Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:24](=[O:26])[CH3:25])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-acetylamino-2-(3-aminobenzoyl)-6-chloroindole (Example 135) and acetyl chloride. m.p.: 225-228° C. (ethyl acetate/hexane) 1H-NMR (DMSO-d6) δ: 10.59 (1H, br s), 9.75 (1H, br s), 9.45 (1H, br s), 7.96 (1H, d, J=8.8 Hz), 7.93-7.82 (2H, m), 7.58-7.40 (3H, m), 7.04 (1H, d, J=8.8 Hz), 2.17 (3H, s), 2.10 (3H, s)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH2:32][C:33](O)=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(OP(C#N)(OCC)=O)C>CN(C)C=O.O>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH2:32][C:33]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:34])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NCCN1CCCCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine (368 mg) and 2,4-dibenzyloxyphenylacetic acid (1.0 g) in N,N-dimethylformamide are added triethylamine (1.2 ml) and diethylcyanophosphate (561 mg) in sequence. The mixture is stirred at room temperature for 30 minutes. To the reaction solution is added water and stirring carried out for 10 minutes. The product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue obtained is purified by silica gel column chromatography. The fractions eluted with dichloro-methane-methanol mixture (10 : 1) is recrystallized from dichloromethane-n-hexane mixture (1 : 5) to obtain 1-[2-(2,4-dibenzyloxyphenylacetyl)aminoethyl]piperidine (950 mg) in the colorless needle-like crystal form.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (100 mg, 74%), MS (ISP) m/z=451.3 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:17][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C(CCn2ccnc2)c2ccc(Br)cc2)cc1
Product: Clc1ccc(C(CCn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 363.28. 1H NMR (Me-d3-OD) δ 2.55-2.70 (2H, m), 3.85-3.95 (1H, m), 3.95-4.10 (2H, m), 7.05 (1H, s), 7.10-7.60 (9H, m), 7.65 (1H, s), 7.90-8.00 (2H, d).
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH2:12])[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Yield: 99.7 %

Procedure:
Using the procedure described in Example 161C, 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.19 g, 1.08 mmol) was reacted with phenyl chloroformate (0.235 g, 1.5 mmol) in the presence of K2CO3 (0.276 g, 2 mmol) in THF (10 mL), and purified by silica gel chromatography with 10-25% EtOAc/hexane as eluants to afford phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate as solid (0.319 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.17-7.45 (m, 5H), 6.23 (s, 1H), 4.69 (dq, 2H), 4.50 (dq, 2H), 1.40 (s, 3H); LC-MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.ICCC>CN(C)C=O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH3:3])[CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCN1CCC(O)(c2cccc(F)c2F)C1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
In a sealed tube a mixture of (+)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.40 g, 1.38 mmol), dimethyl formamide (3 mL) and iodopropane (1.35 mL, 13.8 mmol) was heated under microwave irradiation at 80° C. for 45 minutes. The resulting mixture was evaporated, morpholine (2 mL) was added and the mixture was heated under micro-wave irradiation at 130° C. for 30 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was washed with aqueous LiCl (5%, 50 mL), dried (Na2SO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 40:60 to 60:40) gave the title compound (0.115 g). [α]D=+22.8° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 95-98° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 8), 212, (bp), 182 (41), 84 (88), 57 (24).
Reaction SMILES: BrC1C=CC(CN)=C(COC2C=CC(Cl)=CC=2I)C=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2I)=[C:25]([CH:28]=1)[CH2:26][NH2:27].O(C(C)(C)C)[Na].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[NH:27][CH2:26][C:25]=2[CH:28]=1
Reactant: NCc1cc(Br)ccc1COc1ccc(Cl)cc1I
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: NCc1ccc(Br)cc1COc1ccc(Cl)cc1I
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)NCc1cc(Br)ccc1CO2
Temperature: 95 °C
Yield: 20.5 %

