Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[N:8]1.[N:23]([Sn](CCCC)(CCCC)CCCC)=[N+:24]=[N-:25].O1CCOCC1.Cl>C1(C)C=CC=CC=1.O1CCCC1>[N:23]1[NH:24][N:25]=[N:17][C:16]=1[C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[NH:7][N:8]=[C:9]2[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1ccsc1)nn2C1CCCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: c1cc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cs1

Procedure:
The title compound was prepared from 1-perhydro-2H-pyran-2-yl-3-(3-thienyl)-1H-indazole-5-carbonitrile (0.233 g, 0.75 mmol), azidotributyl tin (0.375 g, 0.3 10 mL, 1.13 mmol) in toluene (10 mL) as described for the preparation of Example 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0N aqueous solution of hydrogen chloride. The solid obtained upon completion of the reaction was partially dissolved in 3 mL of tetrahydrofuran and was precipitated out by adding 20 mL of hexanes (0.108 g, 0.85 mmol, 79% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.8 (s, 1H), 8.2 (t, 1H), 8.1 (dd, 1H), 7.8–7.7 (m, 3H); ES-MS (m/z) 269 [M+1]+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:21]1([C:27]2[NH:31][N:30]=[C:29]([C:32]([OH:34])=O)[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:32]([C:29]1[CH:28]=[C:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:31][N:30]=1)=[O:34]
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
HOBt (45 mg, 0.33 mmol) and DIPEA (137.5 mg, 1.06 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid hydrochloride (50 mg, 0.22 mmol) in DMF (1.0 mL). The reaction mass was cooled to 10° C. and EDCI.HCl (64 mg, 0.33 mmol) was added, followed by the addition of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (as TFA salt) (125 mg, 0.29 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the resulting precipitate was filtered and dried in vacuo to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide as a solid product in 62% yield, LC-MS purity: 99.127%, 1H NMR (DMSO): δ 13.6 (s, 1H), 8.1 (s, 1H), 7.7 (m, 5H), 7.4 (m, 4H), 7.1 (s, 1H), 4.1 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9](=[O:11])(=[O:10])[NH2:12])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1cccc(F)c1F
Reactant: Nc1ccc(F)cc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(F)ccc1NS(=O)(=O)c1cccc(F)c1F
Reaction time: 8 h
Yield: 45.5 %

Procedure:
2-Amino-5-fluorobenzenesulfonamide (29 mg, 0.15 mmol) was dissolved in pyridine (1 ml) and 2,3-difluorophenylsulfonyl chloride (19 μl, 0.15 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (25 mg, 46%).
Reaction SMILES: BrCC1C=C(C=CC=1)C(OC)=O.Cl[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Cl:22])[CH:16]=1.BrCC1C=C(C=CC=1)C=O.[CH2:33]([N:35](CC1C=C(C=CC=1)C(OC)=O)[CH2:36]/[CH:37]=[CH:38]/[C:39]#[C:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:34]>>[CH2:33]([N:35]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Cl:22])[CH:16]=1)[CH2:36]/[CH:37]=[CH:38]/[C:39]#[C:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH3:34]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(C(=O)OC)c1
Reactant: ClCc1cccc(CCl)c1
Agent: COC(=O)c1cccc(CBr)c1
Agent: O=Cc1cccc(CBr)c1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CCl)c1

Procedure:
When the same reactions as in Referential Example 4 are carried out using methyl 3-bromomethylbenzoate [synthesized by brominating methyl m-toluate with N-bromosuccinimide] or α, α'-dichloro-m-xylene instead of the starting 3-bromomethylbenzaldehyde, methyl (E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)benzoate or (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-chloromethylbenzylamine is obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]1=[O:32])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Product: O=C1c2ccccc2C(=O)N1CCOc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Yield: 48.6 %

