Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([CH3:40])=[CH2:39])[CH:31]=2)=[N:27][CH:28]=1.[Cl-].[CH3:42][C@@:43]([NH3+:50])([CH2:48][CH3:49])[C:44](OC)=[O:45]>C(Cl)Cl>[CH2:48]([C@:43]1([CH3:42])[C:44](=[O:45])[N:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([CH3:40])=[CH2:39])[CH:31]=3)=[N:27][CH:28]=2)[C:5](=[O:11])[NH:50]1)[CH3:49]
Reactant: C=C(C)c1cc(Oc2ccc(N)cn2)ccc1C#N
Reactant: CC[C@@](C)([NH3+])C(=O)OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1cc(Oc2ccc(N3C(=O)N[C@](C)(CC)C3=O)cn2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of triphosgene (118 mg, 0.40 mmol) in dry DCM (3 mL) at 0° C. DIPEA (0.695 ml, 4.0 mmol) was added followed by a solution of 4-[(5-amino-2-pyridinyl)oxy]-2-(1-methylethenyl)benzonitrile (Intermediate 154, 100 mg) in dry DCM (6 mL) slowly added (5 minutes). After that (2R)-2-methyl-1-(methyloxy)-1-oxo-2-butanaminium chloride (268 mg, 1.6 mmol) dissolved in dry DCM (3 mL) was added at the same temperature and the reaction mixture was stirred for 45 minutes at 0° C. The reaction was quenched with water and aqueous buffer (pH 3) was added while the pH was allowed to reach ˜5-6. Ethyl acetate (40 ml) was added and two phases were separated. The organic layer was washed with brine (2×10 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as yellow foam. This urea was dissolved in MeOH (10 mL), NaOMe (10 mg) was added and the reaction mixture was refluxed for 45 minutes under stirring. After cooling the mixture was quenched with an aqueous saturated solution of ammonium chloride (10 mL) and diluted with ethyl acetate (20 mL). Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 10 g) eluting from 75:25 to 50:50 cyclohexane/ethyl acetate affording the title compound as a white solid (100 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:24][S:21]([N:18]1[CH2:17][CH2:16][N:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:20][CH2:19]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)N1CCN(c2ccc(OCc3ccccc3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCN(c2ccc(O)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97122.3 %

Procedure:
1-[5-(benzyloxy)pyridin-2-yl]-4-(methylsulfonyl)piperazine (120 g, 278 mmol) was dissolved in TFA (1.3 L) and the reaction heated to reflux, with stirring, for 3 hours then cooled to room temperature. The TFA was then removed in vacuo and the residue azeotroped with toluene (2×300 mL). The resulting liquor was diluted with DCM (100 mL) and slowly neutralised to pH8 with sat. NaHCO3 (700 mL). The suspension was filtered, washed with water, minimum DCM and ether and dried to give 6-[4-(methylsulfonyl)piperazin-1-yl]pyridin-3-ol as a beige solid (69 g, 270 mol, 97%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:27]1([C:7]2[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:16]3[NH:24][C:23]4[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=4[CH:17]=3)[N:8]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CNC1
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1N1CCC1
Yield: 60.7 %

Procedure:
This compound (18 mg, 61% yield) as a yellow solid was prepared according to the procedures described for Example 346, using 2-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (345) (28 mg, 0.076 mmol), azetidine (25.5 pt, 0.37 mmol, Matrix Scientific, Columbia, S.C.), and DIEA (26.4 μL, 0.15 mmol) in DMSO (0.75 mL) at 50° C. for 1 h. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H) 2.30 (quin, J=7.58 Hz, 2H) 2.85 (t, J=6.85 Hz, 2H) 3.43 (td, J=6.85, 2.35 Hz, 2H) 4.22 (t, J=7.63 Hz, 4H) 5.68 (s, 1H) 6.95 (s, 1H) 6.95 (s, 1H) 7.23 (t, J=7.82 Hz, 1H) 7.35 (dd, J=8.02, 1.37 Hz, 1H) 7.60 (dd, J=7.43, 1.37 Hz, 1H) 12.01 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]#[N:7])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)Cc1ccccc1

Procedure:
Cyanoacetic acid ethyl ester was alkylated with benzyl bromide in the presence of sodium ethylate in ethanol to give benzyl-cyanoacetic acid ethyl ester [MS: 203 (M)+ ] which was then subsequently hydrolyzed with 1N sodium hydroxide solution in a 9:1 mixture of methanol and water to give the corresponding acid. Recrystallization of the crude product from methylene chloride/hexane yielded benzyl-cyanoacetic acid as crystals of melting point 97°.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10]Br.[CH3:17][O:18][C:19]1C(C)=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1C.C[N:51](C=O)C>>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10][N:30]1[C:29]2[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=2[S:27](=[O:48])(=[O:47])[N:26]([C:22]2[CH:23]=[N:51][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:31]1=[O:32]
Reactant: CN(C)C=O
Reactant: Fc1cccc(Cl)c1CBr
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)cn1

Procedure:
The title compound (79 mg, 0.18 mmol) was prepared from (IntA15) (75 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2-chloro-6-fluorobenzyl bromide (67 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH2:11])[O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][C:21]#[N:22]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][C:21]([NH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)=[NH:22]
Reactant: N#CNc1c(Cl)cccc1Cl
Reactant: NC1CCCCC12OCCO2
Product: N=C(Nc1c(Cl)cccc1Cl)NC1CCCCC12OCCO2
Reaction time: 0.75 h
Yield: 43.5 %

Procedure:
1,4-Dioxaspiro[4.5]dec-6-ylamine (500 mg) was reacted with 2,6-dichloro-phenylcyanamide (595 mg, prepared as described in J. Med. Chem., 1975, 18, 90-99) at 130° C. After 45 minutes, the reaction was stopped and the reaction product was purified by preparative HPLC. The product-containing fractions were combined, the acetonitrile was stripped off in a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with dichloromethane. Drying over magnesium sulfate was followed by evaporation to dryness. 476 mg of the desired guanidine were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]#[N:16].[C:18](Cl)(=[O:20])[CH3:19]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([C:18](=[O:20])[CH3:19])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: CC(=O)Cl
Reactant: COC(=O)CNc1cc([N+](=O)[O-])ccc1C#N
Agent: CN(C)c1ccncc1
Product: COC(=O)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1C#N
Yield: 86 %

Procedure:
At 50° C., (2-cyano-5-nitro-phenylamino)-acetic acid methyl ester (0.5 g, 2.1 mmol) was heated in acetyl chloride (100 mL) for 3 hours in the presence of catalytic DMAP. The mixture was poured over ice and then partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed once with 1 M NaOH (100 mL) and dried over sodium sulfate. Concentration and silica gel purification (EtOAc/hexanes 9:1) gave [acetyl-(2-cyano-5-nitro-phenyl)-amino]-acetic acid methyl ester (0.5 g, 1.8 mmol, 86%): 1H NMR (300 MHz, CDCl3) δ 8.59 (d, 1H), 8.36 (dd, 1H), 7.99 (d, 1H), 3.9 (b, 2H), 3.78 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [N+]([C:4]1[C:9]([CH3:10])=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[CH3:12])([O-])=O.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH3:12]
Reactant: BrP(Br)Br
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Br
Yield: 31.4 %

Procedure:
By proceeding in a similar manner to the procedure contained in J.Chem.Soc., 1956, page 771 but using 4-nitro-3,5-dimethylpyridine-N-oxide (23.06 g), phosphorous tribromide (111.47 g) in toluene (50 ml) there was prepared the title compound (8 g) as a yellow oil.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[CH2:5]([O:7][C:8](=[O:26])[C@@H:9]([OH:25])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:6].C(OCC)(=O)C.O>CN(C=O)C.[Ag]=O>[CH2:5]([O:7][C:8](=[O:26])[C@@H:9]([O:25][CH2:1][CH2:2][CH3:3])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH3:6]
Reactant: CCCI
Reactant: CCOC(=O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 50 °C

