Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[C:19]1([CH2:29][CH2:30][C:31]([N:14]2[C@@H:13]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:17][O:16][C:15]2=[O:18])=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1cccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCc1cccc2ccccc12)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
14.8 mmole of butyllithium in hexane were added dropwise to a solution of 2.63 g (14.8 mmole) of (S)-(-)-4-benzyl-2-oxazolidinone dissolved in 50 ml of anhydrous tetrahydrofuran at -78° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at this temperature, and then 2.95 g (13.5 mmole) of 1-naphthylpropionyl chloride in 15 ml of anhydrous tetrahydrofuran were slowly added dropwise at the same temperature=the mixture was then stirred for 3 hours. At the end of this time, a saturated aqueous solution of sodium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then freed from the solvent by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: a 1: 4 by volume mixture of ethyl acetate and hexane), to afford 4.65 g (96%) of the title compound as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=[O:16])[CH2:11][CH:10]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:11][CH:10]2[C:12](=[O:14])[O:17][C:15]3=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1CC1(C(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)Cl
Product: O=C1OC(=O)C2(c3ccc(Cl)c(Cl)c3)CC12
Temperature: 25 °C

Procedure:
To a stirred solution of the 1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylic acid (28.3 g) in acetyl chloride (142 ml) was heated to reflux for 3 h, cooled to room temperature and evaporated. The oil was dissolved in toluene (100 ml) and evaporated to dryness. This was then repeated twice before triturating the semi-solid in hexane (100 ml). The solid was filtered off, washed with hexane and pulled dry under a nitrogen atmosphere to give a brown solid, yield=26.7 g (101%); 1HNMR (300 MHz, CDCl3) δ 7.52-7.46 (m, 2H, ArH), 7.27-7.24 (m, 1H, ArH), 3.35-3.30 (m, 1H, CH), 2.13-2.10 (m, 1H, CH), 1.97-1.95 (m, 1H, CH).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])[N:11]=1)=[O:6].[I-].[Na+].[CH3:37][NH:38][CH3:39]>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:10]2[N:11]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][N:38]([CH3:39])[CH3:37])=[O:6])[N:8]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=3)[CH:9]=2)=[O:14])=[C:17]([CH3:23])[CH:18]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCCl)n1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCN(C)C)n1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
25.7 mg (0.05 mmol) of N-(2-chloroethyl)-4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxamide (Example 21A) are dissolved in 200 μl of a 2 molar solution of dimethylamine in THF, and 7.5 mg (0.05 mmol) of sodium iodide are added. The reaction mixture is stirred in a tightly closed reaction vessel at 55° C. for 16 h. The reaction solution is then evaporated in vacuo, and the residue from evaporation is dissolved in DMSO, filtered and purified by preparative HPLC (Method 10).
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[F:24])[CH:13]=2)=[CH:6][CH:5]=1.[C:28]([O-:31])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([N:10]3[CH2:7][CH2:6][C@@H:28]([OH:31])[CH2:11]3)=[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[F:24])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(-c2[nH]ncc2F)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-4-fluoro-3-(4-fluoro-1H-pyrazol-5-yl)benzamide (Stage 24.1, 62 mg, 0.147 mmol), R-3-hydroxypyrrolidine (0.031 mL, 0.206 mmol) and TEA (0.062 mL, 0.442 mmol) in DMSO (0.5 mL) was stirred at 100° C. for 16 h. The RM was diluted with EtOAc (30 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed under reduced pressure. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in DCM and treated with n-hexane to give the title product as a white solid. HPLC (Condition 5) tR=6.61 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=467.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.95 (m, 2H) 2.79 (d, J=10.56 Hz, 1H) 3.06-3.20 (m, 2H) 3.22-3.35 (m, 1H) 4.13-4.30 (m, 1H) 4.79-4.96 (m, 1H) 6.75-6.92 (m, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.86 (m, J=9.38 Hz, 5H) 10.11 (s, 1H) 12.67-13.12 (m, 1H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH3:31][NH2:32]>O1CCCC1.O>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:32][CH3:31])=[O:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CN
Reactant: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoyl chloride hydrochloride (100 mg; 0.23 mmol) was suspended in tetrahydrofuran (5 ml) and treated with a solution of methylamine in water (40% w/v; ml) and the resulting mixture stirred at ambient temperature for 18 h. The title compound (55 mg; 60%) was obtained as a brown powder by filtration, washing with water and drying at 40° C. under reduced pressure. 1H NMR (250 MHz; CD3OD) δ: 2.84 (3H, s), 5.89 (2H, s), 6.76 (1H, d), 6.85-7.80 (5H, m), 7.82 (2H, d), 8.00 (2H, d), 8,49 (1H, br); m/z (ESMS): 399 [M+HM]⊕.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCN(CC)CCN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNCCN(CC)CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.3 %

