Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.[CH3:11][C:12]1([CH3:19])[O:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].BrC1C=CC=CC=1CCN1C(=O)CN(C)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][N:14]1[C:13](=[O:18])[C:12]([CH3:19])([CH3:11])[O:16][C:15]1=[O:17]
Reactant: OCCc1ccccc1Br
Reactant: CC1(C)OC(=O)NC1=O
Agent: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Product: CC1(C)OC(=O)N(CCc2ccccc2Br)C1=O

Procedure:
2-Bromophenethyl alcohol (402 mg, 2 mmol) and 5,5-dimethyl-oxazolidine-2,4-dione (361 mg, 2.8 mmol) were treated as described in the preparation of compound 436. Purification was done by flash chromatography (petroleum ether/ethyl acetate 4:1) to provide the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29][C@H:28]1[CH3:33])[CH3:26]
Reactant: CCN1CCNC[C@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (m, J=7.20, 7.20 Hz, 6 H) 2.36 (s, 3 H) 2.39 (br. s., 1 H) 2.45-2.52 (m, 1 H) 2.53-2.68 (m, 1 H) 2.71-2.90 (m, 2 H) 2.99 (br. s., 1 H) 3.41-3.66 (m, 1 H) 3.97 (br. s., 1 H) 7.53 (d, J=7.83 Hz, 1 H) 7.60 (s, 1 H) 7.84 (d, J=8.08 Hz, 1 H) 7.94 (d, J=7.79 Hz, 1 H) 7.99 (s, 1 H) 8.36 (d, J=8.59 Hz, 1 H) 8.44 (d, J=1.77 Hz, 1 H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:15][C:16]1[C:21]([C:22]#N)=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14].[OH2:41]>C1(C)C=CC=CC=1.CO>[CH2:11]([O:15][C:16]1[C:21]([CH:22]=[O:41])=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Temperature: 25 °C

Procedure:
Diisobutyl aluminum hydride (1.0M in toluene, 3 mL, 3 mMol) was added in three portions over 26 hours (0 hours, 24 hours, 26 hours) to a solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile, Example 14, (0.42 gm, 1 mMol) in toluene (75 mL) and stirred at room temperature. Methyl alcohol (5 mL) was added dropwise followed by a solution of water (5 mL) in methyl alcohol (25 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a semi-solid. The products were separated and purified by silica gel chromatography. Example 29 Anal. Calc'd. C23H24NO4SF: C, 64.32; H, 5.63; N, 3.26. Found: C, 64.27; H, 5.59; N, 3.23. Example 30 Anal. Calc'd. C23H22NO4SF: C, 64.62; H, 5.19; N, 3.28. Found: C, 64.84; H, 5.39; N, 3.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([O:21]CC)=[O:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][C:10]([C:19]([OH:21])=[O:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2ccccc2)n(-c2cccc(Cl)c2)n1
Yield: 92 %

Procedure:
Starting from 400 mg (1.22 mmol) of ethyl 1-(3-chlorophenyl)-5-phenyl-1H-pyrazole-3-carboxylate from example 19A and 686.8 mg (12.24 mmol) of potassium hydroxide, 335.8 mg (1.1 mmol, 92% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: P(=O)([O-])O[C:3]([CH2:19][CH3:20])(CC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH2:12][CH2:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1.[F:23][C:24]1[CH:31]=[CH:30]C(C=O)=[CH:26][CH:25]=1>>[CH3:11][O:10][C:8]1[CH:9]=[C:4]([CH:3]=[CH:19][C:20]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCc1c(OC)cc(C(CC)(CC)O[PH](=O)[O-])cc1OC
Product: CCCc1c(OC)cc(C=Cc2ccc(F)cc2)cc1OC