Procedure:
Propyl iodide (41.6 mmol) was added at room temperature to a solution of (2S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid ethyl ester (Example 377, Step 2) (8.3 mmol) and silver oxide (12.45 mmol) in 40 mL of DMF. The mixture was heated at 50° C. for 24 hours. After that the mixture was cooled to room temperature, 300 ml of ethyl acetate and 200 ml of water were added. The aqueous layer was separated and the organic layer were washed with brine (3×100 ml), and then dried over (MgSO4), filtered and concentrated under vacuum. The crude was purified by chromatography (silica gel, hexanes/ethyl acetate 6:1) to produce a yellow oil. 1H-NMR (CDCl3, 200.15 MHz): 7.42–7.31 (m, 5 H), 7.17 (d, 2 H, J=8.6 Hz), 6.90 (d, 2 H, J=8.6 Hz), 5.05 (s, 2 H), 4.17 (q, 2 H, J=7.0 Hz), 3.97 (dd, 1 H, J=7.0, 6.2 Hz), 3.53 (dt, 1 H, J=8.9, 6.4 Hz), 3.23 (dt, 1 H, J=9.1, 6.7 Hz), 2.97 (d, 2 H, J=6.7 Hz), 1.66–1.48 (m, 2 H), 1.23 (t, 3 H, J=7.3 Hz), 0.86 (t, 3 H, J=7.5 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)=[O:29]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)=[O:29])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCBr)c1cccc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCC(=O)c2cccc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride and 5-bromo-1-(1-naphthyl)-1-pentanone were reacted and treated in the same manner as in Example 172 to give 4-amino-5-chloro-2-methoxy-N-((1-(4-(1-naphthoyl)butyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]#[N:25])=[N:11]2)=[CH:6][C:5]=1[F:26])#[N:3].[C:27](Cl)(=[O:32])[O:28][CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[C:24]([C:12]1[C:13]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:27]([O:28][CH:29]([CH3:31])[CH3:30])=[O:32])[CH2:22][CH2:23]2)=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[C:5]([F:26])[CH:6]=2)[N:11]=1)#[N:25]
Reactant: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirring solution of 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt (Example 36, step A) (19 mg, 0.05 mmol) in DCM (3 mL) at room temperature under argon was added TEA (0.014 mL, 0.10 mmol) and isopropyl carbonochloridate (12 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 15 mg (43%) of isopropyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.72-7.81 (1H, m), 7.56-7.72 (2H, m), 6.30 (1H, s), 4.82-5.04 (1H, m, J=6.6, 6.3, 6.2, 6.2 Hz), 4.65 (1H, ddd, J=7.0, 3.4, 3.3 Hz), 3.65-3.84 (2H, m), 3.37-3.61 (2H, m), 1.96-2.12 (2H, m), 1.81-1.96 (2H, m), 1.13-1.33 (6H, m). MS (ESI) 426 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][NH:11]2)[CH:6]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1c1cc(F)cc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4S)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidine-1-carboxylate (I-14) (0.6 g, 1.95 mmol) in DCM (2 mL) at room temperature was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours. All the solvents were removed under reduced pressure. The crude was diluted with EtOAc, washed with aqueous NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to yield 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15). 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1 H), 7.43-7.37 (m, 1 H), 7.24-7.20 (m, 1 H), 5.28 (dt, J=3.6, 53.6 Hz, 1 H), 4.57 (dd, J=6.4, 9.6 Hz, 1 H), 3.44-3.18 (m, 2 H), 2.63-2.50 (m, 1 H), 1.72 (dddd, J=4.4, 10.0, 14.4, 39.6 Hz, 1H). MS m/z 209.1 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17]C)=[O:16].O[Li:20].O>O1CCOCC1.O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C@@H:3]([C:15]([O-:17])=[O:16])[CH2:4]1)=[O:9])([CH3:14])([CH3:12])[CH3:13].[Li+:20]
Reactant: [Li]O
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)[O-]
Product: [Li+]
Temperature: 80 °C
Yield: 126.8 %

