Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[CH3:8][Si:9]([CH3:28])([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[O:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[CH2:19][O:18]1>C(O)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:19][CH:17]([OH:18])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][Si:11]([CH3:20])([CH3:21])[O:10][Si:9]([CH3:28])([CH3:8])[CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Reactant: NCCOCCO
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC(O)CNCCOCCO
Temperature: 70 °C

Procedure:
2-(2-Amino-ethoxy)-ethanol (3.02 g) and ethanol (40 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,1,3,3-Tetramethyl-3-(3-oxiranylmethoxy-propyl)-1-(2-trimethylsilanyl-ethyl)-disiloxane (2.0 g) mixed with ethanol (10 mL) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, ethanol was removed under vacuum, and the mixture was vacuum distilled to remove impurities and excess raw material.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:18])=[O:12])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(C(=O)O)c21
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2ccn(C)c12
Yield: 59 %

Procedure:
To 70 ml of a methanol solution of 1.82 g (10.4 mmol) of 1-methyl-7-indolecarboxylic acid was added dropwise 3.09 g (26.0 mmol) of thionyl chloride at 0° C. The reaction mixture was refluxed for 2 hours and the solvent was then distilled off under reduced pressure. Ice water was poured onto the resulting residue and ammonium hydroxide was added to render the mixture alkaline. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 1.16 g (59.0%) of methyl 1-methyl-7-indolecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].NCCC(O)=O>C(O)CCC>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C=O)cc1
Reactant: CC[N+](=O)[O-]
Agent: NCCC(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc(-n2ccnc2C)cc1)[N+](=O)[O-]

Procedure:
Similar to example 4(a), the reaction is carried out with 66 g 4-(2-methyl-1-imidazolyl)-benzaldehyde (DE-OS No. 33 06 196), 31.7 g nitroethane, 3.2 g β-alanine and 250 ml n-butanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].C1C=CC=CC=1.N1C=CC=CC=1.[C:28]([OH:32])([CH3:31])([CH3:30])[CH3:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Yield: 49 %

Procedure:
The crude 3,4-dinitrobenzoyl chloride, 500 ml. of benzene, 25 ml. of pyridine and 22 g. (0.30 of t-butyl alcohol were reacted as in Example 6 (A), second paragraph, to provide 33 g. (49 percent yield) of t-butyl 3,4-dinitrobenzoate.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]1[CH:9]([C:10](=[O:21])[CH2:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[S:8][CH2:7][NH:6]1)C.[OH-].[Na+]>C(O)C>[CH:12]1([CH2:11][C:10]([CH:9]2[S:8][CH2:7][NH:6][C@@H:5]2[C:4]([OH:22])=[O:3])=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 1.45 g of 3-(2-indanylacetyl)-L-thioproline ethyl ester prepared in Reference Example 1 in 17 ml of ethanol was added 28 ml of 1 N sodium hydroxide, and the mixture was stirred at room temperature. After 1 hour, ethanol was evaporated under reduced pressure. Twenty (20) ml of water was added to the residue and the solution was washed with ethyl acetate. The water layer was acidified with the addition of diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to produce 0.76 g of 3-(2-indanylacetyl)-L-thioproline (yield: 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11](OC)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)(=O)C>[C:17]([O:16][C:14]([N:12]1[CH2:11][CH2:10][CH:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC1CC(c2cc(Cl)cc(Cl)c2)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Synthesized according to General procedure 3. To a stirred solution of tert-butyl 4-(3,5-dichlorophenyl)-2-methoxypyrrolidine-1-carboxylate (20 g, 0.058 mol) in acetic acid (200 mL) under N2 at 0° C. was added sodium borohydride (4.37 g, 0.116 mol) in portions over 20 minutes. The resulting solution was allowed to warm to RT and then stirred at RT for 1 hour. The reaction mixture was slowly poured into 2 M aqueous NaOH solution (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic extracts were dried over Na2SO4, filtered through a pad of Celite and then concentrated under reduced pressure to afford tert-butyl-3-(3,5-dichlorophenyl)pyrrolidine-1-carboxylate as a brown oil (18.3 g, 0.058 mol, 100% yield). 1H-NMR (400 MHz, CDCl3) δ 7.28-7.24 (m, 1H), 7.13 (d, J=1.3 Hz, 2H), 3.80-3.76 (m, 1H), 3.65 (t, J=8.4 Hz, 1H), 3.56 (t, J=8.1 Hz, 1H), 3.46-3.39 (m, 1H), 3.35-3.23 (m, 1H), 2.27 (d, J=4.3 Hz, 1H), 2.01-1.93 (m, 1H) and 1.51 (s, 9H) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([C:21]2[N:29]3[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH2:38][CH2:39][O:40][CH2:41][CH2:42]5)=[CH:33][CH:32]=4)=[N:28]3)=[CH:23][CH:22]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CC1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Into a 30 mL vial, Palladium Acetate (35 mg, 0.16 mmol) and Triphenylphosphine (100 mg, 0.4 mmol) were added and purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (5.9 mL) was added and stirred for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.250 g, 0.668 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.413 g, 1.34 mmol), N,N-Dimethylformamide (5.9 mL) and 1.50 M of Sodium carbonate in Water (2.47 mL, 3.70 mmol) were added and heated at 85° C. for 8 hours. The reaction was partitioned with DCM. The solid was filtered and washed with DCM. The organic solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (180, 56%). LCMS (E/I+) 477.8 (M+H). NMR 1H (DMSO-d6)-9.15 (s, 1H), 8.88 (s, 1H), 7.57 (d, 2H, J=8.75 Hz), 7.10 (bs, 1H), 6.91 (d, 2H, J=8.75 Hz), 6.82 (d, 1H, J=4.66 Hz), 6.79 (d, 1H, J=4.66 Hz), 4.12 (bs, 2H), 3.74 (t, 4H, J=4.66 Hz), 3.58 (t, 2H, J=5.25 Hz), 3.06 (t, 4H, J=5.25 Hz), 2.58 (bs, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[NH2:19][C@H:20]([C:22]([NH2:24])=[O:23])[CH3:21].[BH3-]C#N.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:19][C@@H:20]([CH3:21])[C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=1
Reactant: C[C@H](N)C(N)=O
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NCc1ccc(OCc2cccc(F)c2)cc1)C(N)=O

