Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]=[O:14])[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][Mg+].[Br-].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:14])[CH3:16])[CH2:10][C:9]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Reactant: C[Mg+]
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(O)CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
1-(t-butyldimethylsilyl)-4-(2-oxoethyl)-2-azetidinone (2.27 g, 0.01 mole) is dissolved in 50 ml ether and cooled to -20° C. under N2. A solution of CH3MgBr in ether (0.011 mole CH3MgBr) is added dropwise over 1/2 hours at -20° C. and the reaction mixture is stirred for another 1/2 hr at -20°, allowing to rise to 25° C. The reaction mixture is treated with a saturated solution of MgSO4 (2 ml) and allowed to stir for 15 min. The Mg salts are filtered off and washed with ether. The combined filtrate and washings are dried and evaporated. Chromatography of the residue on silica gel gives 1-(t-butyldimethylsilyl)-4-(2-hydroxypropyl)-2-azetidinone.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C@H:5]1[CH2:20][C:9]2=[CH:10][NH:11][C:12]3=[CH:13][CH:14]=[C:15]([C:16]([NH:18][NH2:19])=[O:17])[C:7](=[C:8]23)[CH2:6]1)[CH2:2][CH3:3]>COC(OC)(OC)C1C=CC=CC=1.C(Cl)Cl>[C:7]1([C:15]2[O:17][C:16]([C:15]3[CH:14]=[CH:13][C:12]4[NH:11][CH:10]=[C:9]5[CH2:20][C@H:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:21][CH2:22][CH3:23])[CH2:6][C:7]=3[C:8]=45)=[N:18][N:19]=2)[CH:8]=[CH:9][CH:20]=[CH:5][CH:6]=1
Reactant: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(C(=O)NN)c(c23)C1
Agent: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4nnc(-c5ccccc5)o4)c(c23)C1
Yield: 163.9 %

Procedure:
A solution of 0.20 g (0.64 mmol) of (4R)-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole-6-carboxylic hydrazide in 2.0 ml of trimethylorthobenzoate was heated at 135° C. under nitrogen for 5 hours. After cooling, the semisolid mixture was dissolved in methylene chloride and the product was extracted into aqueous tartaric acid. The aqueous solution was basified with sodium carbonate and the product was extracted into methylene chloride. Evaporation of the methylene chloride left crystalline product which was then chromatographed over 3 g of silica gel using ethyl acetate as eluent. The product from the column was recrystallized from toluene to give 0.21 g of title compound. m.p. 215°-216° C. MS (FD) 400 [60 ]D -23.0° (MeOH)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[Na+].[Br:14]Br>C(O)(=O)C.[Zn]>[Br:14][C:6]1[C:2]([CH3:1])=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH:5]=1
Reactant: CCOC(=O)c1sccc1C
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1scc(Br)c1C
Temperature: 85 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of ethyl 3-methyl-2-thiophenecarboxylate (20.0 g, 0.118 mol) and sodium hydroxide (12.3 g, 0.307 mol) in acetic acid (75 mL) was heated to 60° C. Bromine (46.9 g, 0.294 mol) was added dropwise at such a rate so as to maintain the temperature of the reaction mixture at <85° C. When the addition was complete, the resulting solution was stirred at 85° C. for 6 hours, at which time analysis by gas chromatography/mass spectrometry showed complete conversion to ethyl 4,5-dibromo-3-methyl-2-thophenecarboxylate. The solution was allowed to cool to 50° C. and zinc dust (15.4 g, 0.236 mol) was added in 3 gram portions such that the exotherm was controlled to remain below 85° C. When the addition was completed, the resulting slurry was stirred at 85° C. for one hour. The solution was filtered hot through a small bed of celite. Water (300 mL) was added and the mixture was extracted with heptanes (300 mL). The organic phase was washed with water, then concetrated to dryness to give 26.9 g (89%) as an off white oil which slowly crystallized upon standing at ambient temperature. In a similar fashion, methyl 3-methyl-2-thiophenecarboxylate may be converted methyl-4bromo-3-methyl-2-thiophenecarboxyltate in 97% yield.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][CH:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)OC1(C)C>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:35]3[CH:36]=[CH:37][C:38]([N:41]4[CH2:46][CH2:45][CH:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]4)=[CH:39][CH:40]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)C1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Product: CCOC(=O)C1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2)CC1
