Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[N:10][NH:11][C:12]2=[O:17].N([O-])=[O:19].[Na+].B(O)(O)O>O>[OH:19][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[N:10][NH:11][C:12]2=[O:17]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2c(O)cccc12
Yield: 97 %

Procedure:
Concentrated sulphuric acid (8 ml) was added to a stirred mixture of 5-amino-1(2H)-phthalazinone (9.4 g, 0.058 mole) and water (50 ml). The resultant stirred paste was cooled in ice and diazotised by the addition of sodium nitrite (4.15 g, 0.06 mole) in water (15 ml). The filtered diazonium sulphate solution was added over 1.5 hours to a stirred boiling solution of concentrated sulphuric acid (30 ml) and boric acid (5.42 g, 0.088 mole) in water (200 ml). The solution was heated for a further 30 minutes then cooled and the collected solid was washed with water to give 5-hydroxy-1(2H)-phthalazinone 9.12 g, 96% m.p. 351°-355°). 5-Hydroxy-1(2H)-phthalazinone was purified as the 5-acetoxy derivative m.p. 162° (ethanol).
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[C:5]([O:7]C)=O.C[O-].[Na+].Br.[N:23]1([C:29]([NH2:31])=[NH:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CO>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:4]1[C:3]([OH:18])=[N:30][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:31][C:5]=1[OH:7]
Reactant: COC(=O)C(Oc1cccc(OC)c1)C(=O)OC
Reactant: N=C(N)N1CCOCC1
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Oc2c(O)nc(N3CCOCC3)nc2O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.7 %

Procedure:
To a solution of dimethyl-(3-methoxyphenoxy)-malonate (11.19 g) in methanol (100 ml) was added sodium methylate (6.48 g). The yellow solution was stirred for 6 h at rt. Then, morpholine-4-carboxamidine hydrobromide (8.40 g) was added and the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was dissolved in water (150 ml) and extracted twice with diethyl ether (150 ml). The aqueous phase was acidified with 10% aq. citric acid. The solid that separated was collected, washed with water, evaporated twice from EA, and dried under high vacuum to give 5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine-4,6-diol (9.66 g) as a beige powder. LC-MS: tR=2.88 min, [M+1]+=320.19, [M−1]−=318.02.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][C:50]1=[O:54]>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][C:50]1=[O:54])[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C1CCCN1CCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCCC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 1-(2-chloroethyl)pyrrolidin-2-one as the alkylating reagent in Step 1. The product was isolated as a white solid (19 mg, 62%). LCMS: m/e 641.57 (M+H)+, 2.58 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.55 Hz, 2H), 5.37 (d, J=4.88 Hz, 1H), 4.91 (s, 1H), 4.76 (s, 1H), 3.89-3.73 (m, 2H), 3.72-3.56 (m, 3H), 3.55-3.45 (m, 1H), 2.93-2.80 (m, 1H), 2.57 (td, J=8.24, 3.97 Hz, 2H), 2.34-1.19 (m, 24H), 1.78 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH3:20]
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 48 h

Procedure:
To a suspension of 5-hydroxy-2-nitrobenzaldehyde (500 mg) and cesium carbonate (1.46 g) in N,N-dimethylformamide (10 mL) was added ethyl iodide (0.265 mL) at room temperature, and the mixture was stirred for 2 days. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (519 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(NC1C=CC=CC=1)C>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N(CC)c1ccccc1
Solvent: CCNc1ccccc1
Product: CCOC(=O)C(Cc1ccc(O)cc1)N(CC)c1ccccc1

