Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH:4]=[O:5].[Si:8](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.O>CN(C)C=O>[Si:8]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH:2]=[O:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
3-Hydroxy-2,2-dimethylpropanal (5.1 g, 50 mmol) and tert-butyl-diphenylsilyl chloride (15.10 g, 55 mmol) were dissolved in dimethylformamide (50 ml). Imidazole (3.74 g, 55 mmol) was added in one portion. After stirring for 18 hours the mixture was hydrolyzed with water and extracted several times with ether. The combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (hexane/ethyl acetate 15:1) to give the title compound (9.55 g, 56%) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:51])[CH2:17][C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27](OC4CCCCO4)[CH2:28][C@@H:29]2OC2CCCCO2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:14]>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16](=[O:51])[CH2:17][C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:14]
Reactant: CCOC(=O)C[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C[C@H]1CC[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 mL of diisopropylamine in 3 mL of tetrahydrofuran at -30° C. was added 3.82 mL (0.0061 mol) of 1.6 M of butyllithium in hexane. After stirring for 0.5 hr, 3.03 g (0.0056 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]pregn-5-en-21-oic acid ethyl ester in 30 mL of tetrahydrofuran was added dropwise to yield the lithium enolate of [1α,3β]-1,3-bis[tetrahydro-2H-pyran-2-yl)oxy]pregn-5-en-21-oic acid ethyl ester. The mixture was stirred for 1 hr at -30° C. and cooled to -70° C. A solution of 2.30 g (0.0068 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-1-iodo-4-methylpentane in 5 mL of hexamethylphosphoramide was added dropwise. The mixture was stirred at -70° C. for 1 hr and was allowed to warm to 25° C. and stir for 1 hr. The mixture was then diluted with 9:1 hexane-ether. The solution was washed with water, and saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to give [1α,3β]-1,3-bis[(tetrahydro-2H-yran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-oic acid ethyl ester, [α]D20 +10° (c 1, CHCl3).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17](F)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[O:23][CH3:24])(C)C)(C)(C)C.[NH2:25][C:26]1[S:27][C:28]([C:38]([NH2:40])=[O:39])=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[Cl:37][C:33]1[CH:32]=[C:31]([C:29]2[N:30]=[C:26]([NH:25][C:17]3[CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[C:14]([O:23][CH3:24])=[CH:15][C:16]=3[N+:20]([O-:22])=[O:21])[S:27][C:28]=2[C:38]([NH2:40])=[O:39])[CH:36]=[CH:35][CH:34]=1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1OCCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1OCCCO
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
A mixture of 0.469 g (1.31 mmole) of tert-butyl-[3-(5-fluoro-2-methoxy-4-nitro-phenoxy)-propoxy]-dimethyl-silane (IV.42), 0.331 g (1.31 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 1.28 g (3.93 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 70 degrees for 3 hours. The mixture was cooled and 3 mL of 6M hydrochloric acid was added dropwise. Stirring was continued for 15 minutes. The mixture was poured into 50 mL of water, and the precipitated orange solid was collected by filtration, washed with water, and air-dried to give 0.535 g of 4-(3-chloro-phenyl)-2-[5-(3-hydroxy-propoxy)-4-methoxy-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.42).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33](OC)=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:41].[Na+]>CO.C1COCC1>[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:39])[CH3:40])[C@H:20]2[CH2:21][C@@H:22]([C:33]([N:6]3[CH2:7][CH2:8][O:41][CH2:1][CH2:5]3)=[O:34])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:25]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (219 mg) was dissolved in methanol (3 ml) and THF (2 ml), 1M aqueous sodium hydroxide solution (2 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the aqueous layer of the mixture was adjusted to pH 5-6 with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue, morpholine (41 μl), 1H-benzotriazol-1-ol (30 mg) and triethylamine (140 μl) were to dissolved in 1,2-dichloroethane (4 ml), WSC.HCl (115 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object product (88 mg).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:23]([C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=3[OH:12])=[O:24])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1O