Yield: 44.7 %

Procedure:
Compound 2b (350 mg, 0.760 mmol) was subjected to Suzuki coupling conditions with ethyl 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carboxylate (881 mg, 2.28 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 18d as a brown solid (200 mg, 42% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C35H36N6O3: 589.3 (M+H). Found 589.2.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)[CH2:5][CH2:4][C:3]1[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=1[O:1][CH2:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:34][CH:33]=1
Reactant: ClCc1ccc(C=Cc2ccccc2)cc1
Reactant: COC(=O)CCCCN(CCc1ccccc1O)Cc1ccc(C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(/C=C/c2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
1.0 g (2.50 mmol) of methyl 4-{[(2-hydroxyphenethyl)-(5-methoxy-5-oxopentyl)-amino]methyl}benzoate from Ex. I, 0.687 g (3.00 mmol) of 4-(chloromethyl)stilbene and 0.520 g (3.75 mmol) of potassium carbonate in 10.0 ml of acetonitrile are heated at reflux for 18 hours. The solution is filtered and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography over silica gel using the mobile phase cyclohexane/ethyl acetate 4/1.
Reaction SMILES: [C:1]([P:5]([CH2:10][C:11](=[CH2:22])[CH2:12]P1C2CCCC1CCC2)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C(PC(C)(C)C)(C)(C)C.[Cl:32]CC(CCl)=C>C(#N)C>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:10][C:11]([CH2:12][Cl:32])=[CH2:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(CP1C2CCCC1CCC2)CP(C(C)(C)C)C(C)(C)C
Reactant: C=C(CCl)CCl
Agent: CC(C)(C)PC(C)(C)C
Solvent: CC#N
Product: C=C(CCl)CP(C(C)(C)C)C(C)(C)C
Temperature: 60 °C
Yield: 40 %

Procedure:
FIG. 1: 9-(2-{[di(tert-butyl)phosphino]methyl}-2-propenyl)-9-phosphabicyclo[3.3.1]nonane A mixture of di-tert-butylphoshine (5 g, 34.1 mmol) and 3-chloro-2-chloromethyl-1-propene (14.04 g, 69 mmol) was dissolved in degassed acetonitrile (70 ml) and heated to 60° C. for 16 hours. The solvent was removed in vacuo and the product was suspended in hexane (50 ml). After filtration the product was washed with hexane (2 times 40 ml). The white solid salt was neutralized in a mixture of toluene (50 ml) and water (30 ml) with HNEt2 (5 ml) under reflux conditions. The toluene layer was separated, washed with water (2 times 30 ml) and removed in vacuo, to yield 3.14 g (40%) of di(tert-butyl)[2-(chloromethyl)-2-propenyl]phosphine. The product could be characterized by showing a distinct resonance signals in 31P NMR at δ=+21.7 ppm.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CO[C:17](OC)([CH3:22])[C:18](OC)=[O:19]>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:19])[CH:17]=[CH:22][C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Reactant: COC(=O)C(C)(OC)OC
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2ccc(=O)[nH]c21
Temperature: 110 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
To 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (5.0 g, 25.9 mmol) in AcOH (25 mL) was added methyl dimethoxypropionate (7.4 mL, 51.8 mmol), and then the reaction was heated to 110° C. After 24 hr, the reaction mixture was cooled to room temperature, and concentrated to a viscous oil that was treated with EtOAc. The organic layer was washed with aqueous NaHCO3 dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a 45L Biotage® column eluting with 20% EtOAc/hexanes. The product-containing fractions were collected and concentrated under reduced pressure, and the resulting solid was washed with hexanes and dried to afford the title compound (2.0 g, 32% yield) as a colorless solid. Rf=0.33 (10% MeOH/CH2Cl2); 500 MHz 1H NMR (CDCl3) d 7.72 (d, J=9.1 Hz, 1H), 6.26 (d, J=9.1 Hz, 1H), 3.68 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.46-2.32 (m, 4H), 2.14-1.89 (m, 2H), 1.71 (s, 9H); LRMS m/z (APCl+) 246 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)[CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c(C2CCCNC2)nc2ccc(Cl)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)nc21
