Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:34]5[C:35]6[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:31]=[CH:32][CH:33]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc5ccccc45)cc32)n1)c1ccccc1
Yield: 87.9 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 415) (50 mg), 1-naphthyl boronic acid (22 mg), potassium carbonate (31 mg), and tetrakis(triphenylphosphine)palladium(0) (5 mg) were dissolved in degassed n-propanol (2.6 mL) and water (0.4 mL) and stirred at 80° C. under argon atmosphere for 15 hours. Upon cooling, the reaction mixture was filtered through Celite® (the ppt was washed with 10 mL of EtOAc) and evaporated. The residue was purified by preparative thin layer chromatoraphy eluted with 5% MeOH/CH2Cl2) giving 44 mg of the title compound. 1H NMR (500 MHz, CDCl3), δ 8.82 (br s, 1H), 8.38 (s, 1H), 7.97-7.75 (m, 4H), 7.54-7.29 (m, 9H), 7.19 (t, 1 H, J=7.5 Hz), 7.01 (d, 1H, J=Hz), 5.7 (s, 1H), 1.67 (d, 3H, J=7.0 Hz); Mass spectrum (ESI) 442.3 (M+1).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.[ClH:20].[N:21]1([C:28](=[NH:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+]>C(O)C.O>[ClH:20].[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][N:29]=[C:28]([N:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:30]=1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Reactant: N=C(N)N1CCCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1occc1-c1nc(N2CCCCCC2)ncc1-c1ccccn1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(2-pyridinyl)-2-propen-1-one (205 mg, 0.8 mmol) and hexahydro-1H-azepine-1-carboximidamide hydrochloride (213 mg, 1.200 mmol) in ethanol (4 ml) was stirred at room temperature. Potassium tert-butoxide (180 mg, 1.600 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC. The product was dissolved in a mixture of dichloromethane (2 ml) and methanol (0.5 ml) and hydrogen chloride (1M in ether, 0.5 ml) was added and the solvent was evaporated. The residue was co-evaporated with ether and triturated with ether. The solid was collected and dried to give the title compound (67 mg, 23%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.74 (2H, d), 8.54 (1H, s), 8.12-8.10 (1H, m), 7.65-7.55 (2H, m), 7.43 (1H, d), 5.74 (1H, d), 3.84-3.80 (4H, m), 2.41 (3H, s), 1.85-1.70 (4H, m), 1.60-1.48 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:19])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ccc(Br)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 64.1 %

Procedure:
To a solution of 5.66 g of 1-(4-bromophenyl)-cyclobutanol (24.92 mmol, described in example S2-A) in 70 ml DCM were added 4.23 g of (diethylamino)sulfur trifluoride (95%, 24.92 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 35 min, then sat. NaHCO3-solution was added and the resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane) to give 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (3.66 g, 64%) as a colourless liquid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=1[O:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][C:19]=3[O:29][CH3:30])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(NS(C)(=O)=O)ccc1N
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: ClCCl
Product: COc1cc(NS(C)(=O)=O)ccc1NC(=O)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and N-(4-amino-3-methoxyphenyl)methanesulfonamide (Kaironkem), the title compound was obtained as a white solid after trituration in DCM.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([C:29]5[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH2:36][CH:37](OCC)[O:38]CC)[CH:30]=5)=[CH:28][C:23]4=[N:22][CH:21]=3)=[CH:16][C:15]=2[F:44])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:45]>C(OCC)(=O)C>[ClH:45].[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([C:29]5[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][CH2:36][CH:37]=[O:38])[CH:30]=5)=[CH:28][C:23]4=[N:22][CH:21]=3)=[CH:16][C:15]=2[F:44])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(CCc1cc(-c2ccn3c(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)c(F)c4)cnc3c2)ccn1)OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccnc(CCC=O)c5)ccn34)cc2F)no1
Reaction time: 1.5 h
Yield: 105 %

