Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C@@H:9]1[OH:25])([CH3:4])([CH3:3])[CH3:2].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([S:14][CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C@@H:9]1[O:25][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O)c(C)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CS[C@@H]2CCC[C@@H](NC(=O)OC(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(C)c1
Temperature: 80 °C
Reaction time: 120 h
Yield: 94 %

Procedure:
A solution of [(1R,2R,3R)-2-hydroxy-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (2.46 g, 6.49 mmol) in 50 ml of dimethylformamide was treated with tert-butyldimethylsilyl chloride (978 mg, 6.49 mmol) and imidazole (552 mg, 8.11 mmol) and stirred at 80° C. for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 0.1 N HCl and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. After chromatography (silica, cyclohexane/ethyl acetate=10/1) [(1R,2R,3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclo-hexyl]-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (Rf=0.25, 3.0 g, 94% yield) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=[C:6]2[C:14]=1[CH:13]([CH2:15][OH:16])[C:12]1([OH:18])[O:17][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([N:10]1[CH:9]2[CH:11]1[C:12]1([OH:18])[O:17][N:7]([CH2:8]2)[C:6]2[C:14](=[C:2]([OH:1])[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=2)[CH:13]1[CH2:15][OH:16])(=[O:23])[CH3:22]
Reactant: O=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2CO
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1C2CN3OC(O)(C(CO)c4c(O)cc(C=O)cc43)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (98 mg) in methanol (3 ml) was added acetic anhydride (40 μl). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (10:1, v/v) to afford 11-acetyl-6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (71 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].Br[CH2:34][CH2:35][CH2:36][CH:37]1[NH:41][C:40](=[O:42])[CH2:39][CH:38]1[CH3:43]>C1COCC1>[NH2:6][CH:5]([CH2:34][CH2:35][CH2:36][CH:37]1[CH:38]([CH3:43])[CH2:39][C:40](=[O:42])[NH:41]1)[C:4]([O:3][CH2:1][CH3:2])=[O:20]
Reactant: CC1CC(=O)NC1CCCBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)CCCC1NC(=O)CC1C
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(diphenylmethylene)glycine ethyl ester (Aldrich, 37 mmol) in THF (20 mL) is added to −72° C. solution of sodium bis (trimethylsilylamide) (35 mmol, 0.5 M in THF), while the solution is kept below −65° C. The resulting solution is then stirred at −72° C. for 30 min.; followed by the rapid addition of a cooled solution (−72° C.) of the product from EXAMPLE 236 (24 mmol) in THF via canula. The cooling bath is removed immediately and the mixture allowed to warm to 0° C. for 4 h. The reaction mixture is partitioned between ether and 10% aqueous sodium bisulfate, then dried and concentrated. The product is purified by column chromatography. This intermediate is then treated with 0.1 N aqueous hydrochloric acid for 3 h, followed by extraction with ether and lyophilization of the aqueous solution, to yield the title material.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:20]2[CH2:19][CH2:18][C@@:15]2([CH:16]=O)[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25][C:26](=[O:28])[CH3:27])[CH2:6]1)(=[O:3])[CH3:2].[Cl-].[Cl:30][CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.C([Li])CCC>O1CCCC1.CCCCCC>[C:1]([O:4][C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7](=[CH:8][CH2:9][C@H:10]3[C@H:11]4[C@@:15]([CH:16]=[CH:31][Cl:30])([C@@H:14]([O:25][C:26](=[O:28])[CH3:27])[CH2:13][CH2:12]4)[CH2:18][CH2:19][C@@H:20]32)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C=O)CC[C@@H]32)C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCNCC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C=CCl)CC[C@@H]32)C1