Procedure:
In the same manner as in Synthesis Example 6, 500 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 382 mg of N-(2-hydroxyethyl)phthalimide were reacted to obtain 380 mg of 6-chloro-4-phenyl-2-(2-phthalimidoethoxy)quinazoline. Mp. 154.7° C. 1H NMR (CDCl3): 4.25 (2H, t, J=5.8 Hz), 4.84 (2H, t, J=5.8 Hz), 7.53-7.60 (3H, m), 7.67-7.71 (3H, m), 7.72-7.76 (3H, m), 7.78-7.82 (2H, m), 7.97 (1H, d, J=2.2 Hz).
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[C:22]1([CH:29]=[CH:28][CH:27]=[C:25]([OH:26])[CH:24]=1)[OH:23]>C(#N)C.C(OCC)C>[F:21][C:27]1[CH:28]=[CH:29][C:22]([OH:23])=[CH:24][C:25]=1[OH:26]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: Oc1cccc(O)c1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Oc1ccc(F)c(O)c1
Temperature: 100 °C

Procedure:
[1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR) (1.61 g., 4.54 mmoles) in anhydrous acetonitrile (50 mL) was treated with resorcinol (0.500 g., 4.54 mmoles) and heated at 100° C. overnight. The reaction was diluted with diethyl ether, washed with H2O (2×), saturated NaHCO3 (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. MS (DCI) m/z 129 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:3]1
Reactant: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(=O)n(Cc2ccccc2)c1C(F)(F)F

Procedure:
5 g of ethyl (2,3-dihydro-2-oxo-4-trifluoromethyl-thiazol-5-yl)-carboxylate (CA Vol. 92 110 998P), 80 ml of toluene, 1.16 g of potassium hydroxide, 3.7 ml of benzyl bromide and 1.61 g of tetrabutyl-ammonium bromide were heated at 70° C. for 7 hours and the mixture was allowed to return to ambient temperature, and was decanted, washed and dried to obtain 7.2 g of product which was chromatographed on silica. Elution with a hexane-isopropyl ether mixture (8-2) yielded 5.46 g of the expected product with a Rf=0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:37][OH:38])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:18][C:17]3[C:19]([C:27]4[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=4)=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:16]=3[N:15]=2)[C@H:10]([CH3:36])[CH2:9]1>O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[O:38])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:18][C:17]3[C:19]([C:27]4[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=4)=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:16]=3[N:15]=2)[C@H:10]([CH3:36])[CH2:9]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1
Agent: O=[Mn]=O
Product: C[C@@H]1CN(c2ncc(C=O)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
(5-Chloro-6-{(3R)-3-methyl-4-[6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazol-2-yl]-piperazin-1-yl}-pyridin-3-yl)-methanol (110 mg, 0.2 mmol, Example 162) reacted with MnO2 (348 mg, 4.0 mmol, Aldrich) under the conditions of Example 154a to give the title compound as a gum, which is was used in the next step without additional purification. MS ESI, pos. ion) m/e: 554 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:13]1([CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:8][CH:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1ncnn2c(C=O)ccc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnn2c(CN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde(235 mg, 1.45 mmol) in 1,2-dichroloethane (5 ml) was added morpholine (0.25 ml, 2.9 mmol) and sodium triacetoxyborohydride (611 mg, 2.9 mmol). The reaction mixture was stirred at rt under N2 for 16 h. The reaction was quenched with saturated aq. sodium bicarbonate and followed by extraction with CH2Cl2. The organic was dried over Na2SO4, concentrated and purified via column chromatography (5:95 v/v CH3OH—CH2Cl2) to afford 66 mg of the title compound (yield 20%). 1H-NMR (DMSO-d6) δ 7.80 (s, 1H), 7.62 (br, 2H), 6.83 (d, J=4 Hz, 1H), 6.52 (d, J=4 Hz, 1H), 3.75 (s, 2H), 3.51(t, J=4 Hz, 4H), 2.37(t, J=4 Hz, 4H); MS [M+H]+=234; LCMS RT=1.00 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]([C:16]([F:19])([F:18])[F:17])=[O:15].C(=O)(O)[O-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:7][C:5]1[O:6][CH2:13][C:14]([OH:15])([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)OCC1(O)C(F)(F)F
Reaction time: 18 h
Yield: 65.9 %

Procedure:
A solution of 18.8 g of sodium hydride in 175 ml of ethanol was added over 3 hours into a mixture of 51 g of ethyl acetoacetate, 74.8 g of 1-bromo-3,3,3-trifluoroacetone and 200 ml of toluene while maintaining a temperature below +10° C. The mixture was stirred for 18 hours and an aqueous sodium bicarbonate solution was added. The mixture was stirred and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain 62 g of the expected product with a boiling point of 64°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.COC1C=C(C=CC=1OC)C=[N:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[N:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COc1ccc(C=NCC(OC)OC)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C=NCC(OC)OC)c(OC)c1OC
Yield: 100 %