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 1-hydroxy-2-naphthoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.95-2.04 (m, 2H), 2.15-2.27 (m, 1H), 2.33-2.46 (m, 3H), 2.56-2.64 (m, 1H), 3.48-3.90 (m, 6H), 4.42-4.53 (m, 1H), 7.05-7.28 (m, 1H), 7.37-7.57 (m, 2H), 7.67-7.78 (m, 1H), 7.81-7.90 (m, 1H), 8.34-8.44 (m, 1H); MS (APCI/NH3) m/z 323 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1[O:31][C:30]2[C:25](=[CH:26][CH:27]=[C-:28][CH:29]=2)[O:24]1.[Mg+2].[Br-].C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([CH:21]([OH:22])[CH2:20][C:10]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([Cl:19])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: [c-]1ccc2c(c1)OCO2
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.380 mmol) in tetrahydrofuran (4 mL) at −78° C. was dropwise added a 1M solution of 3,4-(methylenedioxy)phenylmagnesium bromide in 1:1 toluene/tetrahydrofuran (0.380 mmol, 1.0 eq.) and stirring at −78° C. was continued for 10 min. The reaction mixture was then allowed to warm to room temperature and was stirred 1 h then quenched with saturated aqueous sodium bicarbonate solution (2 mL). After stirring 15 min the reaction mixture was extracted with ethyl acetate (3×5 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give a brown oil that was purified by column chromatography using 30% ethyl acetate/hexanes to give the final product as a white foam (0.126 mmol, 33%). MS (ESI) m/z 434.2; HRMS: calcd for C25H20ClNO4+H+, 434.11536; found (ESI, [M+H]+ Obs'd), 434.1150.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.C(O[C:29](=[O:45])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=2)[CH:34]=1)=O)(C)(C)C.[C:46](O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:46][C:12]1[C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]2[NH:22][C:29](=[O:45])[CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]4[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=4)[CH:34]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1ccnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Solvent: ClCCl
Product: Cc1cc2c(cc1C#Cc1ccccc1)NC(=O)CC(c1cccc(-c3nccn3C)c1)=N2

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (620 mg, 2.0 mmol) and 3-[3-(1-methyl-1H-imidazol-2-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H21) (1.26 g, 4.2 mmol) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (81 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[OH:32])[C:6]([NH:8][NH:9][C:10]([C:12]1[O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])=[O:7])#[N:2].C1(=O)O[CH2:36][CH2:35][O:34]1>[I-].C([N+](CC)(CC)CC)C.CN(C=O)C>[OH:34][CH2:35][CH2:36][O:32][C:31]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][NH:9][C:10]([C:12]2[O:13][CH:14]=[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[O:7])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1OCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
A mixture of the compound of Example 18 (0.42 g), ethylene carbonate (0.088 g), tetraethylammonium iodide (0.026 g) and DMF (10 ml) was stirred at 100° C. for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 50%→90% ethyl acetate/hexane gradient), thereby giving 0.26 g of the desired compound. HPLC retention time: 6.31 minutes.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[C:26]2[C:37]2[CH:42]=[CH:41][N:40]=[C:39](SC)[N:38]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>C(OCC)(=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[C:26]2[C:37]2[CH:42]=[CH:41][N:40]=[C:39]([S:45]([CH3:2])(=[O:49])=[O:47])[N:38]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)n1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)ccn2C2CCN(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
3.51 g (15.26 mmol) of 69–75 wt. % of m-chloroperbenzoic acid were added in small portions to a solution of 3.50 g (7.63 mmol) of 1-(1-benzylpiperidin-4-yl)-3-(4-fluorophenyl)-2-(2-methylthiopyrimidin-4-yl)-1H-pyrrole [prepared as described in step 42(i) above] in 35 ml of ethyl acetate with ice-cooling. The resulting mixture was stirred at room temperature 2 days, after which a 10% aqueous solution of sodium thiosulfate was added to the reaction mixture followed by extraction with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 9:1 by volume mixture of dichloromethane and methanol as the eluant to give 2.48 g (yield 66%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([CH3:46])[C:31]([C@H:33]1[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=[O:32]>C(Cl)Cl>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]([CH3:46])[C:31]([C@H:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)=[O:32]
Reactant: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of (S)-tert-butyl 3-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl(methyl)carbamoyl)piperidine-1-carboxylate (720 mg) in DCM (2 mL) and stirred at RT for 30 minutes. The solvents were removed under vacuum to give a TFA salt of (S)—N-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl)-N-methylpiperidine-3-carboxamide (760 mg).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:15]([C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Product: CCOC(=O)c1cnc(Nc2ccccc2)[nH]c1=O
Temperature: 130 °C
Yield: 61.2 %

