Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1.[OH-].[NH4+:32].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl.O>[Cl:12][CH2:13][C:14]1[N:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:32])[C:17]=2[N:26]=1
Reactant: [NH4+]
Reactant: CC(C)Cn1c(CCl)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA) (32.7 g of 77% pure material, 146 mmol) was added over a period of five minutes to a solution of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20.0 g, 73.1 mmol) in chloroform (500 mL); the reaction mixture was stirred at ambient temperature for one hour. Ammonium hydroxide (200 mL) was added, and then p-toluenesulfonyl chloride (16.7 g, 87.7 mmol) was added in portions over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for one hour, and then water (200 mL) was added. The aqueous layer was separated and extracted with dichloromethane (2×200 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 32 g of crude product as a tan solid. The crude product was dissolved in dichloromethane (50 mL), and the resulting solution was divided into two portions. Each portion was purified by column chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) using a FLASH 65I silica cartridge (also available from Biotage, Inc.) (eluting with ethyl acetate:methanol in a gradient from 98:2 to 85:15) to provide 11.24 g of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [CH3:1][C:2](=[CH2:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:43][N:41]1[C:40](=[O:44])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([CH3:1])=[CH2:35])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:5][C:6]3=[O:28])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)N1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
(S)-4-(2-methylallyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one (38 mg, 0.08 mmol), 5-bromo-1-methylpyridin-2(1H)-one (23 mg, 1.5 equiv.), Pd(PPh3)2Cl2 (2 mg, cat. amount), 2M aq Na2CO3 (500 μL, excess), and 1,4-Dioxane (4 mL) were mixed. The mixture was evacuated and refilled with nitrogen gas (3×), before being heated to 90° C. overnight. After being cooled down, the mixture was concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-1-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (16 mg, 44%). LC-MS Method 1 tR=1.76 min., m/z 456 (M+1); 1H NMR (CD3OD) δ 7.90 (s, 1H), 7.80 (dd, 1H), 7.47 (d, 2H), 7.39 (t, 2H), 7.30 (d, 3H), 6.96 (d, 2H), 6.61 (d, 1H), 5.32 (q, 1H), 5.02 (d, 1H), 3.61 (s, 3H), 2.59-2.45 (m, 2H), 1.49 (d, 3H), 1.15 (s, 3H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]([NH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2)[C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:11]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH2:10][CH2:9][OH:8])[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]=2[CH:23]=1
Reactant: Fc1ccc2nc([C@H](CCOCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: OCC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of [(S)-3-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]-(9H-purin-6-yl)amine (296 mg, 0.6 mmol) in anhydrous DCM (6 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron tribromide (1.0 M in DCM, 1.2 mL, 1.2 mmol). The reaction mixture was stirred at 0° C. for 1 h. MeOH was then added and the volatiles were removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 187 (160 mg, 66%). LCMS (Method K): RT 3.10 min [M+H]+ 404.1 1H NMR (DMSO-d6, 400 MHz): δ 12.55 (1H, s), 8.28-7.83 (3H, m), 7.81-7.44 (6H, m), 7.16-7.01 (1 m), 6.91-6.79 (1H, m), 5.56 (1H, br s), 4.60 (1H, br s), 3.57-3.38 (2H, m), 2.23-2.00 (2H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [S:1]1[C:5]2[C:6](=[S:10])[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Br[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14].C(N(CC)CC)C>C(Cl)Cl>[OH-:14].[OH:14][C:13]1[N+:7]2=[N:8][CH:9]=[C:4]3[CH:3]=[CH:2][S:1][C:5]3=[C:6]2[S:10][C:12]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: S=c1[nH]ncc2ccsc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1c(-c2ccccc2)sc2c3sccc3cn[n+]12
Product: [OH-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
66.95 g of thieno[2,3-d]pyridazine-7(6H)-thione are suspended in 3200 ml of methylene chloride under argon, whereupon 102.7 g of α-bromophenylacetyl chloride are added dropwise thereto. The mixture is stirred at room temperature for about 30 minutes and then 121 ml of triethylamine are added dropwise thereto, whereby the mixture is cooled to 25°-30°. It is stirred for about 40 minutes. After evaporation of the solvent in vacuo the residue is taken up in 1000 ml of water and 200 ml of ether, whereupon the mixture is stirred for about 30 minutes. The separated crystals are filtered off under suction, washed with water and ether and dried overnight. The dried crystals are again triturated with 1000 ml of water. After suction filtration the red-violet crystals are washed with water and dried in vacuo. There is obtained 3-hydroxy-2-phenylthiazolo[3,2-b]thieno[2,3-d]pyridazin-4-ium hydroxide (internal salt) of m.p. 260°-264° (decomposition).
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2>[Cu]I.O1CCOCC1>[I:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1ccc2ncccc2c1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1ccc2ncccc2c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72 mmol), 6-bromo-quinoline (3 g, 14.4 mmol), N,N′-dimethyl-cyclohexane (0.227 mL, 1.44 mmol) and dioxane were charged in a microwave tube (25 mL). The tube was purged with nitrogen for 10 min and sealed with a Teflon septum. The reaction mixture was stirred at 110° C. for 15 h. After cooling, the mixture was poured onto ice-water and extracted with DCM. The crude was purified by silica gel column to give 6-iodo-quinoline as light green solid (3.5 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](SC)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:41][C:42]1([CH3:51])[CH2:47][CH:46]([NH2:48])[CH2:45][C:44]([CH3:50])([CH3:49])[NH:43]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:48][CH:46]3[CH2:47][C:42]([CH3:51])([CH3:41])[NH:43][C:44]([CH3:50])([CH3:49])[CH2:45]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: NCCc1ccccc1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound is prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid by following the procedures in Example 19 using 2-phenylethanamine for the amide formation and 2,2,6,6-tetramethyl-4-piperidinamine for the displacement reaction: LC-MS m/z 651 (M+H)+, 1.87 min (ret time).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH2:28])(=[S:27])[CH2:25][CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:28]=[C:24]([CH2:25][CH3:26])[S:27][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Reactant: CCC(N)=S
Product: CCOC(=O)c1c[nH]c2c1-c1nc(CC)sc1CC2

Procedure:
The title compound is prepared by reacting 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester with thiopropionamide essentially according to the procedures described in Example 15, Step 3. 1H NMR (CDCl3) 1.33-1.42 (m, 6H), 2.80-2.90 (m, 2H), 2.98-3.10 (m, 4H), 2.37 (q, 2H), 7.24 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1.[H-].[Na+].[CH3:22]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[O:10])=[C:4]([Cl:19])[CH:3]=1
Reactant: CI
Reactant: Cn1cc(C(=O)Cc2ccc(Br)cc2Cl)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of the 5-[2-(4-bromo-2-chloro-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one obtained in step 1 (583 mg) in tetrahydrofuran (12 ml) was added sodium hydride (60% dispersion in mineral oil, 72 mg). The mixture was stirred at room temperature for 2 h and at 40° C. for 30 min. The mixture was cooled in an ice bath. Methyl iodide (267 mg) was added dropwise. After 10 min the ice bath was removed and the mixture was stirred at room temperature for 4 h. Sodium hydride (60% dispersion in mineral oil, 35 mg) and methyl iodide (121 mg) were added and the mixture was stirred overnight at room temperature. The reaction was quenched with ice water and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 7:3=>0:1) to give the title compound (353 mg) as a colorless foam. MS (m/e, ISP neg. ion)=352.0 [M−H+].
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]#[C:15][Si](C)(C)C)=[CH:8][CH:7]=1>O.C1COCC1>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:20])=[O:4])=[CH:11][CH:10]=1)#[C:13][C:14]#[CH:15]
Reactant: COC(=O)c1ccc(C#CC#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC#Cc1ccc(C(=O)O)cc1
Reaction time: 16 h
Yield: 91.4 %

Procedure:
Potassium hydroxide (3.700 g, 65.9 mmol) was dissolved in H2O (10 mL) and added to a solution of 4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid methyl ester 3 (3.420 g, 13.5 mmol) in THF (26 mL) in the absence of light. After stirring 16 h, the reaction was quenched with 1.0 M HCl (120 mL) and the resulting precipitate was filtered, washed with 1:1 hexanes/benzene (150 mL) and dried in vacuo to afford 2.100 g (91% yield, 98% pure) of 4-(buta-1,3-diynyl)-benzoic acid 4 as a brown solid, mp >230° C. Although diyne 4 was found to be unstable at room temperature it could be stored for several weeks at 0° C. with only small amounts of decomposition observed by TLC. Rf=0.2 (4:1 Hexanes/EtOAc); HPLC (300 nm, 28 min run) 16.0 min; LRMS (ES+) m/z 171.0 (C11H6O2+H requires 171.04).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=1
Reactant: Brc1ccccc1I
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Na+]
Product: FC(F)(F)c1ccc(-c2ccccc2Br)cc1
Temperature: 85 °C
Reaction time: 32 h
Yield: 67.1 %

Procedure:
An oven dried Schlenk tube was evacuated and backfilled with argon and charged with tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol, 5.0 mol %), 2-bromoiodobenzene (0.83 mL, 6.50 mmol), 4-(trifluoromethyl)phenylboronic acid (950 mg, 5.0 mmol), and sodium carbonate (2.86 g, 27.0 mmol). The tube was evacuated and backfilled with argon. To the tube was added (degassed) dimethoxyethane (45 mL), ethanol (2 mL), and water (15 mL) through a rubber septum. The reaction mixture was heated to 85° C. with stirring for 32 hours. The reaction mixture was then diluted with 2:1 hexane/ethyl acetate (100 mL) and poured into a separatory funnel. The mixture was washed with water (80 mL), and brine (80 mL). The organic layer was dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 1.01 g (67%) of the product.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.Br[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.O>CN(C)C=O.C(N(CC)CC)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:8][CH2:7][C:6]3([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]3)[CH2:11][CH2:10]2)=[CH:17]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C1COC2(CCNCC2)CN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COC2(CCN(CCc3c[nH]c4ccccc34)CC2)CN1
Yield: 42.4 %

Procedure:
A solution of the hydrobromide salt of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one (15 g) and 3-(2-bromoethyl)indole (13.5 g) in 75 ml of dimethylformamide and 20 ml of triethylamine was stirred at 65° C. for 16 hours. Water was added and the mixture was extracted with methylene chloride. The organic layer was extracted with 5% hydrochloric acid and the aqueous layer was made basic with ammonium hydroxide and extracted with methylene chloride. Evaporation left a residue which was chromatographed on silica gel with 10% methanol-methylene chloride to give 8.0 g of 9-[2-(3-indolyl)ethyl-]-1-oxa-4,9-diazaspiro[5.5] undecan-3-one as the free base, mp 48°-50° C. The free base was dissolved in methanol and acidified with methanolic hydrochloric acid. The precipitate was washed with ether to give 7 g of the hydrochloride salt of 9-[2-(3-indolyl)ethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, mp 272°-275° C. (dec).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].C(O)(=O)C.[Br:21]Br>C(OCC)C.C(Cl)Cl>[Br:21][CH2:14][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:4])[F:5])[CH:8]=1)=[O:15]
Reactant: CC(=O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]ethanone (6.1 g, 25.8 mmol) was dissolved in diethyl ether (36.9 mL), and acetic acid (44.4 mL, 775 mmol) was added, followed by bromine (1.397 mL, 27.1 mmol). The reaction was stirred at 25° C. for 3 hours, then was diluted with DCM and extracted with saturated sodium bicarbonate solution. The combined organic layers were dried with anhydrous MgSO4, filtered, and concentrated. The crude product was purified on a silica gel column with a 340 g cartridge, using a 10% EtOAc/Hexanes isocratic mobile phase. 2-Bromo-1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]ethanone (5 g, 15.87 mmol) was obtained. 1H NMR (400 MHz, CDCl3) 84.45 (s, 2H), 5.96 (t, J=53, 2.7 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.91 (d, J=7.7 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:10]([NH:19][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine (0.25 g, 1.0 mmol) in THF (5 ml) was added a solution of K2CO3 (0.25 g, 1.8 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.119 g, 1.1 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (3.5 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (0.5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (20 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.21 g (82%) of rac-((3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-yl)-methyl-amine as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:17])[CH2:14][CH2:13][NH:12][CH2:11][C@:10]2([CH3:16])[OH:15])=[CH:5][CH:4]=1.[CH:18]1([C:23]([NH:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28](O)=[O:29])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(C(F)(F)F)=O.C(#N)C.O.C(O)(C(F)(F)F)=O>O.CC#N>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:17])[CH2:14][CH2:13][N:12]([C:28](=[O:29])[CH2:27][C:26]([NH:25][C:23]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:24])([CH3:32])[CH3:31])[CH2:11][C@@:10]2([OH:15])[CH3:16])=[CH:5][CH:4]=1
Reactant: C[C@]1(O)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)(CC(=O)O)NC(=O)C1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)[C@@](C)(O)C1)NC(=O)C1CCCC1

Procedure:
Example 96 was prepared from (3S,4S)-4-(4-chlorophenyl)-3-methylpiperidine-3,4-diol hydrochloride and 3-(cyclopentanecarboxamido)-3-methylbutanoic acid using the procedure described in Example 93, step 6. MS (ESI+)=437.3 (M+H)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) δ ppm 7.55-7.50 (m, 2 H), 7.31 (d, J=8.5 Hz, 2 H), 4.53 (dd, J=10.7, 1.9 Hz, 0.4 H), 4.28 (dt, J=12.4, 0.8 Hz, 0.6 H), 4.04 (dd, J=13.2, 2.7 Hz, 0.6 H), 3.69 (dd, J=13.1, 2.3 Hz, 0.4 H), 3.59-3.52 (m, 1 H), 3.24 (d, J=14.6 Hz, 0.4 H), 3.09 (d, J=12.1 Hz, 1 H), 2.65-2.49 (m, 2 H), 2.42 (td, J=13.3, 4.7 Hz, 0.4 H), 1.89-1.53 (m, 10 H), 1.47-1.40 (m, 6 H), 0.93 (s, 1.1 H), 0.92-0.86 (m, 2.4 H); HPLC Method: Inj. Vol.=5 uL, Start % B=10, 12 Min. 100%, 15 Min. 100%, Flow Rate=2 mL/min (1 mL/min on each column), Wavelength 1=220 nm, Wavelength 2=254 nm, Solvent Pair=TFA−ACN/H2O, Solvent A=0.05% TFA in H2O:MeCN (95:5), Solvent B=0.05% TFA in H2O:MeCN (5:95), Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Retention Time=8.27 minutes, Col-2: Xbridge Phenyl 3.5 um, 4.6×150 mm; Retention Time=7.76 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[CH3:10].S(OC)(OC)(=O)=O.[C-:18]#[N:19].[K+]>CC#N.O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[N:5]=[C:6]([C:18]#[N:19])[CH:7]=1
Reactant: Cc1c(Br)cc[n+]([O-])c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: COS(=O)(=O)OC
Product: Cc1nc(C#N)cc(Br)c1C
Temperature: 70 °C
Reaction time: 3.25 h

Procedure:
A mixture of 4-bromo-2,3-dimethyl-1-oxido-pyridin-1-ium (15.8 g, 78.2 mmol) (which may be prepared as described in Description 5) and dimethyl sulfate (8.88 mL, 93.84 mmol) in MeCN (36 mL) was stirred at block temp of 70° C. under N2 for 3.25 h. The reaction mixture was evaporated to an oil which was stirred with Et2O (2×50 ml) and the solvent was decanted from the oil. The oil was dried in vacuo and dissolved in water (105 mL) and then was added over 25 mins to a stirred solution of potassium cyanide (20.37 g, 312.79 mmol) in water (75 mL), cooled in a salt-ice Dewar bath (range during addition −5 to 0° C.). The turbid mixture was stirred in the ice/salt bath whilst it warmed slowly to ambient temperature overnight. The beige precipitate was then filtered under suction and washed with water (3×50 ml) and pressed dry. This moist solid was then dissolved in DCM (300 ml), dried (Na2SO4), filtered and evaporated to a beige solid, approximately 90% pure 4-bromo-5,6-dimethyl-pyridine-2-carbonitrile (D144) by NMR;
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].CCOC(C)=O>CN(C)C=O>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCSc1ccc(C(=O)O)cc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A stirred mixture of 4-(ethylthio)benzoic acid (0.36 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.670 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×100 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (hexanes/EtOAc, gradient, product eluted at 95% EtOAc). The product fractions were combined and concentrated to give 4-ethylsulfanyl-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.37 g, 61% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.03 min (99.73%); mp: 135-137° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7.3 Hz, 3H), 1.89 (s, 3H), 1.95-2.11 (m, 1H), 2.53-2.61 (m, 2H), 2.61-2.77 (m, 1H), 3.06 (q, J=7.3 Hz, 2H), 4.61 (d, J=5.7 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.72-7.88 (m, 5H), 9.18 (t, J=5.9 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 13.92, 21.02, 25.19, 28.57, 29.11, 42.58, 58.76, 121.60, 123.18, 126.32, 127.83, 129.59, 130.38, 131.38, 133.38, 141.22, 147.51, 165.86, 167.73, 167.88, 172.13, 172.19; LCMS: MH=466; Anal Calcd for C21H23N3O5S+0.3H2O: C, 61.21; H, 5.05; N, 8.92. Found: C, 61.27; H, 5.13; N, 8.80.