Procedure:
Reaction and post-treatment were carried out according to Reference example 5(b) using 6.30 g of a mixture of ethyl 3-(4-benzyloxyphenyl)-2-(phenyl-N-ethylamino)propionate and N-ethylaniline obtained in Reference example 6(a) to obtain 2.37 g of the desired compound as a syrup.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[OH:25]>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:27](=[O:28])[CH2:26][C:21]3[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([OH:18])[CH:20]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Nc1nc(C2CCN(C(=O)Cc3ccc(O)c(O)c3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To an ice-cold solution of 2-amino-4-(4-piperidinyl)quinazoline (600 mg, 2.63 mmol) obtained in example 11(1), 3,4-dihydroxyphenylacetic acid (530 mg, 3.16 mmol) and 4-dimethylaminopyridine (386 mg, 3.16 mmol) in dimethylformamide (20 ml) was added 1-ethyl-3-(N,N'-dimethylaminopropyl)carbodiimide hydrochloride (605 mg, 3.16 mmol) under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was crystallized from methanol to give the titled compound (599 mg).
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]3[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=3)[CH2:63][CH2:62]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[CH2:50][CH2:49]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:61]2[CH2:62][CH2:63][N:64]([CH2:67][C:68]3[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=3)[CH2:65][CH2:66]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([N:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[CH:46][CH:47]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1cnc2[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Yield: 75 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (16 mg, 0.025 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (10 mg, 75%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.50 (hidden by DMSO peak, 2H, piperazine NCH2), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.00 (s, br, 2H, piperazine NCH2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2), 3.64 (s, br, 4H, piperazine N(CH2)2), 7.06 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.03 (d, J=8.9 Hz, 2H, phenyl H-2 & H-6), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.23 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([C:17]([OH:19])=[O:18])=[CH:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(=O)C>O1CCOCC1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH:7]=[C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[C:3](=[O:20])[C:4]([C:17]([OH:19])=[O:18])=[CH:5]2)=[CH:10][CH:11]=1)#[N:16]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(Cn2cc(Br)c(=O)c(C(=O)O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: N#Cc1ccc(Cn2cc(C(=O)O)c(=O)c(-c3cccc(C(F)(F)F)c3)c2)cc1
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 12b, 0.56 g, 1.68 mmol), 3-(trifluoromethyl)phenylboronic acid (0.39 g, 2.05 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75 mg, 0.10 mmol) and Cs2CO3 (0.82 g, 2.51 mmol) in dioxane (4 mL) is heated for 24 h at 60° C. The reaction mixture is acidified with acetic acid and purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 186 mg (28% of theory); ESI mass spectrum: [M+H]+=399; Retention time HPLC: 1.22 min (Z002—002).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)#[N:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
230 mg (0.77 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 37 mg (0.92 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 196 mg (1.00 mmol) of 4-cyanobenzyl bromide was added to the obtained mixture, and they were stirred at room temperature for 4 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[N:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B(F)(F)F.[OH-].[Na+]>ClC(Cl)C>[C:1]([C:10]1[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]([CH3:6])[C:11]=1[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: Cc1cc(=O)n(-c2ccccc2)n1C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1c(C(C)(C)C)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C

Procedure:
To a solution tert-butanol (800 μL) and 1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.150 g) in dichloroethane (1 mL) was added boron trifluoride diethyletherate (400 μL). The reaction was heated to 40° C. over seven days. The reaction mixture was then cooled and poured onto an ice/water mixture, was basified to pH 10 using sodium hydroxide solution and was extracted with EtOAc. The solution was acidified with AcOH to pH=4 and further extracted with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate. Filtration and evaporation of the volatiles in vacuo afforded a crude residue which was purified via flash column chromatography to afford 4-tert-butyl-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.025 mg) as a white solid. MS (ESI+): 245.4 [M+H]+).
Reaction SMILES: C(C1C=C([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])N(C2C=C(C=CC=2)C(OCC)=O)N=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11](=[O:12])[NH2:10])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(=O)Nc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 226.1 %

Procedure:
To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL) was added LiAlH4 powder (413 mg, 10.9 mmol) at −10° C. under N2. The mixture was stirred for 2 h and excess LiAlH4 was quenched by adding ice. The solution was acidified to pH=7 with dilute HCl. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200+100 mL). The filtrate was concentrated to yield 1-{3-tert-butyl-1-[3-hydroxymethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (1.40 g, 97%). 1H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.47 (s, 1H), 7.47-7.27 (m, 8H), 6.35 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 1.26 (s, 9H); MS (ESI) m/z: 399 (M+H+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:23]=[O:24])[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:12][CH:13]=1)([CH3:4])[CH3:3].[C:27]([Mg]Br)([CH3:29])=[CH2:28]>C1COCC1>[CH3:4][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([OH:24])[C:27]([CH3:29])=[CH2:28])[CH:9]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C=O)c1
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cc(CO[Si](C)(C)C(C)(C)C)ccc1-c1cc(OC)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 250 mL round bottom flask was charged with 83.18C (1.05 g, 2.80 mmol) and THF (15 mL) and cooled to −78° C. under N2. To the cold solution was added isopropenylmagnesium bromide (0.5 M in THF) (available from Aldrich) (11.2 mL, 5.61 mmol) dropwise. The mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 83.18D (1.05 g, 90% yield) as a colorless oil.
Reaction SMILES: C(OC(C)C=CC1C=CC([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][N:15]=2)=CC=1)(=O)C.C>[Pd].O1CCCC1>[CH2:21]([O:20][C:17]1[CH:16]=[N:15][CH:14]=[N:19][CH:18]=1)[CH3:22]
Reactant: CCOc1cnc(-c2ccc(C=CC(C)OC(C)=O)cc2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1cncnc1

