Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][PH3+].[CH2:19]([O:21][C:22](=[O:33])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=O)[CH3:20]>C(Cl)Cl.C1COCC1.C1COCC1>[CH2:19]([O:21][C:22](=[O:33])/[C:23](/[C:25]1[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=1)=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])[CH3:20]
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Reactant: CC(C)(C)CC[PH3+]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)/C(=C/CC(C)(C)C)c1ccc(SC)cc1
Temperature: 25 °C

Procedure:
Add sodium bistrimethylsilylamide(4.67 mL, 2.0 M in THF, 9.35 mmol) to a solution of (3,3-Dimethyl-butyl) phosphonium bromide (4.00 g, 9.35 mmol)in CH2Cl2/THF at 0° C. Dissolve (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (prepared as described by I. T. Barnish et. al. J. Med. Chem. 1981, 24, 399-404) in THF and add the resulting solution to the reaction mixture at 78° C. Stir at room temperature over-night. Add water and extract 3 X with dichloromethane, dry over sodium sulfate and concentrate under vacuum to afford 2.79 g raw material as a yellow oil. Further purify this material via silica gel chromatography, eluting with a gradient from 100% hexane to 50:50 hexane:dichlormethan to afford a colorless oil (700 mg). MS (m/e): 293 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].C(N(CC)CC)C.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC1CCCCNC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCCCCC1Nc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 28 %

Procedure:
5 g (39 mmol) of α-amino-ε-caprolactam are dissolved in 50 ml of dimethylformamide and 5.5 ml (1 eq) of triethylamine in a 100 ml three-necked flask equipped with a reflux condenser and a thermometer. 4.1 ml (1.5 eq) of 4-fluoronitrobenzene are then run into the reaction mixture, which is subsequently brought to a temperature of 70° C. for 48 hours. The mixture is cooled and is then precipitated from water. An orangy-yellow precipitate is isolated by filtration and is then purified on a silica column (eluent: dichloromethane 95/methanol 5). 2.7 g of a yellow product are obtained, i.e. a final yield of 28%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 69.8 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][OH:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].C(Cl)CCl.[C+](=O)C1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][O:29][C:40](=[O:41])[CH2:39][NH:38][C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=[C+]c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(COC(=O)CNC(=O)OC(C)(C)C)cc3F)CC2)CC1
Reaction time: 20 h

Procedure:
Compound 10-1 (40 mg, 0.094 mmol), tert-butoxycarbonylamino-acetic acid (17 mg, 0.097 mmol), DMAP (3 mg, 0.024 mmol), EDC(22 mg, 0.11 mmol) and DCM (1 mL) were combined in that order and the reaction mixture was stirred for 20 h. The mixture was then washed with aqueous NaHCO3 (1 mL), concentrated under a stream of nitrogen and purified by Jones flash LC(eluent: 10-40% ethyl acetate+0.1% triethylamine in hexanes) to afford 12-1: LC-MS 408.2 (benzylium fragment).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COCCBr
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COCCOc1cccc(CO)c1
Yield: 71.7 %