Procedure:
Slurry 1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[2-(3,3-diethoxy-propyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-3-yl}-2-fluoro-phenyl)-urea (1 g, 1.7 mmol) in ethyl acetate (35 mL). Add aqueous 1 N HCl (3.3 mL, 2 equiv.) and stir at room temperature. After 1.5 hours, concentrate to dryness to give an orange solid (0.98 g, 105%). MS (ES), m/z 527 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Br:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:13])[CH3:14])=[CH:10][CH:9]=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc([N+](=O)[O-])c(C(C)C)c1NC(=O)CBr
Reaction time: 0.17 h
Yield: 95 %

Procedure:
2-Bromo-N-(2,6-diisopropylphenyl)acetamide (5.96 g, 20 mmol) was dissolved in concentrated sulfuric acid (100 ml) with ice-cooling, a solution of fuming nitric acid (1.51 g, 24 mmol) dissolved in concentrated sulfuric acid (10 ml) was dropped thereinto and the mixture was stirred for 10 minutes. The reaction solution was poured onto ice water, the separated matters were filtered off and the extraction with ethyl acetate was conducted. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was recrystallized from acetone-hexane to provide 6.52 g (yield 95%) of 2-bromo-N-(2,6-diisopropyl-3-nitrophenyl)acetamide as pale yellow needles.
Reaction SMILES: [ClH:1].[CH2:2]([C:9]#[N:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:13]CC)[CH3:12]>>[ClH:1].[C:3]1([CH2:2][C:9](=[NH:10])[O:13][CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: CCOCC
Agent: Cl
Product: CCOC(=N)Cc1ccccc1
Reaction time: 12 h

Procedure:
Hydrogen chloride was blown into a solution of benzyl cyanide (5.8 ml) in diethyl ether (10 ml) with ice-cooling, and the mixture was stood at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated. The obtained solid was washed with diethyl ether, collected by filtration and dried under reduced pressure to give the title compound (9.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)([CH2:12][CH2:13][CH2:14][CH3:15])C(O)=O)=[CH:4][CH:3]=1.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:36])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCCCC(N)(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 48 h
Yield: 56.3 %

