Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:15][CH:16]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)nc1C
Yield: 75.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (64 mg) described in Preparation Example 18 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (51 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (83 mg) was obtained.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]([C:12](OCC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7]([C:6]1[S:3][C:1]([CH3:2])=[N:4][C:12]=1[OH:13])=[O:8])[CH3:11]
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(C)nc1O
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a solution of thioacetamide (17.2 g, 0.229 mol) in toluene (130 mL) was added diethyl bromomalonate (55.0 g, 0.230 mol) and the mixture heated at reflux for 3 h. The reaction mixture was cooled to RT, filtered through Celite, then concentrated in vacuo. The resultant solid was triturated with hexane to give the title compound as a yellow solid (11.0 g, 26%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[N:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+].Cl>ClCCl.O1CCOCC1.C(OCC)C.C(OCC)(=O)C.CO>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[N:38][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2c3cnc(Nc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)nc3n(C3CCCC3)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 78.7 %

Procedure:
Compound 269 (120 mg, 220 μmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (0.400 mL, 2203 μmol) was added and the reaction stirred at room temperature for 70 minutes. The reaction was added to aqueous K2CO3 (10%, 30 mL) and extracted thrice with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a pale yellow solid, 82 mg. This residue was dissolved in dioxane (2 mL) and methanol (2 mL) and 1 mL of a saturated solution of HCl in dioxane was added. ethyl acetate (30 mL) followed by diethyl ether (30 mL) were added to precipitate the HCl salt, which was collected and dried in vacuo to give compound 266 as a yellow solid (77 mg, 84%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.24-9.36 (m, 4 H) 9.19 (s, 1 H) 8.52 (s, 1 H) 7.97 (s, 1 H) 7.92-7.96 (m, 1 H) 7.44-7.54 (m, 1 H) 6.83 (d, J=8.56 Hz, 1 H) 5.31-5.43 (m, 1 H) 3.94 (s, 3 H) 3.33-3.41 (m, 4 H) 3.21 (br. s., 4 H) 1.95-2.11 (m, 4 H) 1.70 (none, 2 H) ppm.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=CC=CC=1O>>[OH:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2O)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Oc1ccccc1I
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccccc2O)o1
Yield: 34 %

Procedure:
2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenol. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (88 mg, 0.134 mmol) and 2-iodophenol following General Procedure A. Flash chromatography (10-30% EtOAc/hexanes) yielded the title compound as a clear oil (21 mg, 34%): 1H NMR (CDCl3, 500 MHz) δ 7.80-7.76 (m, 1H), 7.62 (s, 1H), 7.56 (br s, 1H), 7.36-7.20 (m, 6H), 7.09-7.04 (m, 2H), 4.94 (t, 1H, J=6.0 Hz), 2.62 (t, 2H, J=7.5 Hz), 2.05-1.93 (m, 2H), 1.68-1.65 (m, 2H), 1.47-1.32 (m, 6H), 0.97 (s, 9H), 0.17 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.3, 154.3, 148.8, 143.2, 130.0, 128.8, 128.6, 126.5, 126.0, 124.9, 119.2, 116.8, 115.6, 70.1, 37.0, 35.3, 31.8, 29.6, 26.2, 26.2, 25.5, 18.6, −4.4, −4.6.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(CC)C(C)C)(C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (2.5 g, 4.77 mmol) in N,N-dimethylformamide (15 mL) was added N,N-diisopropylethylamine (0.90 mL, 5.01 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (927 mg, 5.01 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, water (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (150 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (2.14 g, 77%) as a pale-yellow solid.
Reaction SMILES: C1C(C(C(F)(F)F)(C(F)(F)F)C2C=CC(O)=CC=2)=CC=C(O)C=1.BrCCCCCCBr.C([O-])([O-])=O.[K+].[K+].[N+]([C:41]1[CH:42]=[C:43]([C:49]#[N:50])[C:44](=[CH:47][CH:48]=1)[C:45]#[N:46])([O-])=O.Cl>O.CS(C)=O>[C:49](#[N:50])[C:43]1[C:44](=[CH:47][CH:48]=[CH:41][CH:42]=1)[C:45]#[N:46]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: BrCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 90 °C

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer and a nitrogen inlet were added bisphenol AF (149 g, 0.442 mol), 1,6-dibromohexane (53.4 g, 0.219 mol), powdered anhydrous K2CO3 (150 g, 1.09 mol), and dimethylsulfoxide (DMSO) (1000 mL). The resulting mixture was degassed with nitrogen at ambient temperature and heated at 90° C. under a nitrogen atmosphere for 8-16 hr. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (80.1 g, 0.463 mol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 hr. The mixture was allowed to cool to ambient temperature and poured into 1000 mL of distilled water. The mixture was made acidic by the addition of 6 M aqueous HCl and the resin was extracted out of the water layer by toluene (200 mL). The toluene extracts were washed 3 times with 500 mL of distilled water and dried using magnesium sulfate. Removal of the toluene resulted in an amber oil, which was dried at 80° C. under vacuum. The 2:1 oligomeric phthalonitrile was isolated as an amber glassy solid (224 g, 97%). 1H-NMR [CDCl3]: λ 7.75 (m, aromatic-HR), 7.32 (m, aromatic-HR), 7.08 (m, aromatic-HR), 6.97 (m, aromatic-HR), 6.81 (m, aromatic-HR), 4.10 (m, aliphatic-HR), 1.80 (m, aliphatic-HR), 1.51 (m, aliphatic-HR).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=NO)[C:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([OH:26])([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH:8]=1)(=[O:3])[CH3:2].C([O-])(=[O:32])C.[NH4+].C(O)(=O)C.CC(C)=O>[Cl-].[Cl-].[Cl-].[Ti+3].O>[C:1]([O:4][CH2:5][C:6](=[O:32])[C:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([OH:26])([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=NO)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 15% (w/v) aqueous solution of titanium trichloride (4.1 ml) was added to a stirred suspension of 21-acetoxy-9α-hydroxy-20-hydroxyiminopregna-4,16-dien-3-one (0.50 g), ammonium acetate (1.5 g), acetic acid (10 ml) and acetone (3.75 ml) under nitrogen. After stirring at room temperature for 6 hours the reaction mixture was poured into water (30 ml) and extracted three times with diethyl ether. The combined organic layers were washed three times with 1N sodium hydroxide solution, then washed with aqueous sodium chloride solution and dried. The extract was evaporated under reduced pressure to afford the title compound as a foam.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:17]2[C:16](=O)[CH2:15][C@@:14]2([CH3:23])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1.Cl.[NH2:25][OH:26].[OH-].[Na+]>O>[OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:17]2[C:16](=[N:25][OH:26])[CH2:15][C@@:14]2([CH3:23])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=NO)C[C@]12C
Reaction time: 6 h

Procedure:
A solution of (Z)-3α-hydroxy-5α-pregn-17(20)-en-11-one (10.264 g) in warm industrial methylated spirits (320 ml) was heated with hydroxylamine hydrochloride (3.25 g) and sodium hydroxide (5.123 g) in water (10 ml). The mixture was refluxed for 41 hours and, after addition of more hydroxylamine hydrochloride (15.35 g) in water (20 ml) and sodium hydroxide (25.04 g) in water (50 ml) refluxing was continued for a further 6 hours. The mixture was then poured into water and the crystalline material (10.419 g) collected by filtration. Crystallisation of a portion from aqueous ethanol afforded an analytical sample of title compound m.p. 233°-235°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:39][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:38])[F:36])[CH:29]=2)[N:24]=1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3cccc(OC(F)(F)F)c3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
28 mg (0.69 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.66 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 234 mg (72%) of the title compound as slightly yellow powder.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[OH:13][CH2:14][CH2:15]C#N>>[C:14]([O:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])(=[O:13])[CH3:15]
Reactant: N#CCCO
Reactant: CC(O)C(C#N)c1ccccc1
Product: CC(=O)OC(C)C(C#N)c1ccccc1
Yield: 93 %

Procedure:
This mixture of esters was prepared using the procedure described in Example 5, except 3-hydroxy-2-phenylbutanenitrile was used in place of 2-(2-chloro-5-difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 3-hydroxy-2-phenylbutanenitrile is shown in Example 17. The recovered ester product was a colorless oil (93% yield) as a mixture of diastereoisomers (Esters 9A and 9B), separated by chromatography into two pairs, Rf 0.40 and 0.32 (silica gel, EtOAc:hexane=1:4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[C:10]=1[O:11][CH3:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:8]=[N:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: C1=COCCC1
Reactant: COc1c(Br)ccc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: COc1c(Br)ccc2c1ncn2C1CCCCO1
Temperature: 90 °C
Yield: 60.3 %

Procedure:
A 500 ml tube was charged with 6-bromo-7-methoxy-1H-benzoimidazole (36 g, 0.16 mol, 1.0 equiv.), dihydropyran (40.01 g, 0.48 mol, 3.0 equiv.) and pyridinium-p-toluenesulfonate (7.96 g, 0.032 mol, 0.2 equiv.) in EtOAc (400 mL), sealed and the reaction mixture was heated at 90° C. overnight. The reaction mixture was concentrated in vacuo and the crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30-40% EtOAc) to afford 5-bromo-4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (30 g, 60% yield) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>CS(C)=O>[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: COC[C@@H]1CCCN1
Solvent: CS(C)=O
Product: COC[C@@H]1CCCN1c1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
To a solution of N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg, 0.51 mmol) in DMSO (2 mL) was added (s)-(+)-2-(methoxymethyl)-pyrrolidine (0.29 mL, 2.55 mmol). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics were dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, followed by reverse-phase preparative HPLC using a Phenomena Gemini™ column (10 micron, C18, 110 Å, 150×30 mm), 0.1% TFA in CH3CN/H2O as mobile phase, gradient 10% to 90% over 15 min., then treated with Si-carbonate resin to provide (S)—N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 434.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:17]([C:19]2[S:20][C:21]([S:24]([N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[O:18])[C@@H:14]2[CH2:32][C@H:11]1[CH2:12][CH2:13]2.[OH-].[Na+]>CO.O1CCCC1.O>[N:27]1([S:24]([C:21]2[S:20][C:19]([C:17]([NH:16][C@H:15]3[C@@H:14]4[CH2:32][C@@H:11]([CH2:12][CH2:13]4)[C@@H:10]3[CH2:9]/[CH:8]=[CH:7]\[CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[O:18])=[CH:23][CH:22]=2)(=[O:26])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28]1
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a solution of 350 mg (0.713 mmol) of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid methyl ester (I-1a) in 1 ml of methanol and 0.5 ml of tetrahydrofuran was added under ice-cooling 0.5 ml (2.0 mmol) of 4N sodium hydroxide. The mixture was warmed to room temperature and stirred at 25° C. for 2 h. The reaction mixture was diluted with water and washed with ether. The aqueous layer was acidified with 0.5 ml of 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane (3:4) to give 234 mg of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)-thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid (I-1b) as needles.
Reaction SMILES: [Li][CH2:2]CCC.[CH:6]([C:8]1[S:9][CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:13])=O.CCOC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC.CCCCCC>[CH:6]([C:8]1[S:9][CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:13])=[CH2:2]
Reactant: Cc1csc(C=O)c1C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=Cc1scc(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (714 mg, 2 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (1.25 mL, 2.00 mmol). The resultant solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-3,4-dimethylthiophene trimer (432 mg, 1.2 mol) was added slowly and the mixture was stirred overnight. The reaction mixture was quenched with ammonium chloride solution and diluted with ether. The organic phase was washed with water and brine, and dried with MgSO4. The ether was removed in vacuo to afford the crude product as an oil (260 mg). Column chromatography (2% EtOAc in hexane) afforded the purified 2-vinyl-3,4-dimethylthiophene trimer (140 mg, 37% yield). EI-MS: 358 (M+). 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.90 (dd, 1H), 5.52 (d, 1H), 1.15 (d, 1H), 2.22 (s, 1H), 2.19 (s, 1H), 2.11 (s, 1H), 2.10 (s, 1H), 2.09 (s, 1H), 2.08 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:26])[C:7]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[CH3:4].[CH3:27][O:28][CH2:29]Cl.[Cl-].[NH4+]>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:26])[C:7]([O:25][CH2:27][O:28][CH3:29])([C:21]([F:22])([F:23])[F:24])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[CH3:4]
Reactant: COCCl
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)(C)c1cc(F)ccc1OC)(OCOC)C(F)(F)F
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a suspension of 525 mg (13.1 mmol) of 60% sodium hydride in mineral oil in 25 mL of dry DMF was added 3.1 g (8.8 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester (see Example 1) in several portions. The mixture was stirred for 15 minutes and was then treated with 1.4 mL (18.4 mmol) of chloromethyl methyl ether in several portions. After 15 minutes, the mixture was poured into 60 mL of saturated aqueous ammonium chloride and extracted with three 25 mL portions of EtOAc. The combined organic layers were washed with three 25 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3.4 g (99%) of 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester which was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[CH3:29])=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:29][N:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[C:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)=[O:22]
Reactant: CN1CCCCC1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCCC1C(=O)N1CCNCC1
Reaction time: 6 h
Yield: 26.3 %

Procedure:
2 ml of TFA are added to a solution of 0.84 g of the compound obtained in step 5.3, in 2 ml of DCM. The medium is stirred at AT for 6 h. The medium is evaporated, taken up several times in DCM, and evaporated so as to entrain the TFA. The medium is taken up in DCM and then treated with a 10% NH4OH solution. The organic phase is dried over MgSO4 and then evaporated, to give 0.15 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH2:10][Br:24])=[CH:4][CH:3]=1
Reactant: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (61.46 g, 0.197 mole) [prepared in Step C], N-bromosuccinimide (35.06 g, 0.197 mole) and catalytic amount of azobis isobutyronitrile or benzoyl peroxide in carbon tetrachloride (1.2 liters) was heated to reflux in an inert atmosphere for a period of 2 hours. The reaction mixture was cooled to ambient temperature and the solid from the reaction was filtered. The filtrate was concentrated under reduced pressure and the solid obtained was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals; m.p.=159°-160° C.
Reaction SMILES: Cl[C:2]1[C:7](C(F)(F)F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:26])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])N1CC(C)(C)C.C(=[O:34])C1C=CC=CC=1>>[O:26]=[C:14]1[N:13]([CH2:12][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C@H:18]([C:17]([OH:20])=[O:34])[CH2:19][CH2:15]1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
5-oxo-1-(phenylmethyl)proline was prepared in an analogous manner to that described above for the synthesis of 1-(2,2-dimethylpropyl)-5-oxoproline (example 100) but using benzaldehyde in the place of trimethylacetaldehyde.