Procedure:
A solution of 2.92 g of 3β,17β-diacetoxy-androst-5-en-18-al in 30 ml of tetrahydrofurane is added dropwise to a solution of a Wittig reagent prepared from 7.83 g of chloromethyl-triphenyl-phosphonium chloride, 144 ml of tetrahydrofurane, 2.23 ml of piperidine and 11.25 ml of a 1.56 molar solution of butyl-lithium in hexane and the mixture is allowed to react for 40 minutes at room temperature and is worked up as indicated in Example 1. On purification by chromatography, as also indicated in Example 1A, this gives the cis and trans isomers of 3β,17β-diacetoxy-13-(2-chlorovinyl)-10-methyl-gon-5-ene in a ratio of 1:3. The cis isomer crystallises from methylene chloride/hexane and then melts at 161°-162° C; [α]D25 = -70° (in chloroform); the trans isomer crystallises from methylene chloride/hexane, melting point 155°-156° C, [α]D25 = -42° (in chloroform).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].II.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>O1CCCC1>[CH3:19][C:13]1[N:12]([C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:17]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:14]=1[CH3:18]
Reactant: Cc1ccc(Br)cc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cccnc1C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1=C(C)N(C(=O)Oc2ccccc2)C(c2ccc(C)cc2)C=C1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of p-bromotoluene (13.5 g) in 50 ml of tetrahydrofuran was added to magnesium (1.5 g) and 1 crystal of iodine in a little tetrahydrofuran, and the mixture was refluxed for 1 hour. In a separate flask, a solution of 2,3-lutidine (6.5 g) in 100 ml of tetrahydrofuran was cooled to about -60° C., and the magnesium complex prepared above added, followed by phenyl chloroformate (8 ml). The mixture was stirred for 1 hour at -60° C., then at room temperature overnight. The solvent was removed under reduced pressure, the residue partitioned between ether and 200 ml of 20% ammonium chloride, the organic layer washed with water, followed by dilute hydrochloric acid. The solvent was evaporated under reduced pressure, and the residue flash-chromatographed on silica gel, eluting with 1% ethyl acetate in heptane, to yield 12.4 g of 1,6-dihydro-2,3-dimethyl-6-(4-methylphenyl)-1-phenoxycarbonyl pyridine, m.p. 106° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[N:4]=[C:5](SC)[NH:6][CH:7]=1.[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=2)=[CH:14][C:13]=1[C:28]([F:31])([F:30])[F:29]>C(O)C>[Cl:11][C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:5]3[NH:6][CH:7]=[C:2]([CH3:1])[C:3](=[O:10])[N:4]=3)=[CH:19][CH:18]=2)=[CH:14][C:13]=1[C:28]([F:29])([F:30])[F:31]
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(C)c[nH]1
Solvent: CCO
Product: Cc1c[nH]c(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Yield: 35.4 %

Procedure:
5-Methyl-2-methylsulfanyl-1H-pyrimidin-4-one (25 mg, 0.16 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (60 mg, 0.192 mmol, 1.2 eq) were stirred in 300 μl of absolute ethanol for 50 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 11 g normal phase silica KP-NH column and DCM/MeOH solvent system (gradient 0-7% of MeOH in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the crude was triturated with cyclohexane to obtain 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-methyl-1H-pyrimidin-4-one (24 mg, yield=33.9%, purity=96%) in form of white powder. MS: [M+H]+=424.31. 1H NMR (300 MHz; CDCl3) δ/ppm 1.79 (s, 3H), 2.90 (t, J=6.24 Hz, 2H), 3.52 (s, 2H), 3.56-3.67 (m, 2H), 6.23 (br.s., 1H), 6.92 (d, J=7.56 Hz, 2H), 7.00 (d, J=7.95 Hz, 1H), 7.21 (d, J=7.56 Hz, 2H), 7.28 (s, 1H) 7.38 (d, J=8.32 Hz, 1H), 7.63 (s, 1H), 11.62 (br.s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([C:24]#[N:25])=[CH:20][CH:21]=3)[CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.B.CSC.Cl>C1COCC1.C(OCC)(=O)C>[NH2:25][CH2:24][C:19]1[N:18]=[C:17]2[CH:16]=[C:15]([CH2:14][C:13]([OH:30])([CH2:12][C:11]([C:4]3[C:5]4[O:9][CH2:8][CH2:7][C:6]=4[CH:10]=[C:2]([Cl:1])[CH:3]=3)([CH3:32])[CH3:31])[C:26]([F:29])([F:27])[F:28])[NH:23][C:22]2=[CH:21][CH:20]=1
Reactant: CC(C)(CC(O)(Cc1cc2nc(C#N)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(Cc1cc2nc(CN)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Yield: 47.6 %