Procedure:
3-Hydroxybenzyl alcohol (3.76 g, 30 mmol), 2-bromoethylmethyl ether (8.0 ml, 85 mmol) and cesium carbonate (14.7 g, 45 mmol) were heated at 60° C. for 3 h. The reaction was diluted with water, extracted (3×) with ethyl acetate and dried over sodium sulfate. The solution was filtered, concentrated and purified by silica chromatography (DCM followed by DCM/MeOH 19:1, then 9:1) to yield [3-(2-methoxyethoxy)phenyl]methanol as an orange oil (3.92 g, 72%).
Reaction SMILES: C([Mg]Cl)(C)C.CN(C)CCOCCN(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.[B:32](OC)([O:35]C)[O:33]C>C1COCC1>[N:26]1([C:24]([C:21]2[CH:22]=[CH:23][C:18]([B:32]([OH:35])[OH:33])=[CH:19][CH:20]=2)=[O:25])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: CN(C)CCOCCN(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
Isopropylmagnesium chloride (27.8 mL, 2 M in THF, 55.6 mmol) was added to a solution of bis(2-dimethylaminoethyl)ether (10.5 mL, 55.6 mmol) in THF (230 mL) 15° C. After 20 minutes, (4-iodophenyl)-(morpholino)methanone (14.7 g, 46.4 mmol) was added and the reaction was removed from the cooling bath. After 1 hr, another 0.8 eq of isopropylmagnesium chloride was added. Trimethyl borate (10.6, 93 mmol) was added after 15 minutes, and after stirring 40 min, the reaction was quenched with 150 ml 1 N aqueous HCl. After stirring at room temperature for 2 hr, THF was removed on the rotary evaporator and the residue was extracted three times with EtOAc. The organic extracts were dried with Na2SO4. The solvent was removed and the residue was twice suspended in toluene and the solvent removed on the rotary evaporator. The resulting white solid was suspended in hexane and this was heated at reflux for 5 minutes. After cooling to room temperature, the white solid was collected by filtration and air-dried to afford 4-(morpholine-4-carbonyl)phenylboronic acid (8.7 g). MS (ESI) m/z 236.1 (M+H). 1H NMR (MeOD) δ ppm 7.78 (2H, d, J=7.30 Hz), 7.36 (2H, d, J=8.06 Hz), 3.72-3.41 (8H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid (4.75 g) and 4-nitrophenol (2,5 g) in 25 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.1 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, 4.85 g of (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid 4-nitrophenyl ester was obtained as an oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([CH:19]([CH3:21])[CH3:20])[N:16]([C:22]3[CH:27]=[CH:26][N:25]4[N:28]=[CH:29][C:30]([C:31]5[CH:36]=[CH:35][C:34]([C:37]6[N:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:38]=6)=[CH:33][CH:32]=5)=[C:24]4[N:23]=3)[C:15]2=[O:50])(=O)=O)=CC=1.Cl.[F:52][C@@H:53]1[CH2:57][CH2:56][NH:55][CH2:54]1.C(N(C(C)C)C(C)C)C.[OH-].[Na+]>CN(C=O)C>[F:52][C@@H:53]1[CH2:57][CH2:56][N:55]([CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([CH:19]([CH3:20])[CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][N:25]4[N:28]=[CH:29][C:30]([C:31]5[CH:32]=[CH:33][C:34]([C:37]6[N:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[N:38]=6)=[CH:35][CH:36]=5)=[C:24]4[N:23]=3)[C:15]2=[O:50])[CH2:54]1
Reactant: F[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCN2C[C@H](C(C)C)N(c3ccn4ncc(-c5ccc(-c6ncn(COCC[Si](C)(C)C)n6)cc5)c4n3)C2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(CCN2CC[C@@H](F)C2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.2 %

Procedure:
To a solution of (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl 4-methylbenzenesulfonate (0.070 g, 0.098 mmol) in DMF was added (R)-3-fluoropyrrolidine hydrochloride (0.044 g, 0.49 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.13 g, 0.98 mmol) and the reaction stirred for 4 days at ambient temperature. The reaction was poured into 1N NaOH and the aqueous layer extracted into EtOAc. The organics were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was chromatographed using EtOAc to 3% MeOH/dichloromethane as eluent to yield (S)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.025 g, 40%).
Reaction SMILES: N=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[O:19])[NH:4][C:3]1([CH2:28][O:29]C1CCCCO1)[CH2:20][O:21]C1CCCCO1.CO.Cl.C(=O)(O)[O-:40]>C(OCC)(=O)C>[OH:21][CH2:20][C:3]1([CH2:28][OH:29])[C:2](=[O:40])[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:17])([F:16])[F:18])[CH:8]=2)[C:5](=[O:19])[NH:4]1
Reactant: N#Cc1ccc(N2C(=N)C(COC3CCCCO3)(COC3CCCCO3)NC2=O)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(N2C(=O)NC(CO)(CO)C2=O)cc1C(F)(F)F