Procedure:
A mixture of N,N-diethylethylenediamine (9.6 g, 0.0826 mol) and 8.4 g (0.0826 mol) of triethylamine in 40 ml of chloroform was added dropwise to the ice cold chloroform solution (40 ml) of octanoyl chloride (13.4 g, 0.0826 mol). After addition, the ice bath was removed and the solution was stirred for 5 hours at room temperature. The reaction mixture was stirred with aqueous sodium bicarbonate for one hour. The organic layer was then dried over magnesium sulfate leaving a yellow liquid which was concentrated in vacuo. The yellow liquid was subject to high vacuum distillation to yield 9.65 g (0.040 mol, 48.3%, b.p.0.05mm =115° C.). The above amide (9.65 g, 0.040 mol) was reduced with lithium aluminum hydride (1.7 g, 0.045 mol) to yield 6.94 g (0.030 mol, 76.1%) of the product after vacuum distillation: (b.p.0.05mm =77° C.). NMR (CDCl3) δ 2.7-2.4 (m, 10H, NCH2 and NHCH2), 1.6 (s, 1H, NH), 1.5 (m, 2H, NHCH2CH2), 1.28 (s, 10H, NHCH2CH2 (CH2)5), 1.01 (t, 6H, NCH2CH3), 0.88 (t, 3H, CH3). Elemental Analysis: Caled. for C14H32N2 (228.41): C, 73.61; H, 14.12; N, 12.26. Found: C, 73.68; H, 14.76; N, 12.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[NH:15][CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:28]=1)[C:23]([OH:25])=O>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:28]=1)[C:23]([N:15]([C:9]1[CH:10]=[N:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])[CH3:16])=[O:25]
Reactant: CS(=O)(=O)c1cc(Cl)cc(C(=O)O)c1
Reactant: CNc1cnc(C)cc1-c1ccc(F)cc1OC
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(Cl)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N,6-dimethylpyridin-3-amine and 3-chloro-5-(methylsulfonyl)benzoic acid (example 114, intermediate a) after a reaction time of 15.5 hours. The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless oil (41%). MS (ESI): m/z=463.09 [M+H]+.
Reaction SMILES: [H-].C[O:3]CCO[Al+]OCCOC.[Na+].[H-].[F:15][C:16]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]2)[C:21]([O:30][CH3:31])=[CH:20][C:17]=1[C:18]#N.O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:15][C:16]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]2)[C:21]([O:30][CH3:31])=[CH:20][C:17]=1[CH:18]=[O:3]
Reactant: COc1cc(C#N)c(F)cc1-n1cnc(C)c1
Reactant: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(F)cc1-n1cnc(C)c1
Reaction time: 1 h