Procedure:
2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (100 mg, 0.22 mmol) was dissolved in 3 mL of THF and borane-methyl sulfide (10 M, 0.065 mL, 0.648 mmol) was added. The reaction was heated at reflux for 1 hour and then cooled to room temperature. 1 mL of a 6 N HCl solution was then added. The reaction was heated at reflux overnight. The reaction was cooled to room temperature, diluted with 50 mL of ethyl acetate, and then quenched with saturated sodium carbonate solution until the pH was 12. The organic layer was separated and aqueous layer was extracted with three 50 mL portions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC (polar condition) to give the title compound (49 mg, 49% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1COCC1.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-chloro-3-(1-hydroxypropyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (THF-diisopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[O:11])[C:5]([CH3:20])=[C:4]2[CH2:21][CH2:22][C:23]([CH2:26][CH2:27][CH2:28][CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH3:35])[CH3:30])([CH3:25])[O:24][C:3]=12.[CH3:42][CH2:43]/[C:44](/[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[C:45](/[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][N+:61](C)([CH3:63])[CH3:62])=[CH:54][CH:53]=1)\[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[I-:71].[CH2:72](O)C.O=[Si]=O>O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[O:11])[C:5]([CH3:20])=[C:4]2[CH2:21][CH2:22][C:23]([CH2:26][CH2:27][CH2:28][CH:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH3:35])[CH3:30])([CH3:25])[O:24][C:3]=12.[CH3:42][CH2:43]/[C:44](/[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[C:45](/[C:52]1[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH2:60][N:61]([CH3:63])[CH3:62])=[CH:56][CH:57]=1)\[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[CH3:72][I:71]
Reactant: [I-]
Reactant: CCO
Reactant: CC/C(=C(\c1ccccc1)c1ccc(OCC[N+](C)(C)C)cc1)c1ccccc1
Agent: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)OCCO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: O=[Si]=O
Solvent: O
Product: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Product: CI

Procedure:
TPGS (500 mg) was melted at 40°-60° C. in a water bath. Tamoxifen methiodide (100 mg, from Pharmos Corp., FL., USA) was added to the melted material and the mixture was agitated for several minutes. A small amount of absolute ethanol (up to 5%, v/v) was added in order to get an homogeneous mixture. PVP (Kollidon PF 12, 2.6 ml of a 10% solution in water) was then added and the mixture was agitated again for several minutes. Cab-O-Sil (2.8 ml of a 5% solution in water) was added and the mixture was agitated again for several minutes. The resultant TPGS/PVP/Tamoxifen methiodide mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany). A powdered free-flowing TPGS/PVP/Tamoxifen methyliodide coprecipitate quickly dispersible in water was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH2:21][CH:20]=[CH2:19])[CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OC)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-3-hydroxy-benzoic acid methyl ester (26.3 g, 154.5 mmol) is dissolved in acetone (300 ml). Potassium carbonate (42.7 g, 305.8 mmol) is added, followed 5 minutes later by the addition of allyl bromide (20 ml, 229 mmol). The reaction mixture is stirred overnight at rt, concentrated in vacuo and then diluted with ether and water. The organic layer is washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give the product as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7]#N.C[Si](Cl)(C)C.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C[O:25]CC1>>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:25]
Reactant: Cn1cnnc1C#N
Reactant: C1CCOC1
Reactant: Br[Mg]c1ccccc1
Agent: C[Si](C)(C)Cl
Product: Cn1cnnc1C(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 4-methyl-4H-1,2,4-triazole-3-carbonitrile (70%, 4.27 g, 27.64 mmol, 1 eq.) in 200 ml of THF cooled to −40° C. was added TMSCl (6.0 g, 55.29 mmol, 2.0 eq.) followed by phenylmagnesium bromide (2.8 M, 14.81 ml, 41.47 mmol, 1.4 eq.). The reaction was stirred at −40° C. for 1 h and quenched with 1N HCl. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc and the organics combined, dried over MgSO4 and concentrated. The residue was triturated in EtOAc and the solid removed by filtration. The crude was purified by chromatography on silica gel to give (4-methyl-4H-1,2,4-triazol-3-yl)(phenyl)methanone (2.45 g, 48% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:23]1([C:29]2[O:30]C(=O)[CH:32]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[C:29]([NH:33][CH:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:4](=[O:6])[CH2:3][N:2]([CH3:1])[C:7](=[O:8])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C1OC(c2ccccc2)=NC1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-methyl-N-[(phenylmethoxy)carbonyl]-glycine (2.23 g., 10 mmole) is dissolved in 30 ml. of tetrahydrofuran and cooled in an ice-bath. Oxalyl chloride (1 ml., 11.5 mmole) is added followed by 2 drops of dimethylformamide. After stirring for 30 minutes in the ice-bath, the mixture is then stirred at room temperature for an hour. To this 0.25 ml. of oxalyl chloride is added. The mixture is evaporated, redissolved in 15 ml. of tetrahydrofuran, and stirred in an ice bath. A solution of 2-phenyl-4-(phenylmethyl)-5-(4H)-oxazolone (3.1 g., 12.4 mmole) dissolved in 15 ml. of tetrahydrofuran is added to the above solution stirring in the ice-bath. Triethylamine (1.4 ml., 10 mmole) is added and the solution is stirred at room temperature overnight. The precipitated triethylamine hydrochloride salt is filtered off. Tetrahydrofuran is removed from the residue and it is then redissolved in pyridine (5 ml.) and p-dimethylamino pyridine (20 mg.) is added. After stirring at room temperature for 3 hours, acetic acid (5 ml.) is added and the reaction mixture is kept at 105° for 30 minutes. The reaction mixture is then evaporated, the residue is dissolved in ethyl acetate, and washed with aqeuous sodium bicarbonate and water. After trituration with ethyl acetate/hexane, 2.2 g. of homogeneous [3-(benzoylamino)-2-oxo-4-phenylbutyl]methylcarbamic acid, phenylmethyl ester is obtained; m.p. 140°-141°.
Reaction SMILES: [Br:1]Br.[C:3]([Si:7]([CH3:25])([CH3:24])[N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH:16]=[C:11]2[CH:10]=[CH:9]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH:16]=2)[N:8]([Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:25])[CH3:24])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccc(F)c3)cnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccc(F)c3)cnc21
Yield: 95.8 %