Procedure:
300 mg of the product obtained in Stage 3 above is introduced into 3 ml of methanol and 1.5 ml of 2N hydrochloric acid and the whole is taken to reflux for one hour 30 minutes. It is returned to ambient temperature, poured into 5 ml of bicarbonate, extraction is carried out 4 times with ethyl acetate then the extracts are washed with a saturated sodium chloride solution and dried. 5 ml of methanol is added and purification is carried out on silica eluting with methylene chloride-methanol: 9-1. The residue is taken up in 20 ml of isopropanol under reflux then concentration is carried out and 225 mg of expected product (white crystals) is obtained. M.p.=207-208° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([OH:12])=[C:7]([Cl:13])[CH:6]=1)(=[O:3])[CH3:2].[C:14](OC(=O)CCC)(=O)[CH2:15]CC>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([Cl:13])[C:8]([OH:12])=[C:9]([Cl:11])[CH:10]=1)(=[O:3])[CH2:2][CH2:14][CH3:15]
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CCCC(=O)OC(=O)CCC
Product: CCCC(=O)Nc1cc(Cl)c(O)c(Cl)c1

Procedure:
Using the method described above for the preparation of 4-acetamido-2,6-dichlorophenol (but using butyric anhydride in place of acetic anhydride) there was obtained 4-butyramido-2,-6-dichlorophenol (used as starting material in Example 51) as a solid, m.p. 146°-147°; NMR([CD3 ]2SO): 0.9(3H,t), 1.58(2H,m), 2.25(2H,t), 7.62(2H,s), 9.75(1H,br s) and 9.85(1H,s); m/z 248(M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29]#[N:30])[C:16]([CH2:31][CH3:32])=[C:15]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:49]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23]([Cl:49])=[C:22]3[C:29]#[N:30])[C:16]([CH2:31][CH3:32])=[C:15]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc3c(c2)c(C#N)c(Cl)n3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Yield: 82.3 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-6-(3-cyano-1-methyl-1H-indol-5-yl)-5-ethylnicotinate (1.80 g, 3.39 mmol), prepared in Example 359 step 2, in THF (24 mL) was added LDA solution (1.5M in cyclohexane, 3.40 mL, 5.10 mmol, 1.5 eq) dropwise at −78° C. The reaction mixture was stirred for 15 min before a solution of hexachloroethane (1.21 g, 5.1 mmol, 1.5 eq) in THF (6 mL) was added dropwise at −78° C. The reaction progress was monitored by LC-MS. Upon completion, the reaction was quenched with sat. NH4Cl solution then extracted with Et2O (4×30 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was purified by flash column chromatography (0-10% EtOAc in 1/1 CH2Cl2/hexanes) to afford the title compound (1.58 g, 82%).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH2:2][O:10]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccncn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC1(c2ccncn2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
Trimethylsulfonium iodide (3.34 g, 16.3 mmol) was dissolved in DMF (20 mL) and stirred at RT for 5 min. Sodium hydride (600 mg, 25 mmol) was added portionwise at the same temperature and stirred for 15 min. 4-Acetyl pyrimidine (1 g, 8.1 mmol) in 0.5 mL DMSO was added dropwise and the reaction mixture stirred for 1 h. After completion of reaction, the mixture was poured into ice-cold water and extracted with Ether (3×). The combined organic layer was washed with water several times followed by brine, and dried over sodium sulfate, then evaporated to provide 600 mg of 4-(2-Methyl-oxiranyl)-pyrimidine. 1H NMR (CDCl3, freebase) δ (ppm): 9.15 (s, 1H), 8.7 (d, 1H), 7.35 (d, 1H), 2.95 (d, 1H), 2.88 (d, 1H), 1.8 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[C:13]([CH3:15])([CH3:14])[O:12][BH:11][O:10]1.[CH2:17]([N:21]1[CH2:26][C:25]2([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:24][CH2:23][CH2:22]1)[CH2:18][C:19]#[CH:20]>ClCCl.[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2]>[CH3:8][C:9]1([CH3:16])[C:13]([CH3:15])([CH3:14])[O:12][B:11](/[CH:20]=[CH:19]/[CH2:18][CH2:17][N:21]2[CH2:26][C:25]3([CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH2:24][CH2:23][CH2:22]2)[O:10]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Zr+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(CC/C=C/B3OC(C)(C)C(C)(C)O3)C2)CC1
Temperature: 65 °C
Yield: 86.9 %

