Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[BH4-].[Na+].[CH3:31][NH2:32]>>[CH3:31][NH:32][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (59 mg, 0.16 mmol) was added methanamine (20 ml) and the mixture was stirred at room temperature for 2 h. Then 30 mg of sodium borohydride was added and stirred for another 2 h. The resulting mixture was evaporated under reduced pressure and purified by prep-HPLC. 11.5 mg of 8-(4-((methylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained (yield: 19%). 1H-NMR (400 MHz, CD3OD) δ: 2.66 (s, 3H), 4.33-4.35 (d, J=8 Hz, 1H), 4.83-4.85 (d, J=7.6 Hz, 1H), 7.10-7.12 (m, 2H), 7.15-7.22 (m, 4H), 7.34-7.42 (m, 4H), 7.55-7.57 (m, 1H), 7.63-7.67 (m, 1H). LC-MS (ESI) m/z: 383 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:36](=[O:41])[C:37]([O:39][CH3:40])=[O:38].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:39][C:37](=[O:38])[C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: COC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (85 mg, 0.19 mmol) and methyl 2-chloro-2-oxoacetate (35 μL, 0.38 mmol) in CH2Cl2 (1 mL) was added Et3N (53 uL, 0.38 mmol), and catalytic amount of DMAP. The reaction mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolate. (18 mg, 18%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(c2cccc(Cl)c2)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-benzyl-3-(3-chlorophenyl)-4-piperidone (75 mmol) in anhydrous THF (250 mL) is cooled to −30° C., then treated with a solution of freshly prepared lithium diisopropylamide (2.0 M in THF/heptane, 45 mL). After stirring for 15 minutes, a solution of methyl iodide (80 mmol) in THF (40 mL) is rapidly added. The mixture is stirred for 1 hour at −30° C., warmed quickly to room temperature, and quenched with a saturated aqueous solution of ammonium chloride. The organic layer is collected, washed with water, brine, and dried (MgSO4). After filtering, the filtrate is concentrated in vacuo to afford the desired intermediate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:22]#[C:23]Br.O>C1COCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:7]([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:23]([NH2:22])=[N:1]2)[CH3:8])=[CH:14][CH:13]=1
Reactant: C[C@H](OC[C@H](N)CO)c1ccc(F)cc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](OC[C@H]1COC(N)=N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a stirred solution of (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (1.40 g) in THF (80 ml) were added sequentially K2CO3 (1.82 g) and cyanogen bromide (0.83 g). The mixture was stirred at room temperature for 18 hours, then water was added. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: heptane/ethyl acetate=25:75) yielded the title compound as a white solid, (1.15 g, 73%). MS (ISP): 239.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(Cl)cc3)CCC2)cc1
Yield: 103.7 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 300 mg (1.9 mmol) of 4-chlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 290 mg of 1-[2-(4-chlorophenyl) cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 72°-74° C.; NMR (CDCl3) d 2.04 (m, J=7 Hz, 2H), 2.46 (s, 3H), 2.86 (t, J=7 Hz, 4H) , 7.07-7.21 (m, 8H) .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:12][N+](C)=C.[I-]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:12])[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC(=O)O
Product: C=C(C(C)=O)c1ccc(Cl)cc1
Temperature: 125 °C
Yield: 42.6 %

Procedure:
1-(4-Chloro-phenyl)-propan-2-one (8.6 g, 51 mmol) and Eschenmoser's salt (12.3 g, 66.3 mmol) were dissolved in glacial acetic acid and heated in a closed pressure tube at 125° C. under nitrogen for 1 h. After cooling to room temperature, the solution was concentrated. The residue was dissolved in EtOAc, washed with saturated NaHCO3 aqueous solution, dried (MgSO4), concentrated, and chromatographed (SiO2, 39:1-19:1 hexane/EtOAc) to give 3-(4-chloro-phenyl)-but-3-en-2-one as yellow oil (3.92 g, 43%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][C:33]2[C:34](=[O:40])[NH:35][C:36](=[S:39])[NH:37][CH:38]=2)=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][C:33]2[C:34](=[O:40])[N:35]=[C:36]([S:39][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=4)=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[NH:37][CH:38]=2)=[CH:30][N:31]=1
Reactant: FC(F)(F)c1cccc(Oc2ccc(CCl)cc2C(F)(F)F)c1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4cccc(C(F)(F)F)c4)c(C(F)(F)F)c3)nc2=O)cn1
Yield: 4.4 %

Procedure:
The same procedure as E63 from 4-(chloromethyl)-2-(trifluoromethyl)-1-{[3-(trifluoromethyl)phenyl]oxy}benzene (425 mg, 1.199 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (200 mg, 0.799 mmol) and DIPEA (0.279 mL, 1.598 mmol) in DCE (3.0 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (20 mg, 4.40% yield). LCMS: rt=3.66 min, [M+H+]=569
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: OCc1ccc(F)c(OCc2ccc(F)cc2)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)c(OCc3ccc(F)cc3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.09 (2H, s), 5.16 (2H, s), 5.69 (1H, s), 6.98-7.13 (5H, m), 7.37-7.40 (3H, m), 7.56 (1H, s), 8.03 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C23H16F2N4O2, 419. Found, 419.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]([F:36])[CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]([F:36])[CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
Sodium hydroxide (100 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D138) (230 mg) in THF (4 mL) and water (4 mL). The reaction mixture was stirred at 90° C. for 3 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitate was purified by MDAP and recrystallized in MeCN to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E99) (135 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.63 (2H, t), 2.97 (2H, t), 4.96-5.02 (1H, m), 7.36 (1H, d), 7.55 (1H, d), 7.64-7.69 (2H, m), 8.49 (1H, dd), 8.72 (1H, d), 10.97 (1H, s), 12.13 (1H, br s). δF (DMSO-d6, 376 MHz): −124.9. MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][CH2:33][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=3)[CH:36]=[CH:35]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][N:34]2[CH2:33][CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:38][CH:39]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2ccn(CCC3CNC3)c2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(CCn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.43 g, 0.79 mmol), 1-(2-azetidin-3-yl-ethyl)-6-fluoro-1H-indole (0.25 g, 0.95 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.3 g of the (S)-enantiomer of the title compound as a brown oil. The hydrochloride salt was prepared in ethyl acetate and collected as a yellow solid: m.p. 115° C. (dec).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](=[O:12])(OC)[O:8][CH3:9].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].O>O1CCCC1>[CH3:20][C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:13][C:7](=[O:12])[O:8][CH3:9]
Reactant: COC(=O)OC
Reactant: Cc1ccncc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1cnccc1C
Temperature: 17.5 °C
Yield: 88.2 %

Procedure:
Potassium tert-butoxide (10.3 g, 92.5 mmol) in tetrahydrofuran (25 mL) was stirred at 23 to 27° C. for 30 minutes, and dimethyl carbonate (4.67 mL, 55.5 mmol) was added while the temperature was kept at 35° C. or below. To the reaction mixture, 3-amino-4-methylpyridine (5.00 g, 46.2 mmol) in tetrahydrofuran (40 mL) stirred at 32 to 38° C. for 90 minutes was added dropwise at 20 to 35° C. over 2 hours with stirring. The resulting reaction mixture was cooled to 15 to 20° C., stirred with water (25 mL) at 25° C. or below for 1 hour and extracted with tetrahydrofuran. The organic layer was azeotropically distilled with toluene under reduced pressure to a volume of about 50 mL and stirred at 23 to 27° C. for one day. The precipitated solid was collected by filtration, washed with toluene and dried under reduced pressure to give the title compound as a brown solid (6.77 g, yield 88%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 3-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide as a white solid; MS: m/e=304 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.Cl.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][C:39]([N:43]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:41]=2)[C:36](=[O:56])[N:35]1[CH2:57][C:58](O)=[O:59]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:58](=[O:59])[CH2:57][N:35]1[C:36](=[O:56])[C:37]2[C:42](=[CH:41][CH:40]=[C:39]([N:43]([CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]3)[S:44]([CH3:47])(=[O:46])=[O:45])[CH:38]=2)[C:34]1=[O:33]
Reactant: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCCCC1)c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 96 h
Yield: 52.1 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (188 mg, 0.449 mmol), DMAP (110 mg, 0.897 mmol) and EDC (129 mg, 0.673 mmol) in DCM (10 ml), 2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetic acid hydrochloride (200 mg, 0.449 mmol) was added portion wise over 5 hours, and the resulting mixture was stirred at room and for 96 hours. The solvent was removed and the crude was purified by silica gel chromatography (EtOAc/DCM 2/1 then DCM/MeOH 100/3). The resulting white solid was triturated with EtOH and recovered by filtration affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dioxo-5-(N-(2-(piperidin-1-yl)ethyl)methylsulfonamido)isoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (190 mg, 0.234 mmol, 52.2% yield, LC-MS purity (BPI): 98.3%, MS/ESI+ 811.21 [MH]+, [αD]=+28.12, c=0.653 DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.97 (d, 1H), 7.95 (d, 1H), 7.89 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.91-4.04 (m, 2H), 3.88 (t, 2H), 3.38 (dd, 1H), 3.23 (dd, 1H), 3.15 (s, 3H), 2.35 (t, 2H), 2.17-2.31 (m, 4H), 1.03-1.53 (m, 7H), 0.49-0.68 (m, 2H), 0.28-0.46 (m, 2H).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][CH:5]([CH2:11][S:12]C(=O)C)[CH2:6][S:7][C:8](=[O:10])[CH3:9])#[N:3].CO>O1CCCC1>[C:8]([S:7][CH2:6][CH:5]1[CH2:11][S:12][C:2](=[NH:3])[CH2:4]1)(=[O:10])[CH3:9].[ClH:1]
Reactant: CC(=O)SCC(CC#N)CSC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)SCC1CSC(=N)C1

Procedure:
Gaseous HCl is passed during 0.5 hour through a solution of 3 g of 2-cyanomethyl-1,3-bis(acetylthio)propane, obtained according to Example XIX e), and 1.8 g of methanol in 30 ml tetrahydrofurane; temperature 40°-55° C. The solution is evaporated; diethylether is added to the residue. The precipitate formed is aspirated off, washed with diethylether and dried. The second title compound, viz. 4-acetylthiomethyl-2-iminothiolane is obtained as its HCl sale in a yield of 600 rag; m.p. 186°-188° C. (decomp.). Identification by 1H NMR and 13C NMR. The compound can equally be converted to the free base.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:14].[Cs+]>C(OCC)(=O)C.CCCCCCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([OH:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccccc2)cc1
Yield: 90 %

Procedure:
Following general operating mode B, 4-bromobiphenyl (232 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a brown solid with a yield of 90% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][NH:6][CH3:7])[CH3:2].C(N(CC)CC)C.[CH2:16](Br)[CH:17]=[CH2:18]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][N:6]([CH2:18][CH:17]=[CH2:16])[CH3:7])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)CNC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCN(C)CC(=O)OCC
Yield: 88.5 %

Procedure:
Into a 100 ml four-necked flask there were placed 11.7 g of sarcosine ethyl ester, 15 g of triethylamine and 50 ml of benzene, and 12.1 g of allyl bromide was gradually added dropwise thereto at room temperature with thorough stirring. The reaction solution was then heated and refluxed for 3 hours. After cooling, the deposited triethylamine hydrobromide was removed by filtration and the benzene removed under reduced pressure. The residue obtained was distilled under reduced pressure to obtain 13.9 g of the objective N-allylsarcosine ethyl ester (b.p.110 116° - 118° C, nD27.0 1.4308).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH:9]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Reactant: OB(O)c1ccc(OCc2ccccc2)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+]
Solvent: COCCOC
Solvent: O
Product: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
A mixture of 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.15 mmol) in ethylene glycol dimethyl ether (100 mL) was treated with 4-(benzyloxy)phenylboronic acid (1.79 g, 7.87 mmol), tetrakis(triphenylphosphine)palladium (0.496 g, 0.429 mmol), and a solution of sodium carbonate (1.83 g, 17.16 mmol) in water (50 mL). A precipitate formed after 20 minutes. Reaction was stirred for 5 hours at 80° C. under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and the organic solvent was removed under reduced pressure. The product was partitioned between the aqueous sodium carbonate layer and ethyl acetate. The aqueous layer was further extracted with ethyl acetate three times. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, and partially concentrated until a precipitate formed. The solid was filtered, washed with ethyl acetate, and dried under a high vacuum. Yielded 2.06 g (61%) of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.64(s, 1H), 7.88(s, 1H), 7.52-7.33(m, 7H), 7.08-7.05(d, 2H, J=12 Hz), 5.15(s, 2H), 4.82-4.78 (m, 1H), 3.95-3.89(m, 4H), 2.21-2.13(m, 2H), 1.98-1.96(m, 2H), 1.85-1.75(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 8.356 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:31][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:29])=[CH:24][CH:23]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 79 %

Procedure:
1.0 g (0.00532 mol) of 1-benzyl-4-hydroxypiperidine and 0.72 ml (0.00532 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.7 ml (0.00532 mol) of p-toluoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 1.3 g (80%) of 1-benzyl-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals; m.p. 73°-74°.