Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:12]1[N:13]=[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([C:30]4[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=4)=[CH:3][C:4]=3[O:10][CH2:9][CH2:8][N:7]2[CH:11]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2
Temperature: 25 °C

Procedure:
9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (157 mg, 0.421 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (139.9 mg, 0.5258 mmol), and Tetrakis(triphenylphosphine)palladium(0) (68.05 mg, 0.05889 mmol) dissolved in Acetonitrile (2.66 mL, 50.9 mmol) and with dissolved 2.00 M of Potassium carbonate in Water (0.421 mL). The reaction mixture was degassed. The reaction was microwaved on 150 watts, 140° C. for 10 minutes. The reaction was cooled to r.t., extracted with ethyl acetate to give crude product purified by rHPLC to give 214. MS: (ESI+)=433.2. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.68 (s, 1H), 7.42-7.31 (m, 2H), 7.26 (d, J=1.7 Hz, 1H), 6.94 (s, 1H), 5.66 (dt, J=13.5, 6.7 Hz, 1H), 4.74 (s, 1H), 4.50 (s, 4H), 4.03 (s, 2H), 1.46 (d, J=6.7 Hz, 6H), 1.09 (s, 6H)
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:22]1[S:23][C:24]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=2[N:26]=1.Cl>C1(C)C=CC=CC=1>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([N:10]3[CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8](=[O:18])[NH:9]3)[S:23][C:24]=2[CH:30]=1
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1NN(c2nc3ccc(Cl)cc3s2)C(c2ccccc2)C1c1ccccc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
The reaction was conducted under a dry nitrogen atmosphere. A suspension of 4,5-diphenyl-3-pyrazolidinone (1.19 g, 5.00 mmol) in 35 mL toluene was treated with 0.40 g NaH (60% in mineral oil; hydride content 0.24 g, 10.0 mmol, 2.00 eq.), and the mixture stirred at 45° C. for 2 hours. 2,6-Dichlorobenzothiazole (1.02 g, 5.00 mmol, 1.00 eq.) was added and stirring continued at 80° C. for 20 hours. After cooling, the reaction mixture was poured onto 30 mL ice-cooled 0.5 N HCl, extracted with EtOAc, and the separated organic phase washed twice with brine, dried over Na2SO4, and the solvent evaporated in vacuo. The residue was recrystallized from Et2O:hexane to provide 1.46 g (72%) light tan crystals: mp 170.5°-2.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:24][C:25]1[CH:26]=[N:27][NH:28][CH:29]=1>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C@:12]([OH:13])([CH3:15])[CH2:14][N:27]2[CH:26]=[C:25]([I:24])[CH:29]=[N:28]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@]1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(S)-(2-Methyloxiran-2-yl)methyl 4-nitrobenzoate (2.0 g, 8.4 mmol) and cesium carbonate (4.12 g, 12.7 mmol) were added to a solution of 4-iodo-1H-pyrazole (1.64 g, 8.43 mmol) in DMF (30 mL). The mixture was stirred at room temperature for 14 h, then diluted with EtOAc, and washed with hydrochloric acid (1N). The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-60% EtOAc/Hexane) to afford (S)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropyl 4-nitrobenzoate. MS ESI calc'd. for C14H15IN2O5 [M+H]+ 432. found 432.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH:25]4[CH2:28][CH2:27][CH2:26]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH:25]1([CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CC1(CC2CCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CC2CCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 81.1 %

Procedure:
To a stirring solution of Example 56 (0.080 g, 0.189 mmol) and pyridine (0.122 mL, 1.512 mmol) in dichloromethane was added methanesulfonyl chloride (0.017 mL, 0.227 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.079 g, 84% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (m, 2H) 1.15 (m, 1H) 1.26 (m, 4H) 1.47 (m, 3H) 1.57 (s, 3H) 1.72 (m, 2H) 2.14 (m, 1H) 2.31 (m, 1H) 3.08 (s, 3H) 7.53 (m, 1H) 7.61 (dd, J=11.77, 2.21 Hz, 1H) 8.15 (d, J=7.35 Hz, 1H) 10.25 (s, 1H) 13.83 (s, 1H). MS (ESI+) m/z=516 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.Cl.[F:14][C:15]([F:31])([F:30])[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[C:23]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:21][CH:20]=2>>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:27](=[O:28])[CH2:26][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[CH:25]=[C:16]([C:15]([F:14])([F:31])[F:30])[CH:17]=[N:18]3)[S:5][CH:6]=1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Reactant: O=C(O)Cc1cccc2ncc(C(F)(F)F)cc12
Agent: Cl
Product: O=C(Cc1cccc2ncc(C(F)(F)F)cc12)Nc1scc(Br)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (56 mg, 228 umol) and 2-(3-trifluoromethylquinolin-5-yl)acetic acid hydrogen chloride (200 mg, 784 umol) according to the procedures outlined in Example 1.68.6., above. Method [7] retention time 5.93 min by HPLC (M+ 482 and 484) and (M+Na 504 and 506). 1H NMR (300 MHz, CDCl3) δ 12.45 (s, 1H), 9.23 (s, 1H), 8.84 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.03 (m, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.74 (s, 1H), 6.95 (s, 1H), 4.38 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:9]2[NH:21][N:20]=[N:19][N:10]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(C)c1COc1cccc(C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(-c2nnn[nH]2)c1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,6-Dimethylbenzyloxy)benzonitrile (Step A, 3 g, 11.8 mmol), sodium azide (0.847 g, 13 mmol) and ammonium chloride (0.697 g, 13 mmol) in dry dimethylformamide (30 ml) was heated under argon at 110° C. for 14 hours or until all the starting material is consumed. Water was added to the reaction mixture to dissolve all the solids; the solution was taken in brine and extracted with ethyl acetate (2×). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5) to give the title compound as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:24]([CH3:35])[C:25](=[O:34])[CH2:26][S:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH2:21][CH2:22][CH3:23].[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][S:27][CH2:26][C:25]([N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:35])=[O:34]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)CSCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CSCCCCCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
6.88 g of triphenyl phosphine were added to a solution of 5.27 g of the product of Step B in 52 ml of methylene chloride and the mixture was cooled to 0° C. to +5° C. under a nitrogen atmosphere. 8.68 g of tetrabromo methane were added with stirring for one hour at 0° C. The reaction mixture was chromatographed on silica (eluant: cyclohexane-ethyl acetate 2-1) to obtain 6.2 g of the expected product.
Reaction SMILES: [CH3:1][O-].[Na+].[OH:4][CH2:5][CH2:6][C:7]1[C:8](=[O:15])[NH:9][C:10]([CH3:14])=[N:11][C:12]=1[CH3:13].IC>CO>[OH:4][CH2:5][CH2:6][C:7]1[C:8](=[O:15])[N:9]([CH3:1])[C:10]([CH3:14])=[N:11][C:12]=1[CH3:13]
Reactant: Cc1nc(C)c(CCO)c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cc1nc(C)n(C)c(=O)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Sodium methylate (1.9 g) was added to a mixture of intermediate 4 (6 g) in methanol (50 ml) while stirring at RT. Stirring was continued for 30 minutes and iodomethane (5 g) was added dropwise and the reaction mixture was stirred and refluxed for 4 hours. The solvent was evaporated, water was added to the residue and this mixture was extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated, yielding 6.0 g (94%) of 5-(2-hydroxyethyl)-2,3,6-trimethyl-4(3H)-pyrimidinone (intermediate 5).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11](O)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:21]>>[C:1]1([C:7]2[N:12]=[C:11]([Cl:21])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Yield: 81 %

Procedure:
The title compound was prepared by (a) reaction of diethylethoxymethylenemalonate (31 g, 144 mmol) with benzamidine (22 g, 144 mmol) under basic conditions to afford ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate in 64% yield in analogy to Example 15, (b) reaction of ethyl 2-phenyl-4-hydroxypyrimidine-5-carboxylate (1.5 g, 6 mmol) and POCl3 (9.4 g, 62 mmol) to afford 81% of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 2-phenyl-4-chloropyrimidine-5-carboxylate (12 g, 46 mmol) with hydrazine (4.4 g, 137 mmol) to afford 99% of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-phenylpyrimidine-5-carboxylate (12 g, 46 mmol) with citraconic anhydride (10 g, 92 mmol) to afford 75% (12 g) of the title compound (m.p. 155-156° C.) in analogy to Example 21.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:47])([CH2:43][CH2:44][CH2:45][CH3:46])[C:40](Cl)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:47])([CH3:38])[CH2:43][CH2:44][CH2:45][CH3:46])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCCCC(C)(C)C(=O)Cl
Product: CCCCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 90.1 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.63 g (10.0 mmol) of 2,2-dimethylhexanoyl chloride, to provide 1.22 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:30][C:28]1[CH:29]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(F)cc(Br)c2)(c2ccccc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(F)cc(COCC3(c4ccccc4)CCNCC3)c2)cc1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (100.0 mg, 0.21 mmol), 4-cyanophenylboronic acid (93 mg, 0.63 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.02 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.7 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 48 mg (46%). 1H-NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.31-7.38 (m, 4H), 7.19-7.22 (m, 1H), 7.11-7.13 (m, 1H), 7.08 (s, 1H), 6.84-6.86 (s, 1H), 4.40 (s, 2H), 3.45 (s, 2H), 2.89-2.93 (m, 2H), 2.73-2.78 (m, 2H), 2.17-2.20 (m, 2H), 1.88-1.94 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 163.3 (d, J=247.6 Hz), 144.2, 142.5, 141.2, 132.7, 128.4, 127.8, 127.3, 126.2, 121.3, 118.7, 114.2, 114.0, 113.1, 111.7, 80.1, 72.3, 42.7, 41.9, 33.6. Mass spec.: 401.28 (MH)+. Accurate mass spec.: m/z 401.2026 [MH]+, Δ=0.8 ppm.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]2([C:40]([F:43])([F:42])[F:41])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][N:25]4C(=O)C5C(=CC=CC=5)C4=O)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.NN>C(O)C>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([C:13]2([C:40]([F:41])([F:42])[F:43])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 96.6 %

Procedure:
2-{[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoro-methyl)pyridin-3-yl]methyl}-1H-isoindole-1,3(2H)-dione (0.31 g) and hydrazine hydrate (0.035 ml) were added to ethanol (5 ml), and heated at 80° C. for 5 hours. The solvent was distilled off under reduced pressure, and then t-butyl methyl ether was added. The undissolved matters were removed by filtration, and the target compound (0.24 g) was obtained after concentration under reduced pressure.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].O[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[Cl:7][CH:3]([CH:2]([CH3:1])[CH2:8][CH3:9])[C:4]([O:6][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:4](=[O:5])[CH:3]([Cl:7])[CH:2]([CH3:1])[CH2:8][CH3:9])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:5]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Product: CCC(C)C(Cl)C(=O)Oc1ccc(-c2ccc(OC(=O)C(Cl)C(C)CC)cc2)cc1

Procedure:
An excess of (S,S)-3-methyl-2-chloropentanoic acid is reacted with 4,4'-bis-hydroxybiphenyl analogously to Example 1. Customary working up gives optically active 4,4'-bis-(2-chloro-3-methylpentanoyloxy)-biphenyl.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:21]4[C:16]5[C:17](=[N:18][C:13]([C:3]6[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[F:12])=[N:14][CH:15]=5)[NH:19][N:20]=4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=464.1. 1H NMR (300 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.34 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.3 Hz, 1H), 4.52 (s, 2H), 3.94 (s, 6H), 3.07-2.90 (m, 1H), 0.97-0.76 (m, 4H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH2:25][OH:26])[CH2:3]1>C(Cl)(Cl)Cl.C(O)(C)C.O=[Mn]=O>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[O:26])[CH2:3]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=C/CO)CC[C@]12O