Procedure:
(S)-2-[4-(3-Fluorobenzyloxy)benzylamino]propanamide (Ia) is prepared by reacting 4-(3-fluorobenzyloxy)benzaldehyde (10 mmol), prepared as described in Example 14.1.a., and L-alaninamide hydrochloride (1.37 g, 11 mmol) followed by reduction with NaBH3CN (0.50 g, 8 mmol). After working up the reaction mixture and purification by flash-chromatography, (S)-2[4-(3-fluorobenzyloxy)benzylamino]propanamide is isolated as white solid in 68.7% yield. The product has HPLC purity of 96.2 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (IIa) of 0.15% by weight (see Example 17B).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:35]([C:37]1[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:35][C:37]4[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=4)[CH2:16][CH2:17]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1cccc(F)c1
Reactant: CC(C#N)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)Cc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reaction time: 0.17 h

Procedure:
To a 20 mL dichloroethane solution of 0.35 g (0.92 mmol) 4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one and 0.25 mL (1.4 mmol) DIEA went 0.16 g (0.92 mmol) 3-(3-formylphenyl)-2-methylpropanenitrile (9-3). The suspension was allowed to stir for 10 min then 0.4 g (1.9 mmol) sodium triacetoxyborohydride was added and the reaction was allowed to stir at rt overnight. HPLC/MS showed no starting material so the reaction was quenched with 100 mL sat NaHCO3 and diluted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The remaining oil was purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 5% MeOH+0.5M NH3 in CH2Cl2 at 25 mL/min over 30 min. The product eluted second.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1cccc(SC(C(=O)O)C(=O)O)c1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: COc1cccc(Sc2c(O)cc(-c3ccccc3)oc2=O)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 130-131° C. 1H NMR (400 MHz, DMSO-d6) δ3.69 (s, 3H), 6.69 (dd, 1H), 6.72 (dd, 1H), 6.89 (s, 1H), 7.2 (dt, 2H), 7.58 (m, 3H), 7.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(COCc2ccc(Cl)nc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
(6-Chloropyridin-3-yl)methanol (4.3 g) was dissolved in tetrahydrofuran (150 mL), and the solution was cooled to 0° C. Sodium hydride (63%, 1.4 g) was added thereto, and the mixture was stirred at 0° C. for 1 hour. Subsequently, 4′-(bromomethyl)biphenyl-2-carbonitrile (9.0 g) was added thereto at 0° C., and the mixture was stirred at 50° C. for 19 hours. The reaction solution was brought back to room temperature, and a saturated aqueous ammonium chloride solution was added thereto. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent: hexane/ethyl acetate) to obtain the title compound (6.2 g) as a white solid (yield: 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[NH2:18][CH2:19][C:20]1[C:21]([Cl:36])=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25](C(OC(C)(C)C)=O)[CH:24]=[CH:23]2.ClC1N=C(NC2NN=C(C3CC3)C=2)C=CN=1.C(O)(=O)CCCCC(O)=O.N1C2C(=CC(C(N)C)=CC=2)C=C1>>[Cl:36][C:21]1[C:20]([CH2:19][NH:18][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[CH:5]=[C:4]([CH3:17])[N:3]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2
Reactant: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Agent: CC(N)c1ccc2[nH]ccc2c1
Agent: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Agent: O=C(O)CCCCC(=O)O
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3[nH]ccc3c2Cl)n1

Procedure:
N2-((4-chloro-1H-indol-5-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylpyrimidine-2,4-diamine (I-19) was prepared using procedure analogous to the preparation of I-8, step 1, except 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-pyrimidin-4-amine 185 and tert-butyl 5-(aminomethyl)-4-chloro-1H-indole-1-carboxylate were used in place of 53 and 1-(1H-indol-5-yl)ethanamine adipic acid salt, respectively, to afford I-19; MS (ESI) m/z=394.1 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[O:15]
Reactant: Cc1ncoc1CSCCN
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1ocnc1C