Yield: 61.5 %

Procedure:
Compound 35C (0.288 mmol, 0.122 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.455 mmol, 0.150 g) and N-methylmorpholine (1.15 mmol, 0.127 mL) were then added and the solution was allowed to stir at it for 5 min. HATU (0.317 mmol, 0.120 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (40-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-Butyl 4-(3-(5-chloro-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (35D) as a clear oil (0.177 mmol, 0.110 g, 62% yield). ESI-MS: m/z 620.4 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2([CH:11]=[O:25])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccccc2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 1-phenyl-cyclobutanecarbonitrile, dissolved in 70 ml of toluene, is mixed with 56 ml of diisobutylaluminum hydride in toluene (1.2 molar) at −72 to −69° C. After 4 hours at −75° C., 30 ml of ethyl acetate is added in drops. After heating to room temperature, additional ethyl acetate and water are added. It is filtered on diatomaceous earth, the organic phase is separated, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel (hexane with 0-10% ethyl acetate), 7.6 g of 1-phenyl-cyclobutanecarbalde-hyde is obtained. 3 g of it is dissolved in 10 ml of tetrahydrofuran and added in drops at 0° C., to a solution, in which previously 5 g of triethyl-2-ethoxyphosphonoacetate in 70 ml of tetrahydrofuran was mixed at 0° C. with 10.3 ml of a 2 molar solution of lithium diisopropylamide in tetrahydro-furan/heptane/ethylbenzene. After 20 hours at room tempera-ture, water is added, it is extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. 2 g of this crude product is saponified with 28 ml of 1N sodium hydroxide solution. 1.32 g of the acid, which is heated for 20 hours to 90° C. with 25 ml of 1 molar sulfuric acid while being stirred vigorously, is obtained. After extraction with ether, drying (Na2SO4) and concentration by evaporation, 0.89 g of 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid is obtained as a yellowish oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([Br:5])Br.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].O>CN(C=O)C>[Br:5][C:3]1[CH2:8][CH:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:1][N:2]=1
Reactant: C=CC(=O)OCC
Reactant: ON=C(Br)Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(Br)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred mixture of hydroxycarbonimidic dibromide (15.5 g, 76.4 mmol) and ethyl acrylate (15.3 g, 153 mmol) in DMF (200 mL) was added a solution of 15 wt % aqueous KHCO3 (102 mL, 153 mmol). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted twice with methyl tert-butyl ether. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH3:15])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(-c2ccc(Br)cc2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(-c2ccc(Br)cc2)nn1C
Yield: 22.4 %

Procedure:
A mixture of 3-(4-bromophenyl)-5-hydroxy-1-methylpyrazole (2.5 g), acetone (200 ml), potassium carbonate (1.6 g) and methyl iodide (1.4 g) was heated at reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate/toluene as eluent to give 3-(4-bromophenyl)-5-methoxy-1-methypyrazole (590 mg) as a solid, m.p. 71°-73° C.; NMR: 3.6(3H,s), 3.9(3H,s), 6.2(1H,s), 7.5-7.6(2H,d) and 7.6-7.7(2H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:35][CH3:36])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43]([CH:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH2:35][CH3:36])[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:40]3[CH2:41][CH2:42][N:37]([C:43]([CH:45]4[CH2:49][CH2:48][CH2:47][O:46]4)=[O:44])[CH2:38][CH2:39]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: CCC1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)Cl)C1c1ccc(Cl)cc1