Agent: O=[Mn]=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=C/C=O)CC[C@]12O
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 4.90 g of (E,E)-5-(3β,14β-dihydroxy-5β-androstane-17β-yl)-2,4-pentadien-1-ol in 160 ml of chloroform and 40 ml of iso-propanol, 10.40 g of MnO2 were added at room temperature. The mixture was stirred overnight and then filtered through Celite. The organic solution was evaporated to dryness to give 4.80 g of the title compound (II-a) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30](OS(C(F)(F)F)(=O)=O)[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30]([C:2]1[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)Oc1c(Br)cccc1C#N
Reactant: O=S(=O)(OC1=CC2CCC(C1)N2Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)Oc1c(C#N)cccc1C1=CC2CCC(C1)N2Cc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of 3-bromo-2-tert-butoxy-benzonitrile (30.73 g, 0.121 mol) in THF (100 mL) at 0° C. was added 2 M isopropylmagnesium chloride in THF (60 mL) dropwise. The reaction mixture was stirred for 1 h and then tetrakis(triphenylphosphine)palladium(0) (2.33 g, 0.002 mol) was added followed by trifluoro-methanesulfonic acid 8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester (35.00 g, 0.101 mol) in THF (23 mL). The reaction mixture was refluxed at 80° C. for 1 h, cooled to RT, washed with brine, and extracted with EtOAc (2×). The organic layer was dried over sodium sulfate and the solvent was evaporated to provide the title compound (39.2 g) which was used without further purification. (m/z): [M+H]+ calcd for C25H28N2O, 373.22. found 373.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: NCCOCCO
Solvent: C1COCCO1
Product: O=[N+]([O-])c1c(NCCOCCO)cc(Cl)cc1NCCOCCO
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The mixture consisting of 0.1 mole (22.6 g) of 2,4,6-trichloronitrobenzene, 0.6 mole (63 g) of 2-(β-aminoethoxy)ethanol and 20 ml of dioxan is heated to reflux of the dioxon. After 4 hours, the reaction mixture is poured onto to 200 g of ice. The product expected crystallizes on acidifying with concentrated hydrochloric acid. After draining, washing with water and drying by heating under vacuum, the product is recrystallized from acetonitrile and then from toluene. It melts at 83° C.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.P(Cl)(Cl)[Cl:15].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:15][CH:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: ClP(Cl)Cl
Reactant: COc1ccc2c(c1)C(O)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(Cl)CCO2
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 4-hydroxy-6-methoxy-2,3-dihydro-4H-1-benzopyran (20 g) dissolved in benzene (150 ml), phosphorus trichloride (16.7 g) diluted in benzene (50 ml) is cautiously added under stirring at a temperature maintained below 20° C. by external cooling, then the reaction mixture is kept at 50° C. for 1 hour. After cooling the solution is poured into a 10% NaHCO3 solution (1 l) containing ice, under stirring, then the organic phase is separated and the aqueous phase extracted with ethyl acetate. The organic solutions are evaporated to dryness in vacuo to yield crude 4-chloro-6-methoxy-2,3-dihydro-4H-1-benzopyran as brown oil (21.5 g), which is dissolved in anhydrous dimethylformamide (90 ml) and added under stirring at about 20° C. to a solution of diethylmalonate carbanion (prepared from 19.1 g of diethylmalonate and 5.7 g of 50% sodium hydride) in anhydrous dimethylformamide (30 ml). The reaction mixture is heated at 70° C. for 7 hours, then is cooled at room temperature and diluted with ice water containing excess NaH2PO4.