Procedure:
A solution of Br2 (1.12 mL, 21.8 mmol) in CCl4 was added dropwise to a stirred and cooled (0° C.) solution of 8 (7.10 g, 21.8 mmol) and pyridine (2.1 mL, 26.2 mmol) in dry CHCl3 (330 mL). Progress of the reaction was followed by TLC. When the reaction was completed, aqueous NaHCO3—Na2S2O3 solution was added. The organic solution was separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). Combined organic solutions were dried (MgSO4), concentrated and purified by SGC with hexane:benzene as eluent in gradient (up to 14% benzene) to afford 9 (8.47 g, 91%) as tan solid. 1H NMR (400 MHz, CDCl3) δ 0.65 (s, 6H), 0.97 (s, 9H), 7.02-7.10 (m, 1H), 7.29 (s, 1H), 7.33-7.38 (m, 1H), 7.40-7.47 (m, 2H), 7.97 (d, J=2.2 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:19][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:16]=3[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:17]=2[C:18]([NH:28][NH2:29])=[O:20])=[O:19])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 0.29 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.10 g of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.30 g of 4-bromo-N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]([O:10][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2.0 g (10.8 mmol) of ethyl 4,4,4-trifluoroacetoacetate in 10 ml of DMF was added 2.28 g of p-toluenesulfonyl chloride and 4.24 g of cesium carbonate and stirred at room temperature overnight. The reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.27 g of ethyl 4,4,4-trifluoro-3-p-toluenesulfonyloxy-2-butenoate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[O:12][CH2:13][CH:14]([OH:15])[CH2:16][O:7]1)[CH3:2]
Reactant: OCC(O)CO
Reactant: CCOc1ccccc1C=O
Product: CCOc1ccccc1C1OCC(O)CO1

Procedure:
Using the method of Example 5e, 30 g 2-ethoxybenzaldehyde was reacted with 18.4 g glycerol to form 2-(2-ethoxyphenyl)-5-hydroxy-1,3-dioxane, crude b.p. 140°-148° C/10-5 mm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14](C(C)=C)[C:13]2=[O:24])[CH:4]=[C:3]1[CH3:25].O.Cl>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:24])[CH:4]=[C:3]1[CH3:25]
Reactant: C=C(C)n1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc2cccc(Cn3c(=O)[nH]c4ccccc43)c2n1C
Temperature: 60 °C
Yield: 97.2 %

Procedure:
(1,2-dimethyl-1H-indol-7-ylmethyl)-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (200 mg, 0.60 mmol) was suspended in ethanol (0.5 ml) and water (0.5 ml) and treated with 37% HCl (0.2 ml). The reaction was warmed to 60° C. for 1.5 h, cooled to room temperature and concentrated to low volume. The remaining residue was dissolved into DCM and sequentially washed with water and NaHCO3 (sat.). The organic phase was dried (MgSO4), filtered and concentrated to give 170 mg (97%) of 1-(1,2-dimethyl-1H-indol-7-ylmethyl)-1,3-dihydro-benzimidazol-2-one which was used without further purification.