Procedure:
To stirred mixture of 4-Bromo-2-(4-chloro-2-iodo-phenoxymethyl)-benzylamine Example 347D (25.9 mg, 57.2 μmol), NaO-t-Bu (18.1 mg, 0.19 mmol), and BINAP (14.3 mg, 22.9 μmol) in anhydrous toluene (0.4 mL) under argon was added Pd(dba)2 (6.60 mg, 11.4 umol). This reaction mixture in a sealed tube was heated at 95° C. for 75 min, cooled to room temperature and concentrated in vacuo. This was purified by a Shimadzu auto prep HPLC, employing 0% to 100% 10 min gradient elution with 0.1% TFA in MeOH-water solvent system, 220 nM detection, 20 mL/min elution with a YMC ODS S5 20×100 mm column to give 3.8 mg of 9-Bromo-2-chloro-11,12-dihydro-6H-5-oxa-12-aza-dibenzo[a,e]cyclooctene in 20% yield. HPLC Rt=3.67 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) LC/MS: M+H=324.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[OH:32])([O-:24])=[O:23].O.C(OCC)(=O)C>CN(C)C=O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)=[O:32])([O-:24])=[O:23]
Reactant: COc1ccc(C(O)c2ccccc2[N+](=O)[O-])cn1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)c2ccccc2[N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Pyridinium dichromate (18.7 g) was added to a stirred, cooled (0° C.) solution of (2-nitrophenyl)-(6-methoxypyridin-3-yl)methanol (2.0 g) in dimethylformamide (60 ml). After 2 hours at 0° C. water (100 ml) and ethyl acetate (50 ml) were added and the mixture allowed to warm to room temperature. The organic layer was separated and the aqueous extracted with ethyl acetate (3×100 ml). The combined organics were washed with water (2×100 ml) then brine (100 ml), dried (magnesium sulphate) then evaporated to dryness to give the title compound as a solid (1.90 g). mp 94°-95° C. Rf =0.35 in 33% ethyl acetate/petroleum ether (60-80) on silica plates; 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 6.63 (1H, d, J=9 Hz), 7.47 (1H, dd, J=1 and 8 Hz), 7.70 (1H, dd, J=8 Hz), 7.78 (1H, dd, J=8 Hz), 8.12 (1H, dd, J=3 and 9 Hz), 8.25 (1H, dd, J=1 and 8 Hz), 8.36 (1H, d, J=3 Hz); MS, m/z 258 for M+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7]2)[CH3:2].[CH:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:30]([N:22]2[CH2:23][CH2:24][CH:19]([C:5]3[N:6]4[C:11]([C:10](=[O:12])[NH:9][C:8]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:7]4)=[C:3]([CH2:1][CH3:2])[N:4]=3)[CH2:20][CH2:21]2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCc1nc(C2CCNCC2)n2nc(-c3ccccc3)[nH]c(=O)c12
Product: CCc1nc(C2CCN(C(=O)C3CCCC3)CC2)n2nc(-c3ccccc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 103 Step (b), 30 mg (0.09 mmol) 5-ethyl-2-phenyl-7-(4-piperidinyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one, 14 mg (0.10 mmol) cyclopentanecarbonyl chloride are stirred at room temperature overnight, proportionate amounts of the solvents are used.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(Nc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.33 mmol) and 5-amino-1H-tetrazole (143 mg, 1.68 mmol) were reacted to give the crude material, which was purified preparative hplc to afford the title compound, 17 mg (9%). LC-MS: 451.0 (MH+, m/z), 2.04 (Rt, min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:36][C:23]2=[CH:24][C:25]3[C:26](=[O:35])[N:27]([CH:32]([CH3:34])[CH3:33])[C:28](=O)[C:29]=3[CH:30]=[C:22]2[N:21]=1)[CH3:11]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:21][C:22]2=[CH:30][C:29]3[CH2:28][N:27]([CH:32]([CH3:34])[CH3:33])[C:26](=[O:35])[C:25]=3[CH:24]=[C:23]2[N:36]=1)[CH3:11]
Reactant: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C(C)C)C3=O

Procedure:
2-(4-((1-(2,5-Difluorophenyl)propan-2-yl)amino)-2-oxo-1,2-dihydropyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.115 g) and zinc powder (0.290 g) were suspended in acetic acid (10 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give an off-white solid product, 0.055 g. MS: 475.9 [M+1]. 1H NMR (CDCl3, 500 MHz): δ 12.79 (s, 1H), 12.73 (s, 1H), 11.57 (d, 1H), 11.40 (d, 1H), 11.38 (d, 1H), 11.07 (d, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.30 (t, 1H), 7.26 (t, 1H), 7.06-6.97 (m, 5H), 6.91-6.86 (m, 2H), 6.13 (d, 2H), 4.77-4.71 (m, 2H), 4.43 (d, 5H), 4.07-4.00 (m, 2H), 3.18-3.13 (m, 2H), 2.93-2.89 (q, 2H), 1.74 (s, 6H), 1.44 (d, 8H), 1.34-1.23 (m, 16H).
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]([F:24])[C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[F:24][CH:12]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: Cc1c(C(F)CN2CCN(C(=O)[O-])C(C(C)(C)C)C2)ccc2c1COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C(F)CN2CCNCC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl-4-[2-fluoro-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (0.18 g) was treated with 4M HCl in dioxane (4 mL) and stirred at room temperature for 1 h. The mixture was then concentrated to dryness. Analysis by LC indicated complete removal of the Boc group and formation of compound 5-(1-fluoro-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one hydrochloride. 1H-NMR (DMSO, 500 MHz), δ 7.744 (d, J=7.5 Hz, 1H), 7.612 (d, J=7.5 Hz, 1H), 6.264-6.167 (m, 1H), 5.382 (s, 2H), 3.362-3.309 (m, 2H), 3.255-3.125 (m, 8H), 3.078-3.049 (m, 1H), 2.499 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22](O)([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[FH:40].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([F:40])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 186 mg (0.368 mmol) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile in 3 mL of CH2Cl2 1 mL of hydrogen fluoride-pyridine was added and it was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=478 (M+1 35Cl, 35Cl) and 480 (M+1 35Cl, 37Cl).
Reaction SMILES: Br[C:2]1[O:12][C:5]2=[C:6]([O:10][CH3:11])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.C(B(CC)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)C.[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:11][O:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:5]=12
Reactant: COc1nccc2cc(Br)oc12
Reactant: CCB(CC)c1cccnc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: COc1nccc2cc(-c3cccnc3)oc12
Yield: 50.4 %