Product: CC[C@@]1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)N2CCN(C(=O)C3CCCO3)CC2)[C@@H]1c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4-ethyl-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Aldrich) to give the title compound. LC-MS: 693.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C1(=O)[O:20][CH:19]=[CH:18][O:17]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH:19]([OH:20])[CH:18]([OH:17])[C@@H:5]([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Reactant: O=c1occo1
Product: OC1C(O)[C@H]2c3ccccc3[C@@H]1c1ccc(Cl)cc12

Procedure:
A solution of 15.0 g. of 2-chloroanthracene in 60.8 g. of vinylene carbonate is refluxed for 20 hours and then vacuum distilled. The residue is recrystallized from methylene chloride-methanol giving cis-2-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol, cyclic carbonate as gray crystals, m.p. 200°-230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH:29][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=[N+]([O-])c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 48A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][NH:25][C@@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:35])[C@@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Yield: 48.4 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.6 g, 7.84 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (3.31 g, 15.7 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (1.8 g, 49%): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, 1H), 2.15 (s, 3H), 2.45-2.50 (m, 1H), 2.59 (d, 3H), 2.71 (m, 1H), 2.84 (m, 1H), 3.96 (s, 3H), 4.81 (m, 1H), 7.23 (s, 1H), 7.28 (t, 1H), 7.47-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 474.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:22]([NH2:25])[CH2:23][NH2:24].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:24][CH2:23][CH2:22][NH:25][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH2:12]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@]12CC[C@H](NCCN)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17β-Hydroxy-5α-androstan-3-one (403 mg, 1.39 mmol)(Aldrich Chemical Company) was added to a stirred solution of 0.745 mL 1,2-ethylenediamine (11.1 mmol) and 1.44 mL acetic acid (25.2 mmol) in 16.0 mL dry methanol (MeOH), followed by 104 mg (1.65 mmol, 1.19 equiv.) of sodium cyanoborohydride. After stirring at room temperature for 15 h, the reaction concentrated under reduced pressure. The residue was partitioned between methylene chloride and aqueous 1N sodium hydroxide, shaken, and separated. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][O:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH:11]12[O:25][CH:10]1[CH2:9][O:8][CH:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:14]([O-:16])=[O:15])[CH2:13][CH2:12]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC=CCO1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CCC2OC2CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
To a solution of 1-methyl-4-nitro-5-(2,3,4,7-tetrahydrooxepin-2-yl)pyrazole (1.00 g, 4.74 mmol) in DCM (25 mL) was added m-CPBA (70-75%, 1.75 g, 7.11 mmol) and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL), washed with saturated aqueous NaHCO3 (50 mL), water (50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave racemic 5-(5,8-dioxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-pyrazole as a colourless solid (490 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 8.22-7.87 (m, 1H), 5.07 (d, J=9.9 Hz, 1H), 4.50 (dd, J=14.5, 3.1 Hz, 1H), 4.05 (s, 3H), 3.93 (d, J=14.4 Hz, 1H), 3.35 (t, J=4.5 Hz, 1H), 3.13 (t, J=3.6 Hz, 1H), 2.55-2.47 (m, 1H), 2.31-2.21 (m, 1H), 2.16-2.04 (m, 1H), 1.79 (dd, J=14.4, 1.8 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[C:26]([O:27][CH3:28])=[C:25]([F:29])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[F:19][C:20]1[C:26]([O:27][CH3:28])=[C:25]([F:29])[CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: COc1c(F)ccc(N)c1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COc1c(F)ccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1F
Yield: 67.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 318 mg of 2,4-difluoro-3-methoxyaniline in place of the 2,4-difluoroaniline. 255 mg of N-(2,4-difluoro-3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following: