Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH3:13].[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].[C:22]([O-])([O-])=O.[K+].[K+].CCCCCC.CCOCC>C(#N)C>[OH:14][CH:11]([CH2:12][CH2:13][CH3:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCS
Reactant: O=C([O-])[O-]
Reactant: CCC(O)CCCCCCCCCBr
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC#N
Product: CCCC(O)CCCCCCCCSCCC(=O)OC
Yield: 43.7 %

Procedure:
To a solution of 12-bromo-3-dodecanol (8.78 g, 33.1 mmol) in acetonitrile (80 mL) was added methyl 3-mercaptopropionate (3-98 g. 33.1 mmol) and K2CO3 (5,5 g, 40 mmol). The mixture was allowed to react at room temperature for 20 hr. The mixture was acidified with ice-diluted HCl and the solution was extracted twice with ether (40 mL). The combined ether fractions were washed successively with dilute NaHCO3, water and brine, dried (MgSO4) and evaporated under reduced pressure. The product 7 (4.4 g, 44% yield) was isolated by column chromatography (hexane/ether 1:1) and recrystallized in hexane. TLC (hexane/ether 1:1) Rf=0.4. Melting point=38.8° C. 1H-NMR δ0.93 (t, 3H, C(16)H2), 1.4 (m, 18H, CH2), 2.52 (t, 2H, C(2)H2), 2.61(t, 2H, C(5) H2), 2.79 (t, 2H, C(3)H2), 3.60 (m, 1H, C(13)H), 3.70 (s, 3H,—COO—CH3).
Reaction SMILES: BrCCO[C:5]1[CH:14]=[C:13]2[C:8]([C:9](NC3C=CC([Cl:22])=CC=3F)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].C(N1CCNCC1)(=O)C>C(Cl)Cl.C(OCC)(=O)C>[ClH:22].[CH3:25][O:24][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:5]=1)[N:12]=[CH:11][N:10]=[CH:9]2
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Agent: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2ncncc2c1
Product: Cl
Yield: 220.9 %

Procedure:
7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)6-methoxyquinazoline (150 mg, 0.35 mmol) and 1-acetylpiperazine (135 mg, 1 mmol) were heated together at 140° C. for 10 minutes. The mixture was allowed to cool and was dissolved in a mixture of methylene chloride/ethyl acetate. The solution was washed with water, and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1). The purified product was dissolved in methylene chloride and 2.9M ethereal hydrogen chloride was added. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 7-(2-(4-acetylpiperazin-1-yl)ethoxy)-44-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (152 mg, 79%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Fc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(F)cccc5s4)cc3CC[C@@H]12
Yield: 58 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-fluoro benzothiazole (86 mg, 0.46 mmol and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 91 mg (58%) of the title compound as an amorphous solid mp 140°-145°. FDMS: m/e=412. α[D]589 =+70.06 (c=0.52, chloroform).
Reaction SMILES: C=O.[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[C:7]1=[O:16].[CH:17](O)=O.[OH-].[Na+]>C(O)(CC)(C)C.O.C1(C)C=CC=CC=1>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([CH3:17])[C:8]([CH3:15])([CH3:14])[C:7]1=[O:16]
Reactant: O=CO
Reactant: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CN(CCO)C(=O)C1(C)C
Temperature: 80 °C

Procedure:
24.3 g (0.78 mol) of paraformaldehyde are added to a solution of 120 g (0.6 mol) of 1-(2-hydroxyethyl)-3,3,5,5-tetramethylpiperazin-2-one in 300 ml of tert-amyl alcohol. The mixture is then heated to 80° C. and 35.8 g (0.78 mol) of formic acid dissolved in 30 ml of tert-amyl alcohol are slowly added. Then, the mixture is maintained at 80° C. for further 1 hour and cooled to 50° C. Subsequently, 250 ml of toluene and 100 ml of water are added. The mixture is then stirred and 33 g (0.825 mol) of sodium hydroxide dissolved in 60 ml of water are slowly added. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum (60° C./10 mbar). A white solid with a melting point of 77°-80° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:27]2[C:28]3[C:33]([NH:34][C:26]=2[CH2:25][NH:24][CH2:23]1)=[CH:32][CH:31]=[CH:30][CH:29]=3>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:24]4[CH2:23][CH2:22][C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[NH:34][C:26]=5[CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2c([nH]c3ccccc23)C1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and noreleagnine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=458.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:26][C:17]3=[N:18][CH:19]=[C:20]4[CH:24]=[N:23][N:22]([CH3:25])[C:21]4=[C:16]3[CH:15]=2)=[CH:3]1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29]>ClCCCl.CC(O)(C)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:26][C:17]3=[N:18][CH:19]=[C:20]4[CH:24]=[N:23][N:22]([CH3:25])[C:21]4=[C:16]3[CH:15]=2)=[CH:3]1
Reactant: CS(N)(=O)=O
Reactant: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)O)ccc21
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)c2cc(C(=O)NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
1-Methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indole-5-carboxylic acid (0.047 g, 0.14 mmol, Example #AN.1), methanesulfonamide (0.039 g, 0.41 mmol) and EDC (0.065 g, 0.34 mmol) were combined in a mixture of DCE (1.31 mL) and t-BuOH (1.31 mL). DMAP (0.050 g, 0.41 mmol) was added and the mixture was stirred at rt for about 16 h. The mixture was purified by flash chromatography (12 g silica gel column, (6:3:1 CHCl3/MeOH/saturated NH4OH)/EtOAc 50-85%) to give 1-methyl-3-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-N-(methylsulfonyl)-1H-indole-5-carboxamide (0.024 g, 42%): LC/MS (Table 2, Method a) Rt=1.55 min; MS m/z 423 (M+H)+. Syk IC50=A.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[OH:45][CH2:46][C:47](O)=[O:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([C:46](=[O:45])[CH2:47][OH:48])[CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)CO)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-124, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 124) (75 mg, 0.123 mmol) was coupled with 2-hydroxyacetic acid (14 mg, 0.185 mmol) using HATU (71 mg, 0.185 mmol), HOBt (25 mg, 0.185 mmol) and DIPEA (86 μL, 0.494 mmol) in DMF (2 mL) to get 60 mg (73.1%) yield of the title compound. MS: m/z=665.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH:7]=[N:6]1
Reactant: CN(C)CCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CCn1ncc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture of dimethyl-[2-(6-nitro-indazol-1-yl)-ethyl]-amine (1 g, 4.3 mmol), iron powder (1.9 g, 34 mmol), and ammonium chloride (120 mg, 2.2 mmol) in a 4:1 Ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4), and the filtrate concentrated under reduced pressure to provide the title compound (0.8 g, 92%). 1H NMR (300 MHz, DMSO-d6) ppm 2.17 (s, 6H), 2.63(t, J=6.44, 2H), 4.23 (t, J=6.44, 2H), 5.28(s, 2H), 6.50 (m, 2H), 7.35 (m, 1H), 7.69 (m, 1H); MS (DCI/NH3) m/z 205 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH2:35]([N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43])[C:36]#[CH:37].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:37]#[C:36][CH2:35][N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Reactant: C#CCN1CCCC1=O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCN4CCCC4=O)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 46 h
Yield: 39.3 %

Procedure:
N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazolin-4-amine (250 mg, 0.42 mmol) and 1-prop-2-yn-1-ylpyrrolidin-2-one (103 mg, 0.84 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (30 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (84 mg, 0.84 mmol). The reaction was allowed to warm to room temperature and stirred 46 hr. then filtered through Celite and evaporated. The residue was partitioned between dichloromethane and dilute aqueous ammonium chloride solution, the organic layer separated, dried over magnesium sulphate and evaporated then purified by chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (98 mg, 40%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.12 (m, 4H), 2.44 (t, 2H), 2.49 (m, 4H), 2.57 (t, 2H), 3.55 (t, 2H), 3.72 (m, 4H), 4.00 (s,3H), 4.25 (t,2H), 4.35 (s,2H), 6.08 (s,2H), 7.03 (s,1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.30 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 594/596.
Reaction SMILES: Cl.[F:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)(=[O:21])=[O:20].C(N(CC)CC)C>C(#N)C>[C:28]([C:24]1[CH:23]=[C:22]([S:19]([NH:18][CH2:17][CH2:16][CH2:15][N:10]2[CH2:9][CH:8]([O:7][C:6]3[CH:12]=[CH:13][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:11]2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: N#Cc1cccc(S(=O)(=O)NCCCBr)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCCCN2CC(Oc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A suspension of 3-(4-fluoro-phenoxy)-azetidine hydrochloride (0.049 g, 0.24 mmol) in acetonitrile (1.0 ml) is treated with the crude N-(3-bromo-propyl)-3-cyano-benzenesulfonamide (0.072 g) in acetonitrile (1.0 ml) and triethylamine (0.1 ml, 0.72 mmol). The resulting homogenous reaction mixture is stirred at ambient temperature for 70 hours, the solvent evaporated and the residue partitioned between ethylacetate and aqueous NaHCO3 solution. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution ethylacetate) to afford 3-cyano-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-benzenesulfonamide. [MH]+ 390.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH2:18]([NH:21][CH2:22][CH2:23][CH3:24])[CH2:19][CH3:20]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:21]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:19][CH3:20])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CCCNCCC
Solvent: CCO
Product: CCCN(CCC)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), N-propylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 345 (M+, 0.3), 115 (9), 114 (bp), 95 (5), 86 (14), 72 (6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:20]3[C:19]([O:21][CH3:22])=[CH:18][CH:17]=[C:16]([C:23](OC4C=CC([N+]([O-])=O)=CC=4)=[O:24])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)=[CH:5][CH:4]=1.[Cl:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:46])[C:44]=1[NH2:45].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([Cl:46])[C:44]=1[NH:45][C:23]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)[N:8]([CH2:7][C:6]3[CH:36]=[CH:37][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]=2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=1)=[O:24]
Reactant: COc1ccc(Cn2c3ccc(Cl)cc3c3c(C(=O)Oc4ccc([N+](=O)[O-])cc4)ccc(OC)c32)cc1
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c3ccc(Cl)cc3c3c(C(=O)Nc4c(Cl)cncc4Cl)ccc(OC)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
To a solution of 4-Nitrophenyl 9-(4-methoxy benzyl)-6-chloro-1-methoxy-4-carbazole carboxylate (95 mg, 0.232 mmoles) in dry DMF (5 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (37.8 mg, 0.232 mmoles) was added followed by sodium hydride (60% suspension, 20.0 mg, 0.464 mmoles) and the reaction mixture was stirred at room temperature for two hours. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water and dried under vacuum to give 60 mg of the title compound as an off white solid, m. p: 257-258° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].O[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>O>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1.[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O-:5])=[O:4]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCCCCCC(C)C(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCC(C)C(=O)[O-]
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
Then, 2.02 g (12.8 mmol) of the above (+)-2-methyl octanoic acid, 2.02 g (11.9 mmol) of 4-hydroxy biphenyl and 10 ml of toluene were charged into a flask, and further 1.0 ml (13.7 mmol) of thionyl chloride was added with stirring, which were then reacted for 9 hours while maintaining at a temperature of 70°~80° C. After the completion of the reaction, the reaction mixture was cooled to room temperature, added with water to decompose excess thionyl chloride, washed with water and then dried on anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified through a column chromatography of silica gel to obtain 3.43 g of an oily (+)-biphenyl-2-methyloctanoate having a specific rotary power [α]25D =+16.3° (2.6% by weight, in chloroform).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[S:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1>C(Cl)Cl>[S:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:16])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1C#N
Yield: 83.7 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzothiazole (70 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) to afford N-benzothiazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (118 mg, 84%) as a white foam: mp 115-118° C. (foam to gel); EI-HRMS m/e calcd for C23H23N3O3S3 (M+) 453.1181, found 453.1173.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[CH3:9][CH2:10][O:11][C:12]([C:14]1[N:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16]2[C:21]([CH:22]=1)=[C:20](OCC1C=CC=CC=1)[CH:19]=[CH:18][CH:17]=2)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:9][CH2:10][O:11][C:12]([C:14]1[N:15]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:16]2[C:21]([CH:22]=1)=[C:20]([O:8][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1)[CH:19]=[CH:18][CH:17]=2)=[O:13]
Reactant: Cc1nc(CO)cs1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3csc(C)n3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
(2-Methyl-thiazol-4-yl)-methanol (168, 670 mg, 5.2 mmol) is dissolved in 12 ml of dry THF under argon, followed by addition of 4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (102, see example 42, 1.58 g, 5.2 mmol), triphenylphosphine (1.63 g, 6.2 mmol).) and the solution is cooled to 0° C. A 40% solution of ethyl azadicarboxylate in toluene (2.7 ml, 6.2 mmol) is added dropwise and the mixture is stirred for 2.5 h at 0° C. The solvents are removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with sodium hydrogencarbonate solution and brine. The organic layers are dried over sodium sulphate, filtrated and evaporated. The crude product is purified by flash chromatography (silica gel, ethyl acetate/hexanes 3:7)
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][O:26][CH3:27].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:24][CH2:25][O:26][CH3:27])[CH2:19][CH2:18]3)=[O:14])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCC1CCNCC1)N1CCN(c2ccccc2)CC1
Reactant: COCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(COC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
(Piperidin-4-yl)methyl 4-phenylpiperazine-1-carboxylate from the previous step (2.15 g, 7.10 mmol), 2-bromoethylmethylether (0.67 mL, 7.10 mmol) and DIPEA (1.36 mL, 7.81 mmol) were dissolved in DMF (30 mL) and stirred overnight at 70° C. and then concentrated in vacuo. The residue was dissolved in DCM (300 mL) and then washed sequentially with sat aq NaHCO3 solution (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 98:1:1 mixture of DCM:MeOH:DIPEA) followed by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give the title compound [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-phenylpiperazine-1-carboxylate (0.798 g, 31.1% yield) as a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl.ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: NCCOCCO
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCOCCO)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.150 g, Example 1b) and 2-(2-aminoethoxy)ethanol (0.065 ml) in 1,2-dichloroethane (6 ml) was added sodium triacetoxyborohydride (0.134 g), and the mixture was stirred overnight at room temperature. Water (20 ml) and dichloromethane (20 ml) were added and the layers were partitioned. The organics were washed with brine (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0–10% ethanol in dichloromethane to give the title compound as a white powder (0.016 g).