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl) phosphonate and 4-fluorobenzaldehyde in the same procedure as described in Example 21.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[N+:8]([O-:22])([O:10][CH2:11][C@H:12]([O:18][N+:19]([O-:21])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([O:18][N+:19]([O-:21])=[O:20])[CH2:11][O:10][N+:8]([O-:22])=[O:9]
Reactant: O=[N+]([O-])OC[C@@H](CCCCO)O[N+](=O)[O-]
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1-Chloroethyl chloroformate (6.42 mL, 58.9 mmol) was added dropwise to a stirred solution of (2R)-6-hydroxyhexane-1,2-diyl dinitrate (12 g, 53.5 mmol) and triethylamine (8.95 mL, 64.2 mmol) in DCM (268 mL) at 0° C. After 2 h, the solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5-40% EtOAc/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.40 (q, J=6.0 Hz, 1H), 5.28 (ddd, J=13.0, 6.2, 3.0 Hz, 1H), 4.74 (dd, J=13.0, 3.0 Hz, 1H), 4.47 (dd, J=13.0, 6.5 Hz, 1H), 4.25-4.16 (m, 2H), 1.82 (d, J=6.0 Hz, 3H), 1.82-1.71 (m, 4H), 1.63-1.46 (m, 2H).
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[O:1]([CH2:8][CH2:9][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccccc1
Product: ClCCOc1ccccc1

Procedure:
Reacting 2-phenoxy-ethanol with thionyl chloride in the presence of a catalytic amount of a tetra-alkyl ammonium halide at a temp. of from about 0° C. to 80° C., optionally in the presence of a solvent to form 2-phenoxy-ethyl chloride;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][C:15]=1[F:24]>>[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:16][C:15]=1[F:24]
Reactant: Fc1cc(OCCBr)ccc1Cl
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: Cc1cc(C)n2nc(SCCOc3ccc(Cl)c(F)c3)nc2n1
Yield: 75 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 4-chloro-3-fluorophenoxy-ethylbromide in 75% yield; EM (calc.): 352.1; MS (ESI) m/e: 353.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([NH2:21])[CH2:8][S:9][S:10][CH2:11][C@H:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:33](Cl)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([NH:20][S:33]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:35])=[O:34])[CH2:11][S:10][S:9][CH2:8][C@H:7]([NH:21][S:33]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:35])=[O:34])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CSSC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: CC(C)(C)OC(=O)[C@H](CSSC[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)OC(C)(C)C)NS(=O)(=O)c1cccc2ccccc12

