51.3 mg (quantitative) of the title compound in the form of light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[S:14][C:13]([C:15](OCC)=[O:16])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:9][C:10]1[S:14][C:13]([C:15](=[O:16])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 2-chloro-4-methylpyridine (15.6 mmol) and ethyl 5-chlorothiophene-2-carboxylate (17.2 mmol) in anhydrous THF (17 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 molar solution in hexanes, 31.3 mmol). The mixture was stirred 2 h at 5° C. The solvent was then evaporated and the residue was dissolved in a mixture of water and dichloromethane. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried with MgSO4, and concentrated under reduced pressure to afford 4.3 g (96% yield) of 1-(5-chloro-2-thienyl)-2-(2-chloropyridin-4-yl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:4]([CH:9]=[N:12][OH:13])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NO
Reactant: COc1nccnc1C=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nccnc1C=NO
Temperature: 60 °C
Yield: 32.2 %

Procedure:
A mixture of 3-methoxypyrazine-2-carboxaldehyde (Tetrahedron (1999), 56(2), 265-273) (2.1 g, 15 mmol), hydroxylamine hydrochloride (1.27 g, 18 mmol), ethanol (20 ml) and triethylamine (4.17 ml, 30 mmol) was heated at 60° C. for 90 minutes. The volatiles were removed by evaporation and residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (100:0 increasing in polarity 0:100) to give the title compound (740 mg, 32%) as a white solid.