Procedure:
2-Bromo-7-methoxyfuro[2,3-c]pyridine (0.6 g), diethyl(3-pyridyl)borane (0.387 g), tetrakis(triphenylphosphine)palladium(O) (0.157 g), potassium hydroxide (0.442 g) and tetrabutyl ammonium iodide (0.486 g) were combined in dry tetrahydrofuran (25 ml) under dry nitrogen. The mixture was heated to reflux for 1 hour. The solvent was removed in vacuo, and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The aqueous layer was extracted with dichloromethane (20 ml). The combined organics were washed with water (24×40 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 2:1 heptane:ethyl acetate gave the title compound (0.30 g) as a white solid.
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH2:5][C:6]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:8]#[CH:9])[CH3:2].[CH2:23]([SnH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:21]([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[O:4][CH2:5][C:6]([O:14][Si:15]([CH3:18])([CH3:16])[CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7]/[CH:8]=[CH:9]/[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A mixture of 20.0 g. of 4-triethylsilyloxymethyl-4-trimethylsiloxy-1-octyne, 18.18 g. of tri-n-butylstannane and 70 mg. of azobisisobutyronitrile is stirred under argon and placed in a bath at 100° C. After 5 minutes an exotherm ensues. The mixture is heated at 130°-140° C. for one hour and then the excess tri-n-butylstannane is removed at 130° C. and reduced pressure. The residue is distilled at 130°-140° C., 0.03 mm. in a Kugelrohr apparatus, giving the desired product as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:21][CH:20]=1.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([N:25]([S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=2)(=[O:44])=[O:43])[S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-p-toluenesulfonamidophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine in 5 ml of dimethylformamide and then 1.0 g of p-toluenesulfonyl chloride in 5 ml of dimethylformamide are added dropwise to a suspension of 200 mg of 80% strength sodium hydride in 20 ml of dimethylformamide. After stirring at RT for 2 h, the mixture is added to ice-water and extracted with ethyl acetate/diethyl ether in the ratio 1:1. After drying and concentration of the organic phase, the residue is chromatographed on silica gel using a mixture of ethyl acetate/petroleum ether in the ratio 4:1. After concentration of the corresponding eluate fractions, the title compound of m.p. 120-130° C. is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29]4)[C:17]([C:34]([F:37])([F:36])[F:35])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:40][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4([C:31]([NH2:33])=[O:32])[CH2:29][CH2:30]4)[C:17]([C:34]([F:35])([F:37])[F:36])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2C(F)(F)F)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a mixture of 1-(2-(2-(2-((6-(piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 68 (0.069 g, 0.14 mmol) in anhydrous MeOH (2.0 mL) was added 37% aqueous formaldehyde (0.04 mL, 0.5 mmol) and sodium triacetoxyborohydride (0.147 g, 0.695 mmol). The mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere and then quenched with sat. aq. NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organics were dried using a phase separation cartridge and concentrated in vacuo. Purification by prep-LCMS gave the title compound 69 (0.020 g, 29%) as the formic acid salt (2 equivs. determined by 1H NMR). LCMS-A: rt 4.802 min; m/z 525.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)(=[O:28])=[O:29])[CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3cccc([N+](=O)[O-])c3)c3ccc(F)cc23)CC1

Procedure:
(31.0 mg, 56%), from 5-fluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4b, 30.1 mg, 0.131 mmol) and 3-nitrophenylsulfonyl chloride (58.1 mg, 0.26 mmol); HRMS-FAB+ for C20H19N3O4SF calculated MH+ : 416.10803; found: 416.10631.