Procedure:
9 g of 2-[4-(3-acetoxy-1-butenyl)phenyl]-5-ethoxypyrimidine, 2 g of palladium on active charcoal (10 wt. %) and 150 ml of tetrahydrofuran were hydrogenated in an analogous manner to Example 1(e) to give 8.2 g of 2-(3-acetoxy-1-butyl)phenyl]-5-(ethoxy)pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[S:3]([C:6]1[CH:7]=[C:8]([C:15]([CH3:29])([CH3:28])[CH2:16][C:17]2([C:24]([F:27])([F:26])[F:25])[CH2:21][O:20]C(C)(C)[O:18]2)[C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)(=[O:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(=O)(O)[O-].[Na+]>[CH3:30][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[C:8]([C:15]([CH3:28])([CH3:29])[CH2:16][C:17]([OH:18])([CH2:21][OH:20])[C:24]([F:25])([F:27])[F:26])[C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1cc2c(c(C(C)(C)CC3(C(F)(F)F)COC(C)(C)O3)c1)OCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1cc2c(c(C(C)(C)CC(O)(CO)C(F)(F)F)c1)OCC2
Yield: 78.7 %

Procedure:
A mixture of 1.18 g (2.61 mmol) of 7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethyl-ethyl]-2,3-dihydrobenzofuran-5-sulfonic acid dimethylamide and 303 mg (1.59 mmol) of p-toluenesulfonic acid monohydrate in 20 mL of methanol was warmed at reflux for 3 days. The mixture was then cooled and diluted with 15 mL of saturated aqueous sodium bicarbonate and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with two 15 mL portions of saturated aqueous sodium bicarbonate, two 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ether to afford 845 mg (78% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[CH:37]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:38]([O:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH:37]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:38]([O:40][C:41]3[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=3)=[O:39])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: Cc1cc(C)cc(OC(=O)C(Cl)c2ccccc2)c1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C)cc(OC(=O)C(c2ccccc2)N2CCN([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H](Cc4ccccc4)C3)CC2)c1
Yield: 43.1 %

Procedure:
A mixture of compound 15 (2.5 g), intermediate 5 (1.65 g) and sodium carbonate (0.64 g) in methylisobutylketon (50 ml) was stirred and refluxed for 3 hours. The reaction mixture was washed and the separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 1.59 g (43%) of (±)-3,5-dimethylphenyl cis-4-[1-[3,5-bis(trifluoromethyl) benzoyl]-2-(phenylmethyl)-4-piperidinyl]-α-phenyl-1-piperazineacetate compound 43; mp. 88.1° C.).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]([CH2:21][CH3:22])[C:6](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:7].C1COCC1.[BH4-].[Na+]>O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]([CH2:21][CH3:22])[CH2:6][OH:7]
Reactant: CC[C@@H](Cc1ccc(F)cc1F)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](CO)Cc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
A flask was charged with 29.5 g (˜78.6 mmol) of (4R,5S)-[(S)-2-(2,4-difluoro-benzyl)-butyryl]-4-methyl-5-phenyl-oxazolidin-2-one and 200 mL of dry THF, and the solution was cooled to 0° C. In a separate flask, 11.9 g (314 mmol) of sodium borohydride was taken up in 70 mL of water and added dropwise over 15 minutes to the imide solution. The mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with conc. HCl until pH=3 (keeping the reaction mixture temperature <20° C.). THF was removed under reduced pressure, and the residue was taken up in hexanes. The hexane layer was washed with sat. aq. sodium bicarbonate. The hexane layer was removed under reduced pressure, and the residue was purified by column chromatography (9:1 Hexanes/EtOAc) which gave 7.2 g (46% yield) of the titled compound as a clear oil.
Reaction SMILES: [C:1]1([Pb:7](Cl)(Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[Na]>CC(C)=O>[CH:16](=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[C:8]1([Pb:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cl[Pb](Cl)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CC(C)=O
Solvent: O=Cc1ccccc1O
Product: c1ccc([Pb]c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
Diphenyl lead dichloride (0.01 mol) is mixed with 0.02 mol of sodium salicylaldehyde in acetone. The solution is allowed to stand 10 minutes and then filtered. Water is added to the filtrate to precipitate the lead chelate complex, which is then separated by filtration.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=O)(C)(C)C.[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16]>C(Cl)Cl>[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CNC1
Reaction time: 1.25 h

Procedure:
3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester 9b (0.73 g, 4.2 mmole) was dissolved in CH2Cl2 (2 ml) and trifluoroacetic acid (2 ml). CAUTION: The deprotection generated a rapid evolution of gas. The clear solution was stirred for 75 minutes and the solvent was removed, in vacuo, to a clear oil (1.4 g, >100%): 1H-NMR (DMSO-d6, 400 MHz) δ 8.63 (2H, br. s), 4.55–4.48 (1H, m), 4.09–4.02 (2H, m), 3.76–3.68 (2H, m).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:15]1=[O:37])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(C(F)(F)F)cc2)c(=O)n1OCc1ccccc1
Yield: 85.6 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-trifluoromethylphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example U-2, 0.19 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.18 g of the title compound as a solid, mp 231-233° C.