Procedure:
Reacting 5-[(2-aminoethyl)thiomethyl]-4-methyloxazole with methyl isocyanate by the procedure of Example 24 gives the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH:19]([N:32]1[CH2:37][CH2:36][N:35]([CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:34][CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cc2)nc1
Yield: 24.1 %

Procedure:
Using a method similar to Example 334, using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), 1-benzhydryl-piperazine (0.470 g, 1.86 mmol), and sodium borohydride (0.111 g, 2.93 mmol) in methanol (12 mL), after additional purification by reverse-phase HPLC, provides 0.143 g (24%) of the title compound as a yellow foam: high resolution mass spectrum (electrospray): m/z calc for C30H31N4O2 479.2447, found 479.2462; 1H NMR (methanol-d4): 8.65 (d, 1H, J=2.0 Hz), 8.29 (dd, 1H, J=2.4, 8.8 Hz), 7.49-7.42 (m, 6H), 7.30 (t, 4H, J=7.8 Hz), 7.23-7.17 (m, 2H), 7.14 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=8.8 Hz), 4.28 (s, 1H), 3.63 (s, 2H), 2.72-2.30 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:20][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1OC
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, phenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 50 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 21 mg of the title compound (yield: 41%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][C:15]3=[CH:17][NH:18][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[C:8]2=[O:19])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27]([CH2:29][C:30](ON1C(=O)CCC1=O)=[O:31])#[N:28]>CCO>[O:31]=[C:30]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:16][C:15]3=[CH:17][NH:18][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[C:8]2=[O:19])[CH2:5][CH2:6]1)[CH2:29][C:27]#[N:28]
Reactant: O=C1c2ccnc3[nH]cc(c23)CN1C1CCNCC1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
4-(Piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (34 mg, 0.133 mmol) and triethylamine (0.055 mL, 0.398 mmol) were dissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10 min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (29 mg, 0.159 mmol) dissolved in EtOH (1 mL) was added dropwise and the mixture was allowed to stir for 30 min at 0° C. The solution was concentrated in vacuo and purified via preparative HPLC eluting with 10% to 40% B in A and gave 10 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 7.60 (m, 1H), 7.43 (m, 1H), 4.98 (s, 2H), 4.84-4.88 (m, 1H), 4.68-4.72 (m, 1H), 3.89-3.95 (m, 3H), 3.33 (m, 1H), 2.80-2.88 (m, 1H), 1.86-2.05 (m, 4H). [M+H] found 324.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1.C(=O)([O-])O.[Na+].C(O)(=O)C>O1CCCC1.O>[OH:24][CH:23]([C:22]1[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][C:21]=1[N+:27]([O-:29])=[O:28])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C#CC(=O)OCC
Reactant: Cc1ccc(C=O)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccc(C)cc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 102.6 %

Procedure:
(a-1) To a solution of ethyl propiolate (6.6 ml, 65 mmole) in tetrahydrofuran (70 ml) was added at -65° C. under the argon atmosphere a solution of 1.0M lithium bistrimethylsilylamide in tetrahydrofuran (65 ml, 65 mmole), and the mixture was stirred for 20 minutes. A solution of 4-methyl-2-nitrobenzaldehyde (8.3 g, 50 mmole) in tetrahydrofuran (30 ml) was added, and the reaction mixture was further stirred at 65° C. for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution (80 ml) or a solution of acetic acid (13.0 ml, 220 mmole) in tetrahydrofuran (20 ml), followed by water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4-methyl-2-nitrophenyl)-2-butynoate as an oil (13.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[N:15]2)[N:4]=1>CCOC(C)=O.CCO.O=[Pt]=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:6]=1
Reactant: COc1cc(OC)nc(OCCn2cc([N+](=O)[O-])cn2)n1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(OCCn2cc(N)cn2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4,6-dimethoxy-2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)pyrimidine (2.05 g, 6.93 mmol), in EtOAc (3.0 mL, degassed) and EtOH (9 mL, degassed), PtO2 (135 mg, 0.70 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 3 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain the title compound as a red oil. LC-MS conditions A: tR=0.58 min, [M+H]+=266.02.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([O-:25])=[O:24])=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].[K+]>CN(C)C=O>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH3:26])[C:23]([O:25][CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[O:3]2)=[O:24])=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Reactant: O=C1OC(Br)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(C)C(=O)OC2OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a solution of 10.65 g of 3-bromophthalide in 100 ml of dimethylformamide is added 12.2 g of potassium 2-(4-isobutylphenyl)propionate under stirring at room temperature. The reaction mixture is stirred 24 hours at room temperature, and then poured into 500 ml of ice water. After extraction with chloroform, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, yields 11.8 g of phthalidyl 2-(4-isobutylphenyl)propionate having the same physico-chemical characteristics of the compound of Example 1.