Procedure:
2,3,4-Trimethoxybenzaldehyde (10e, 11.48 g, 0.05851 mol) was dissolved in benzene (200 mL) and aminoacetaldehydedimethylacetal (10.0 mL, 9.75 g, 0.0927 mol) was added. The same procedure was applied as for 11a. The product was isolated as a clear light yellow oil (16.58 g, 100%), bp 153-155° C. (0.45 mm Hg). 1H NMR (300 MHz CDCl3) 8.49 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.61 (t, J=5.4 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.71 (d, J=5.4 Hz, 2H), 3.36 (s, 6H); low resolution ESIMS m/z (rel intensity) 284 (MH+, 100), 252 (45). Anal. Calcd for C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C, 59.67; H, 7.55; N, 4.88.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:14])([CH3:13])[CH:7](O)[C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[N:32]=[C:31]([SH:37])[N:30]=1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([F:14])([CH3:13])[CH:7]([S:37][C:31]1[N:30]=[C:29]([O:28][CH3:27])[CH:34]=[C:33]([O:35][CH3:36])[N:32]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(O)C(C)(F)c1cccs1
Reactant: COc1cc(OC)nc(S)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(F)c1cccs1
Temperature: 0 °C

Procedure:
5.5 g (25 mmol) of methyl 3-(2-thienyl)-3-fluoro-2-hydroxybutyrate (Compound 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added, and 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise with stirring. The mixture is stirred for 2 hours at room temperature, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is taken up in dimethylformamide (DMF), and this is added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium hydrogen carbonate in 100 ml of DMF. After the mixture has been stirred for 2 hours at room temperature and for a further 2 hours at 60° C., the mixture is poured into 1 l of ice-water, and the precipitate which has formed is filtered off with suction. After drying, 2.5 g of a white powder remain.
Reaction SMILES: [ClH:1].[C:2]([C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]([O:26]C)[C:10]=1[O:28]C)([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[OH-].[NH4+].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C(=O)([O-])[O-]>C(Cl)Cl.B(Br)(Br)Br>[ClH:1].[C:2]([C:9]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:12]=[C:11]([OH:26])[C:10]=1[OH:28])([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3]
Reactant: CCCCOC(=O)c1c2c(cc(OC)c1OC)C(c1ccccc1)CNCC2
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCCOC(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1
Reaction time: 4 h