Procedure:
Triethylamine (5.62 mmoles; 0.783 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.56 mL, 59.0 mmol) and zirconocene chloride (1.45 g, 5.62 mmoles) are added to tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (17.21 g, 56.16 mmoles). The resulting mixture is heated to 65° C. for 3.5 hours. The mixture is cooled and dissolved in dichloromethane (150 mL). The resulting solution is passed through a ˜4 cm thick pad of silica gel, eluting with dichloromethane (2×200 mL). The filtrate is concentrated under reduced pressure to give the title compound (21.2 g, 87% yield). 1H NMR (300.11 MHz, CDCl3): δ 6.65-6.55 (m, 1H), 5.49-5.43 (m, 1H), 3.42-3.29 (m, 4H), 2.40-2.27 (m, 6H), 2.25-2.08 (m, 2H), 1.70-1.13 (m, 29H).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1>CS(C)=O.O>[CH:1]12[N:8]([CH2:36][CH:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:29](=[O:33])[O:30][CH2:31][C:32]=4[C:24]=3[CH3:23])[OH:35])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(O)CN2CC3CCC(C2)N3)ccc2c1COC2=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3CC(O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of isomer (37A) of 5-[2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (53 mg, 0.175 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (57 mg, 0.210 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-TLC (MeOH/DCM=1:15) and then separated by SFC chiral chromatography to obtain two separated isomers A and B of 5,5′-[3,8-diazabicyclo[3.2.1]octane-3,8-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1.[CH3:22][O-:23].[Na+].O.Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:23][CH3:22])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1
Reactant: C[O-]
Reactant: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cncc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Yield: 93 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)-pyrimidin-4-ol (see, e.g., Example 120; 1.0 g, 2.8 mmol) and a sodium methoxide solution (25% wt., 2.6 mL) in dimethyl sulfoxide (10 mL) was stirred at 70° C. overnight. Water (100 mL) was added, and the pH of the mixture was adjusted to around 6 with 2N HCl. The mixture was extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo to afford 2-{[(3-chloro-5-methoxypyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (912 mg. 93%); 1H NMR (500 MHz, DMSO-d6): δ 3.97 (s, 3H), 4.59 (s, 2H), 6.68 (s (br), 1H), 8.32 (s, 1H), 8.39 (s, 1H); M+352.
Reaction SMILES: C([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)C1C=CC=CC=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>C(#N)C1C=CC=CC=1>[C:25]([C:27]1[CH:28]=[C:29]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[N:9][OH:8])[C:18]23[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: N#Cc1ccccc1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NO)N3)c1
Yield: 69.2 %

Procedure:
3-[Spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)]benzonitrile[3H]indol]-5-yl]benzonitrile. Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-cyanophenyl boronic acid (0.76 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.75 g, 1.8 mmol, 71%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.41–1.81 (8H, m), 1.96–2.03 (2H, q), 5.01 (2H, s), 6.86 (1H, d), 7.28–7.33 (9H, m), 7.95–7.97 (1H, d), 8.12 (1H, s), 9.65 (1H, s); MS (ESI(−ve)) m/z 406 (M−H)−.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:27]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:30][CH2:29][CH2:28]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:27]1[C:36]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:30][CH2:29][CH2:28]1)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-{4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (0.2466 g, 0.51 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.3 mL, 2.5 mmol), and stirred at room temperature for 18 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1031 g (58%) of
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:23]([F:22])([F:32])[F:33])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: FC(F)(F)c1ccccc1CCl
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccccc3C(F)(F)F)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-trifluoromethylbenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from petroleum ether (60°-95° C.). M.p. 87°-88° C.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:5][CH3:6])[CH2:3][CH3:4].[CH3:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][Cl:11]>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]([CH3:8])[CH2:10][Cl:11])=[CH:14][CH:15]=1)([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CCC(C)(Cl)CC
Reactant: CC(CCl)Cc1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(C)(CC)c1ccc(CC(C)CCl)cc1
Temperature: 20 °C
Reaction time: 14 h

Procedure:
365 parts by weight of 1-methyl-1-ethyl-propyl chloride are added dropwise to a mixture of 510 parts by weight of 2-methyl-3-phenyl-propyl chloride and 49 parts by weight of anhydrous iron (III) chloride at 30° C. The resulting mixture is stirred for 8 hours at 50° C. and for 14 hours at room temperature (20° C.). The crude product is poured into ice water and dissolved in CHCl3, the solution is repeatedly washed with water and dried over Na2CO3, the solvent is evaporated and the residue is distilled.