Procedure:
Preparation in analogy to example 6a from 1 g (2.35 mmol) of (R)-cystine-bis-tert-butylester and 1.32 g (5.8 mmol) of 1-naphthalenesulfonic acid chloride. Yield: 1.78 g (oily crystals).
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: Nc1ccccc1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Product: CC(C)(CC(O)(C=Nc1ccccc1)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 1, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 64 μl of aniline are converted into 180 mg of product.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)=[N+:12]=[N-:13]>>[ClH:1].[S:18]1[CH:19]=[CH:20][C:16]([CH2:15][CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:17]1
Reactant: [N-]=[N+]=NCCc1ccsc1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 60 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.101 g, 0.641 mmol was reacted with 3-(2-Azido-ethyl)-thiophene (0.118 g, 0.769 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(2-Thiophen-3-yl-ethyl)-1H[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride (0.119 g, 60%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), δ 7.19 (t, 1H), δ 6.90 (s, 1H), □ 6.78 (d, 1H), δ 6.09 (s, 1H), δ 4.47 (t, 2H), δ 3.67 (s, 2H), δ 3.09 (t, 2H) ppm; 13C; (75 MHz, CD3OD) δ 151.2, 145.7, 137.7, 130.5, 127.8, 125.8, 122.9, 121.9, 110.3, 50.798, 30.7, 23.3 ppm; HRMS (ESI) calcd for C12H14N6S (M+) 274.1001. Found 274.1007.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:15][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(Cl)nn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of ethyl 2-(6-chloropyridazin-3-yl)propanoate (2.8 g, 13.04 mmol) in THF (28 mL) was added lithium hexamethyldisilazide (1.0 molar in THF, 15.65 mL, 15.65 mmol) at −70° C. in dropwise fashion. The reaction was stirred at −70 for 30 min and then iodomethane (0.816 mL, 13.04 mmol) was added. The reaction was stirred for 2 hrs as allowed to warm to room temperature. The reaction was concentrated to dryness via rotary evaporation and the resulting material was purified by MPLC (98:2, DCM:MeOH) to provide the title compound, ethyl 2-(6-chloropyridazin-3-yl)-2-methylpropanoate (54B, 2.82 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.07 Hz, 3 H) 1.58 (s, 6 H) 4.08 (q, J=7.07 Hz, 2 H) 7.83-7.97 (m, 2 H).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>C1COCC1.CCOC(C)=O>[C:30]([O:29][C:27]([NH:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(N)c1ccc(C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(1-amino-2-ethoxy-2-oxoethyl)benzoic acid, as described in Example 1, Step B, (0.8 g, 3.58 mmol) and DIPEA (1.377 mL, 7.88 mmol) were suspended in THF (8 mL) and BOC2O (0.915 mL, 3.94 mmol) was added. The solution was stirred at room temperature for 2 days. The reaction mixture was diluted with EtOAc, washed with 2N HCl and brine, dried over MgSO4 and concentrated in vacuo to give the desired product as a colorless gum. 1H NMR (DMSO-d6, 600 MHz) δ 12.95 (br s, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 5.25 (d, J=8.4 Hz, 1H), 4.06 (m, 2H), 1.36 (s, 9H), 1.09 (t, J=7.2 Hz, 3H). MS: cal'd 324 (MH+), exp 224 (MH+).
Reaction SMILES: [Mg].[Br:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=1>BrC(Br)C.C(OCC)C>[C:12]1([C:13]2[CH:5]=[CH:4][CH:3]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:6]1([OH:16])[C:5]2[CH:4]=[C:3]([Br:2])[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C1c2ccccc2-c2ccc(Br)cc21
Agent: CC(Br)Br
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2ccccc2-c2ccc(Br)cc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
1.3 g (52 mmol) of magnesium was put into a 200 mL three-neck flask and stirred for 0.5 hours while reducing pressure with a rotary pump. Then, under a nitrogen gas stream, 5.0 mL of diethyl ether and one drop of dibromoethane were added. A solution in which 12 g (50 mmol) of 2-bromophenyl was dissolved in 15 mL of diethyl ether was dropped into this mixture at a pace that maintained reflux flow. After completion of dropping, the reaction mixture was refluxed at 50° C. for 3 hours so as to become a Grignard reagent. 12 g (45 mmol) of 2-bromo-9-fluorenone was put into a 200 mL three-neck flask, and after nitrogen substitution in the flask was carried out, 40 mL of diethyl ether was added into the flask. The synthesized Grignard reagent was dropped into this solution, and after completion of dropping, the solution was refluxed at 50° C. for 3 hours, and then stirred at room temperature for 24 hours. After completion of a reaction, the reaction solution was washed with water, and a water layer was extracted with ethyl acetate. The extracted solution and an organic layer were combined and washed with saturated saline, and then dried with magnesium sulfate. After drying, this mixture was subjected to suction filtration, and when a filtrate was concentrated, 19 g of a light yellow, powdery solid of 9-(biphenyl-2-yl)-2-bromofluoren-9-ol that was a target matter was obtained with the yield of 91%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2.[Cu][C:20]#[N:21]>CN(C=O)C.[Cu]I>[C:20]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2)#[N:21]
Reactant: CCOC(=O)CCc1cc2cc(Br)cc(F)c2[nH]1
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc2cc(C#N)cc(F)c2[nH]1
Yield: 74.3 %