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65% solution in toluene, 11.4 mL) was added dropwise to a suspension of 2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzonitrile (8.85 g) in THF (180 mL) in a nitrogen atmosphere at −15° C., and the reaction solution was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Then, a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added to the mixture and the organic layer was partitioned. The resulting organic layer was made acidic with 5 N aqueous hydrochloric acid, and the mixture was stirred. Then, the mixture was neutralized with 5 N aqueous sodium hydroxide and the organic layer was partitioned. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:ethyl acetate) to obtain 3.32 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C#N)c3)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C#N)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
3-[3-(2-Methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzonitrile (22 mg, 0.048 mmol) was dissolved in 1 mL trifluoroacetic acid. The mixture was stirred at room temperature for 1 h and the solvent was evaporated. The crude product was dissolved in 1 mL of methanol and 50 μL of ethylenediamine was added. After 15 min., mL of DMSO was added and the mixture was directly purified by mass-triggered preparative reverse phase HPLC to give 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzonitrile as a colorless solid (4.6 mg, 30% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J=2.5 Hz, 1H), 8.44 (d, J=2.5 Hz, 1H), 8.28 (t, J=2 Hz, 1H), 8.12 (m, 2H), 7.84 (dt, J1=8 Hz, J2=1 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.64 (dd, J1=7.5 Hz, J2=2 Hz, 1H), 7.46 (m, 1H), 7.21 (d, J=8 Hz, 1H), 7.09 (td, J1=7.5 Hz, J2=1 Hz, 1H), 3.83 (s, 3H); MS: m/z 327 [MH+].
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]3[O:26][C:2]4[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)=[CH:15][CH:16]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3cccnc3)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Yield: 15.1 %

Procedure:
Methyl 2-hydroxy-3-(4-(pyridin-3-yl)benzamido)benzoate (1.04 g, 3 mmol) and 4-methylbenzenesulfonic acid (1.2 g, 6 mmol) were added to toluene (20 mL) and the mixture was stirred under reflux for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 10:1). 150 mg of methyl 2-(4-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxylate as a solid was obtained, yield: 15%. 1H-NMR (400 MHz, DMSO-d6) δ 4.02 (s, 3H), 7.55-7.59 (m, 1H), 7.97-7.99 (m, 1H), 8.04-8.06 (d, J=8.0 Hz, 2H), 8.13-8.15 (m, 1H), 8.21-8.24 (m, 1H), 8.33-8.35 (d, J=8.2 Hz, 2H), 8.65-8.66 (m, 1H), 9.03-9.04 (d, J=2.0 Hz, 1H); LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:50]([CH3:51])=[CH:49][C:39]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][C:44]2=[O:48])=[CH:38][C:37]=1[CH3:52]>>[CH3:52][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][C:44]2=[O:48])[CH:49]=[C:50]([CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCCN2CCCC2=O)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCN6CCCC6=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 1-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)pyrrolidin-2-one following a procedure analogous to that described in Step 5 of Intermediate 1. The product is purified by HPLC on reversed phase. LC (method 8): tR=0.68 min; Mass spectrum (ESI+): m/z=574 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[OH:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccccc1
Yield: 45.6 %

Procedure:
2-(S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester (82 mg) was prepared from 3-biphenyl-4-yl-2-(S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (150 mg, 0.33 mmol) and benzyl bromide (0.047 mL, 0.40 mmol) as described in general procedure G and purified over silica gel (7:3, DCM-hexanes).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH2:9][CH:8]([CH2:13][CH2:14]Br)[C:7]=2[CH:16]=1)#[N:2].[H-].C([Al+]CC(C)C)C(C)C.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C([O-])([O-])=O.[K+].[K+]>CC(CC)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH2:9][CH:8]([CH2:13][CH2:14][N:41]3[CH2:40][CH2:39][CH:38]([C:32]4[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=4)[CH2:43][CH2:42]3)[C:7]=2[CH:16]=1)#[N:2]
Reactant: COc1ccc(C2CCNCC2)cc1OC
Reactant: N#Cc1ccc2c(c1)C(CCBr)CCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: COc1ccc(C2CCN(CCC3CCCOc4ccc(C#N)cc43)CC2)cc1OC
Reaction time: 3 h

Procedure:
3.6 g of 2-(2,3,4,5-tetrahydro-7-cyano-1-benzoxepin-5-yl)ethyl bromide [obtainable starting from 2,3,4,5-tetrahydro-7-cyano-1-benzoexpin-5-one [sic] by reaction with triphenylethylphosphinium bromide, subsequent bromination of the product in the allyl position and reduction of the isolated double bond with diisobutyl-aluminiumhydride (DIBAH)], 1 equivalent of 4-(3,4-dimethoxyphenyl)piperidine hydrochloride, 3.8 g of K2CO3 and 2.1 g of KI are dissolved in 120 ml of ethyl methyl ketone and the mixture is boiled for 3 hours. Customary working up gives 1-(2-(2,3,4,5-tetrahydro-7-cyano-1-benzoxepin-5-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](I)[CH3:26]>>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[CH2:25][CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: CCI
Product: CCN(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C#N)cc1
Yield: 33.3 %