Procedure:
To a solution of (R)-1-tert-butyl 3-methyl 4-methylpiperazine-1,3-dicarboxylate (1.2 g, 4.6 mmol) in 1,4-dioxane (18 mL) and water (18 mL) was added LiOH.H2O (0.290 g, 6.91 mmol). After heating at about 80° C. for about 1 h, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The solid was dried in a vacuum oven at about 65° C. for about 18 h to afford lithium (R)-4-(tert-butoxycarbonyl)-1-methylpiperazine-2-carboxylate (1.46 g, quantitative): LC/MS (Table 2, Method a) Rt=1.17 min; MS m/z: 245 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]#[CH:21])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(NC(C)C)(C)C.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>[C:1]1([S:7]([C:10]([CH3:23])([CH3:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([C:20]#[C:21][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:15]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: C#CC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CC(C)(CCCN1CCCC(C#Cc2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-benzenesulfonyl-4-methylpentyl)-3-ethynylpiperidine (0.33 g, 1.0 mmol), iodobenzene (80 μL, 0.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol) and copper(I) iodide (6 mg, 0.03 mmol) in diisopropylamine (5 ml) was stirred at 70° C. for 2 hours. The reaction mixture was filtered through Celite, washing with dichloromethane (50 ml). The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel, eluting with 2% methanol/dichloromethane, followed by an SCX cartridge and finally preparative thin layer chromatography, eluting with 7% methanol/dichloromethane, to give the title compound. The hydrochloride salt (63 mg, 14%) was obtained by treatment with ethereal hydrogen chloride and crystallisation from ethanol/diethyl ether.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:42](C(OC(C)(C)C)=O)[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=O>C(Cl)Cl>[C:46]([O:45][C:43](=[O:42])[N:16]([C@@H:14]([CH3:15])[C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)[OH:39])[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol (135.5 mg, 0.228 mmol) in CH2Cl2 (5 mL) was added BOC2O (49.7 mg, 0.228 mmol). The reaction was stirred at room temperature for 2 days; during this time, 2 additional portions of BOC2O (25 mg each) were added. After 2 days, the reaction was concentrated, and the residue was purified by flash chromatography with 20% EtOAc/hexanes to afford tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.41 (40% EtOAc/hexanes). LCMS=594.2 (M+1−BOC)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Br:10])=[CH:8][CH:9]=1)[CH:5]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>ClCCl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][NH:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:7]([Br:10])=[CH:8][CH:9]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1c(Br)ccc(Br)c1F
Solvent: ClCCl
Product: COc1ccc(CNCc2c(Br)ccc(Br)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,6-dibromo-2-fluorobenzaldehyde (9.12 g) was dissolved in dichloromethane (45 ml), and 1-(4-methoxyphenyl)methanamine (4.6 ml) was added thereto, followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, toluene was further added thereto, followed by twice-repeated evaporation under reduced pressure and azotripic drying. The residue was dissolved in THF (25 ml), sodium borohydride (2.0 g) was added thereto, methanol (15 ml) was carefully added dropwise thereto, followed by stirring at room temperature overnight. Water was added thereto, the solvent was concentrated under reduced pressure, a 1M aqueous sodium hydroxide solution was added thereto to adjust pH to 8 or higher, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain, as a light yellow oily product, 1-(3,6-dibromo-2-fluorophenyl)-N-(4-methoxybenzyl)methanamine (8.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:11]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([S:43]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:45])=[O:44])[CH2:16][CH2:15]3)[N:11]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
To a solution of the intermediate from Example 142 step F (156 mg, 0.35 mmol) in DCM (5 mL) was added pyridine (5 mL) and benzene sulfonyl chloride (68 μL, 0.53 mmol). After 4 hours the reaction was diluted with DCM and washed with 1N HCl (3×), dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:5 ethyl acetate-hexanes to give the title compound a white foam. 1H NMR (CDCl3, 500 MHz): δ 7.99(d, J=8.3 Hz, 2H), 7.8(d, J=8.7 Hz, 2H), 7.7(d, J=1.9 Hz, 2H), 7.67(t, J=7.3 Hz, 1H), 7.58(t, J=8.0 Hz, 2H), 7.32(t, J=1.8 Hz, 1H), 7.1(d, J=8.2 Hz, 2H), 6.42(s, 1H), 5.55(s, 2H), 3.93(s, 3H), 3.90(d, J=12.2 Hz, 2H), 2.46(m, 1H), 2.31(m, 2H), 1.77(m, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:18]=[C:17]2[NH:19][CH:20]=[CH:21][C:16]2=[CH:15][CH:14]=1>C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:12][C:13]1[N+:18]([O-:9])=[C:17]2[NH:19][CH:20]=[CH:21][C:16]2=[CH:15][CH:14]=1
Reactant: Cc1ccc2cc[nH]c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc[nH]c2[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
65% m-Chloroperbenzoic acid (1374 mg) was added to a solution of 6-methyl-1H-pyrrolo[2,3-b]pyridine (570 mg) in ethyl acetate (20 ml) under ice-cooling and the mixture was stirred at room temperature for 20 minutes. After concentration of the reaction mixture in vacuo, the resulted residue was diluted with 2% aqueous solution of potassium carbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a NH-silica gel column chromatography (eluting solvent: chloroform/methanol=30/1 to 9/1) to give 6-methyl-1H-pyrrolo[2,3-b]pyridin-7-oxide (575 mg) as a colorless powder.