Procedure:
To a suspension of ethyl 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoate (D161) (650 mg), copper(I) iodide (394 mg) in DMF (5 mL) was added copper(I) cyanide (741 mg). The reaction vessel was sealed and heated in Biotage Initiator using initial very high to 200° C. for an hour. After cooling the reaction, the precipitate was filtered, and the filtrate was diluted with EtOAc (30 mL). The organic phase was washed with brine (25 mL), water (25 mL×2). The organic layer was dried over sodium sulphate and the crude product was purified by column chromatography to give ethyl 3-(5-cyano-7-fluoro-1H-indol-2-yl)propanoate (D162) (400 mg) as a yellow solid. MS (ES): C14H13FN2O2 requires 260; found 261.1 (M+H+).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]2[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:39][C@@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.O>CN(C)C=O>[CH3:45][C:42]1([CH3:46])[O:41][C@H:40]([CH2:39][N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:16]([CH:13]3[CH2:12][CH2:11][N:10]([CH2:9][C@H:4]4[CH2:5][CH2:6][CH2:7][CH2:8][C:3]54[CH2:2][CH2:1]5)[CH2:15][CH2:14]3)[C:17]2=[O:25])[CH2:44][O:43]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C[C@H]2CCCCC23CC3)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2c(=O)n(C3CCN(C[C@H]4CCCCC45CC5)CC3)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (2.94 g) was dissolved in dimethylformamide (60 mL), and to which 60-72% sodium hydride (oil dispersion) (706.6 mg) was added at room temperature and stirred for 30 minutes. To the reaction mixture, [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzene-sulfonate (7.25 g) was added and stirred at 80° C. for 7 hours. After cooling the reaction mixture to room temperature, water was added, followed by extraction with ethyl acetate. The extract washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=2/1−1/2) to provide 3.43 g of the title compound as a pale yellow, oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)OC(C2C=CC=CC=2)CC3)=[C:7]([NH2:9])[CH:8]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:42]C3C(=CC=C(O)C=3)[CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:42][CH:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=2)[CH2:35]3)=[C:7]([NH2:9])[CH:8]=1
Reactant: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1
Reactant: Oc1ccc2c(c1)CC(c1cccc(F)c1)C2
Product: COc1ccc(Oc2ccc3c(c2)CC(c2cccc(F)c2)C3)c(N)c1

Procedure:
5-Methoxy-2-[2-(3-fluorophenyl)indan-5-yloxy]phenylamine was prepared as described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine in Example 3(a-b) using 500 mg of 2-(3-fluorophenyl)indan-5-ol. 1H-NMR (400 MHz, CDCl3): 7.26-7.21 (m, 1H), 7.16 (d, 1H, J 2.9 Hz), 7.09 (d, 1H, J 8.2 Hz), 7.02 (d, 1H, J 7.7 Hz), 6.96-6.88 (m, 4H), 6.83 (d, 1H, J 9.1 Hz), 6.72 (dd, 1H, J 2.9, 9.1 Hz), 3.69 (s, 3H), 3.65 (k, 1H, J 8.8 Hz), 3.26-3.19 (m, 2H), 2.94 (dd, 2H, J 8.8, 15.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+]>CCO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 94.4 %

Procedure:
13 g of ethyl 5-nitro-2-indolecarboxylate are placed in 200 ml of EtOH and the solution is treated for 12 hours with 15 g of 30% NaOH solution. After evaporation of the solvent, the residue is acidified with concentrated HCl and then filtered to give 10.8 g of the expected compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH2:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2)[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1Cc1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1Cc1ccccc1
Temperature: 90 °C
Yield: 30.1 %

Procedure:
A mixture of (S)-1-(1-benzyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (322 mg, 1.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (286 mg, 1.20 mmol) and DIPEA (1.07 mL, 5.98 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial overnight. The resultant mixture was allowed to cool to RT and then concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH solution to afford a pale red gum. This was purified by column chromatography (silica gel, gradient 0-10% [2M NH3 in MeOH] in DCM) to afford 393 as a white solid (140 mg, 31%). LCMS (Method K): RT 3.21 min [M+H]+ 388.1 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (1H, s), 8.13 (1H, s), 8.04-7.93 (1H, s), 7.63 (1H, dd, J=8.80, 4.92 Hz), 7.35-7.17 (4H, m), 7.16-7.10 (2H, m), 7.03 (1H, ddd, J=9.91, 8.78, 2.52 Hz), 5.93-5.75 (1H, m), 5.61 (2H, s), 1.59 (3H, d, J=6.77 Hz)
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][CH:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11]2)[CH2:30][CH2:29]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(Cc2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCC1=NN(Cc2ccccc2)C(CCCN2CCN(c3ccccc3F)CC2)C1

Procedure:
180 mg (84.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-benzyl-3-butyl-1H-pyrazol-5-yl)propanal (133 mg, 0.492 mmol), 1-(2-fluorophenyl)piperazine (155 mL, 0.984 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]([OH:32])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Reactant: O=C(O)CBr
Product: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc([N+](=O)[O-])cn2)c1C

Procedure:
Similar to Example 1, equimolar amounts of (5-nitropyridin-2-yl)hydrazine and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 117° C.-119° C.).