Procedure:
The procedure of Preparation Example 38 was repeated, except that 314 mg of 4-[N-(4-benzyloxybenzyl)amino]benzonitrile was used in place of 4-[N-(3-pyridyl)amino]benzonitrile, and 156 mg of ethyl iodide was used in place of 4-benzyloxybenzyl chloride. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 114 mg of 4-[N-(4-benzyloxybenzyl)-N-ethylamino]benzonitrile.
Reaction SMILES: CS(O[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH:18]3[N:22]([CH2:23][CH2:24][C:9]1=2)[CH2:21][CH2:20][CH2:19]3)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+].O>CN(C)C=O>[N:32]([CH:6]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH:18]3[N:22]([CH2:23][CH2:24][C:9]1=2)[CH2:21][CH2:20][CH2:19]3)=[N+:33]=[N-:34]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(F)cc2)CCN2CCCC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(F)cc2)CCN2CCCC12
Yield: 7.1 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethyl methanesulfonate (400 mg, 0.9 mmol) and sodium azide (88 mg, 1.3 mmol) in dimethylformamide (10 mL) was stirred at RT for 18 h. The reaction mixture was diluted with ice cooled water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase HPLC to yield 7-(2-azido-2-(4-fluorophenyl)ethyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (25 mg). 1H NMR (CD3OD, freebase) δ (ppm): 7.32 (m, 3H), 7.26 (s, 1H), 7.13 (m, 2H), 7.09 (d, 1H), 5.09 (t, 1H), 4.8 (m, 1H), 4.32 (m, 2H), 3.44 (m, 2H), 3.3 (m, 1H), 3.1 (m, 1H), 3.0 (d, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 2.4 (s, 3H), 2.18 (m, 2H), 2.0 (m, 1H). Separation by chiral HPLC provides diastereomers V-23a-d.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>CCOC(C)=O.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.[Cu]I>[F:17][C:3]1[C:2]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.80 g, 9.36 mmol, Intermediate 21), Pd(PPh3)2Cl2 (660 mg, 0.94 mmol), CuI (180 mg, 0.94 mmol), and triethylamine (50 mL) was added but-3-yn-1-ol (2.0 g, 28.1 mmol) under N2 atmosphere. The resulting mixture was stirred at 60° C. for 16 hours. Upon completion, the reaction mixture was diluted with EtOAc, and washed with water (3×10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (2.0 g). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.64 (d, 1H), 7.49 (dd, 1H), 5.94 (dd, 1H), 4.99 (t, 1H), 3.98-3.92 (m, 1H), 3.85-3.77 (m, 1H), 3.68 (t, 2H), 2.67 (t, 2H), 2.48-2.35 (m, 1H), 2.12-2.02 (m, 2H), 1.84-1.78 (m, 1H), 1.68-1.62 (m, 2H).
Reaction SMILES: Cl.C([O:4][C:5](=[O:29])[CH:6]([CH2:24][S:25]C(=O)C)[CH:7]([C:10]1[CH:11]=[N:12][C:13]([NH:16]C(OC(C)(C)C)=O)=[CH:14][CH:15]=1)[CH2:8][CH3:9])C>>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([CH:7]([CH2:8][CH3:9])[CH:6]([CH2:24][SH:25])[C:5]([OH:29])=[O:4])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(CSC(C)=O)C(CC)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: Cl
Product: CCC(c1ccc(N)nc1)C(CS)C(=O)O

Procedure:
Hydrochloric acid (38%, 4 mL) was added to 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-pentanoic acid ethyl ester (0.041 g, 0.1 mmol) under argon and the mixture was heated to reflux for 4 h. Concentration under reduced pressure and drying (45° C., 0.3 mbar) afforded the title compound as the hydrochloride salt (0.027 mg, 97%).