Procedure:
The product from Examples 3 (5.7 g, 0.0136 mole) was dissolved in 500 ml of methylene chloride with 5.1 ml of boron tribromide at -15°. After 4 hours, 25 ml of conc. ammonium hydroxide was added with a small amount of ascorbic acid. The pH was taken to 8 with carbonate solution. The water layer was separated and extracted with ethyl acetate using sodium chloride to salt out the product which was collected and stirred with dilute hydrochloric acid overnight. The mixture was filtered. The filtrate was stripped until a solid formed. Cooling gave the desired 6-carbobutoxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 217°-220° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:9][CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1.I([O-])(=O)(=O)=[O:16].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[S:9](=[O:16])[CH2:8][CH2:7][NH:6][C:5]2=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1
Reactant: O=C(O)c1cc(Br)cc2c1NCCS2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c1NCCS2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-1,4-benzothiazine-5-carboxylic acid (500 mg) in methanol (80 ml) was added 0.05M sodium metaperiodate solution (40 ml). The mixture was stirred for 5 hours at room temperature, then diluted with water (500 ml) and concentrated until crystals began to separate. The crystals were collected and dried to give the title compound (300 mg, 57.5%) which was recrystallized from ethanol to give pale yellow crystals, mp 254°-255° C. (decompd.).
Reaction SMILES: [F:1][C:2]([F:23])=[C:3]1[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C)=[CH:13][C:12]=1[CH2:11][CH2:10]3.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])=[C:3]1[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(F)F)C=C[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C=CC2=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of 2.4 g of 17-difluoromethylene-3-methoxy-estra -1,3,5(10),15-tetraene in 49 ml of toluene is refluxed with 49 ml of a 1.6 M diisobutylaluminum hydride solution in toluene for 1 hour at a bath temperature of 140° C. Then, it is cooled to room temperature, slowly added to 200 g of ice, mixed with 400 ml of 2N sulfuric acid, stirred for 1 hour at room temperature, extracted three times with ethyl acetate, the organic phases are washed with water as well as saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 1.37 g of 17-difluoromethylene-estra-1,3,5(10),15-tetraen-3-ol is obtained as colorless crystals with a melting point of 126-127° C., [α]D22 =-120.4° (c=0.505% in pyridine).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2([OH:26])[CH2:22][CH2:21][N:20]([C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[CH2:25][CH2:24]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1CCN(c2ncccn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of 1,4-dibromobenzene (213.3 mg, 0.904 mmol) in THF (4 ml), was added n-BuLi (2.5 M in hexanes, 0.362 ml, 0.904 mmol) at −78° C. After being stirred for 30 minutes at the same temperature, a solution of 1-pyrimidin-2-yl-piperidin-4-one (80 mg, 0.452 mmol) in THF (3 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with addition of water (10 ml) and EtOAc (50 ml). The organic layer was washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 4-(4-Bromo-phenyl)-1-pyrimidin-2-yl-piperidin-4-ol as a colorless oil (140 mg, 93%): 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=6.4 Hz, 2H), 7.47 (d, J=12.0 Hz, 2H), 7.41 (d, J=12.0 Hz, 2H), 6.49 (t, J=6.4 Hz, 1H), 4.72 (m, 2H), 3.40 (m, 2H), 2.05 (m, 2H), 1.78 (m, 2H); MS calc'd for C15H17BrN3O [M+H]+: 335; Found: 335.
Reaction SMILES: C(NCC)C.[NH:6](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:7]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10]>CN(C)C=O>[NH2:6][C@@H:7]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13])[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C(=O)OCc1ccccc1)C(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)C[C@@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 0.25 h

Procedure:
12.05 ml of diethylamine are added to a solution of 8.04 g (11.5 mmol) of Fmoc-D-Leu-Arg-D-Val-OBzl in 60 ml of dimethylformamide. The mixture is left to stand at room temperature for 15 minutes, and is concentrated. The residue is partitioned between n-pentanol and NaHCO3 solution. The pentanol phase is concentrated, and the residue is triturated with diethyl ether.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH:23]2[C:31](=[O:32])[CH:30]3[CH:25]([CH:26]4[O:33][CH:29]3[CH:28]=[CH:27]4)[C:24]2=[O:34])=[C:18]([CH3:35])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39]>ClCCl>[CH3:36][C:37]([CH3:42])([CH3:41])[C:38]([O:32][C:31]1[CH:30]2[CH:25]([C:24](=[O:34])[C:23]=1[C:19]1[C:18]([CH3:35])=[CH:17][C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:21][C:20]=1[CH3:22])[CH:26]1[O:33][CH:29]2[CH:28]=[CH:27]1)=[O:39]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3C=CC(O3)C2C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (5 ml, 35.9 mmol) is added, dropwise, to a solution of 4-(4-benzyloxy-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (5.0 g, 13.4 mmol) and trimethylacetyl chloride (5 ml, 40.6 mmol) in dry dichloromethane (75 ml). The mixture is stirred for 2 hours at room temperature, then silica gel is added and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give rac-(1R,2S,6R,7S)-4-(4-benzyloxy-2,6-dimethylphenyl)-5-oxo-10-oxatricyclo[5.2.1.02,6]deca-3,8-dien-3-yl 2,2-dimethylpropionate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:19]([CH3:43])=[C:20]4[C:25](=[CH:26][CH:27]=3)[CH:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:19]([CH3:43])=[C:20]4[C:25](=[CH:26][CH:27]=3)[CH:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:23]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCCC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 1,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-[4-(ethyloxy)-4-oxobutyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 29; 111 mg, 0.189 mmol) in ethanol (5 ml) was added 2M aqueous sodium hydroxide (0.189 ml, 0.377 mmol) and the resulting mixture was stirred at room temperature for 3 h. More 2M aqueous sodium hydroxide (2 equivalents) was added, and stirring was continued at room temperature for a further 3 h. Most of the solvent was removed and the residue partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N aqueous hydrochloric acid, the layers separated, and the aqueous layer further extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound (102 mg) as a white foam.