Procedure:
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (5 g) and aniline (2.6 g) is heated without solvent at 130° C. for 1 hour. After cooling, the resulting solid is pulverized and recrystallized from DMSO to give ethyl 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylate (3.7 g). M.p. 267°-269° C.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)nc1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-hydroxy-4-(5-methoxy-pyridin-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(N(CC)CC)C.Cl[CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][CH2:20][C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A solution of 2-Amino-4-nitro phenol (6.0 g, 38.93 mmol) in methylene chloride (200 ml) was cooled to 0° C. Triethyl amine (16.3 ml, 116.9 mmol) was added followed by chloroacetyl chloride (3.42 ml, 42.8 mmol) portionwise. The mixture was stirred at room temperature for 18 hours, then diluted with methylene chloride. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.5 g of 6-nitro-4H-benzo[1,4]oxazin-3-one as a solid, 100%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:23][C:24]([O:26][CH2:27]C)=[O:25]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CN2)cc1
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of 2-[(benzyloxy)methyl]aziridine (0.42 g, 2.57 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.90 mmol) in dichloromethane (15 mL) under an atmosphere of nitrogen, ethyl bromoacetate (0.39, 2.5 mmol) was added over a period of 1 h. The resultant mixture was allowed to slowly warm up to room temperature and stirred overnight. The resultant mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 70% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: CO[C:3]([C:5]1([CH3:29])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]([F:21])[F:20])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[NH:6]1)=[O:4].[Br:30][CH2:31][CH2:32][N:33]=[C:34]=[O:35].C(=O)(O)[O-].[Na+].[CH3:41][C:42](=[O:45])[CH2:43]C>>[CH:5]([O:45][CH:42]([CH3:43])[CH3:41])([CH3:17])[CH3:3].[Br:30][CH2:31][CH2:32][N:33]1[C:34](=[O:35])[N:6]2[CH:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:29])[C:3]1=[O:4])=[CH:14][C:13]([O:18][CH:19]([F:21])[F:20])=[CH:12][CH:11]=4
Reactant: CCC(C)=O
Reactant: O=C=NCCBr
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC(F)F)cc23)C(c2cccc(O)c2)N1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)OC(C)C
Product: CC12Cc3c([nH]c4ccc(OC(F)F)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Yield: 61 %

Procedure:
To a solution of 5.5 mg (1RS,3SR)-6-(1,1-difluoro-methoxy)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 10 ml 2-butanon are added 132 μl bromoethyl isocyanate. The mixture is heated to reflux for 30 h. An aqueous solution of sodium bicarbonate is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried with magnesium sulfate. The solvent is removed at reduced pressure. After column chromatography (silica gel; toluene, ethyl acetate 4:1) and trituration with diisopropylether, 550 mg (61%) of the title compound are obtained as a colorless solid. MS: m/z (MH+)=519.9/522.0
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[CH3:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.[CH:27](N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH:2]([CH3:27])[CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[N:6]3)[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: ClCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(N2CCN(C(C)CCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
1-(3-chloropropyl)-1H-benzotriazole (7.02 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-methyl phenylpiperazine (5.3 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.5 g compound (I-39) with a yield of 74.6%. ESI-MS [M+H]+: m/z 335.2.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]>>[F:1][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: [K+]
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1F

Procedure:
reacting potassium fluoride with 4-chloro-3,5-dinitrobenzotrifluoride in the liquid phase, at a temperature of about 75° to about 160° Celsius to form 4-fluoro-3,5-dinitrobenzotrifluoride; and
Reaction SMILES: [K].[O-]CCCC.[C:7]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(OC)=[O:8].C(O)(=O)C>CS(C)=O.O>[O:8]=[C:7]1[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)COc1ccccc1OCC(=O)OC
Agent: CCCC[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1Oc2ccccc2OCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium t.-butoxide (15.8 g.) dissolved in DMSO (130 ml.) is added dropwise over a 45 minute period to 1,2-bis-carbomethoxymethoxybenzene (18.3 g.) in DMSO (30 ml.) under an atmosphere of nitrogen. The mixture then is stirred 3 hours at ambient temperature and a mixture of acetic acid (16 ml.) and water (200 ml.) is added. The reaction mixture is extracted with benzene, the powdery material removed by filtration and the benzene then dried over magnesium sulfate and the benzene then evaporated leaving 3-oxo-4-carbomethoxy-3,4-dihydro-2H-1,5-benzodioxepin that is used in the following step without purification.
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)(=O)[CH3:2].[NH2:18][NH2:19].O>CCO>[CH3:2][C:1]1[C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[NH:19][N:18]=1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C
Yield: 76.3 %

Procedure:
To a solution of tert-butyl 3-acetyl-4-oxopiperidine-1-carboxylate (10.00 g, 41.44 mmol, 1.0 eq) in EtOH was added 98% H2NNH2—H2O (3.11 mL, 62.16 mmol, 1.5 eq). The reaction mixture was heated to 90° C. and refluxed for 2.0 h. The resulted mixture was concentrated in vacuo to give two tautomers as yellow oil (7.5 g, 76.5%), and which were used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 238.31 (M+1);