Procedure:
To a stirred solution of 1.0 g (3.25 mmols) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]hexanoic acid in 10 mL of tert-butanol was added 0.87 mL (3.25 mmols) of diphenylphosphorylazide followed by 0.33 mL of triethylamine. This mixture was heated to relux for 48 hours. The tert-butanol was removed under reduced pressure and the residue was taken up in 5% hydrochloric acid and washed with ethyl acetate. The acidic aqueous layer was made basic with concentrated ammonium hydroxide and extracted with ethyl acetate. Removal of solvents from the organic extract afforded 0.510 g (57%) of the amine as a viscous oil: 1H-NMR (CDCl3, Me4Si) 0.8-1.2 (t,J=6 Hz, CH2 --CH3), 1.2-1.7 (m), 1.7-2.2 (m), 2.0 (br s, --NH2), 4.6 (s, CH2 --N), 7.45 (s, phenyl H), 7.8 (s, CH=N), 8.0 ppm (s, CH=N);
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH2:22])=[CH:15][CH:14]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:6]2[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:20](=[O:24])[C@@H:21]([CH3:23])[NH:22][C:33]4=[O:35])=[CH:17][CH:18]=3)=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c2c(C)noc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c2c(C)noc2c1
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
N1-{4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 23, 54 mg) was dissolved in 7.0 ml of ethyl acetate. Then triethylamine (0.051 ml, 0.37 mmol) was added followed by a solution of triphosgene (24.6 mg, 0.083 mmol) in 2.0 ml of ethyl acetate. After stirring for 5 minutes, DMAP (10.1 mg, 0.083 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with an aqueous solution of NaHCO3, the mixture was extracted two times with ethyl acetate and the collected organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient c-Hex/EtOAc from 100/0 to 0/100 to afford the title compound (11 mg)
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[OH-].[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O.C(OCC)C>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:17]=[CH:18][C:7]([N:2]3[CH:6]=[CH:5][N:4]=[CH:3]3)=[CH:8][CH:9]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(NCCCCOc1ccc(-n2ccnc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.8 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butylamine hydrochloride (Example 2) in 50 ml of water is treated successively with 4 ml of 10N NaOH and 2.0 g of 4-chlorobenzoyl chloride in 100 ml of diethyl ether. Stirring at room temperature for 3 hours gives a precipitate which is collected, washed with diethylether and water, and air dried. Recrystallization from 33% aqueous ethanol gives the desired product, m.p. 138°-139° C.; yield, 1.3 g.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12](/[CH:15]=[CH:16]/[CH:17]([OH:19])[CH3:18])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([O:19][CH:17]([CH3:18])/[CH:16]=[CH:15]/[C:12]1[S:11][C:10]([O:9][C:8]2[CH:20]=[CH:21][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=2)=[N:14][CH:13]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 7D (200 mg, 0.65 mmole) in dichloromethane (10 mL) at room temperature, was added triethylamine (750 μL) followed by acetic anhydride (300 μL, 3.2 mmole) and 4-(dimethylamino)pyridine (5 mg). The reaction mixture was stirred at room temperature, overnight and quenched with methanol for an hour. The solvent was evaporated in vacuum and the product was purified via silica column, using a gradient of 5-20% ethyl acetate in hexane. Yield of the clear oil, 165 mg (72.5%). 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=6.25 Hz, 6H) 1.35 (d, J=6.62 Hz, 3H) 2.06 (s, 3H) 4.40-4.63 (m, 1H) 5.35-5.50 (m, 1H) 5.73 (dd, J=15.81, 6.62 Hz, 1H) 6.57 (d, J=15.81 Hz, 1H) 6.84-6.96 (m, 2H) 7.07 (s, 1H) 7.12-7.22 (m, 2 H). Mass spectrum DCI 348 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[I:5][C:6]1[C:7]([OH:32])=[C:8]([O:30][CH3:31])[CH:9]=[C:10]([C:12](=[O:29])[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:16])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:5][C:6]1[C:7]([O:32][CH2:1][CH2:2][CH3:3])=[C:8]([O:30][CH3:31])[CH:9]=[C:10]([C:12](=[O:29])[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[O:16])[CH:11]=1
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
n-Propyl bromide (29.2 mL, 0.32 mole) was added to a solution of 1-(5-iodo-4-hydroxy-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1,4-dione (100 g, 0.2 mole) in DMF (400 mL) containing potassium carbonate (96 g, 0.35 mole). The mixture was stirred at 70° C. for 2 hours during which time starting material disappeared. The mixture was cooled, filtered, and extracted with ethyl acetate, and the extract was washed with water and brine, dried over anhydrous MgSO4, and evaporated in vacuo to afford the crude product. Crystallization from ether/hexane gave the title compound as white crystals, m.p. 120°-121° C. NMR (CDCl3) δ 1.08 (t, J=7.5 Hz, CH2CH2CH3) 1.87 (m, CH2CH2CH3), 2.41 (t, J=4 Hz, COCH2CH2CO), 3.90 and 3.94 (s, u Ar OCH3), 4.04 (t, J=8 Hz, OCH2CH2CH3), 7.28 (s, trimethoxyphenyl H-2, H-6), 7.51 (d, J=1.5 Hz, Iodophenyl 'H-6), 8.06 (d, J=1.5 Hz, Iodophenyl 'H-2).
Reaction SMILES: [Cl-].[NH4+].[N:3]1([C:9]2[CH:10]=[C:11]([C:18]3[N:23]=[C:22]([C:24]4([OH:28])[CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.O>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[C:11]([C:18]2[N:23]=[C:22]([C:24]3([OH:28])[CH2:27][CH2:26][CH2:25]3)[CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(-c2cccc(C3(O)CCC3)n2)cc(N2CCOCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cccc(C3(O)CCC3)n2)cc(N2CCOCC2)c1
Temperature: 85 °C

Procedure:
Ammonium chloride (22.6 mg, 0.422 mmol) and iron (216 mg, 3.57 mmol) were added to a solution of 1-{6-[3-(morpholin-4-yl)-5-nitrophenyl]pyridin-2-yl}cyclobutanol (250 mg, 0.703 mmol) in ethanol (4.69 mL) and water (2.36 mmol). The reaction mixture was heated to 85° C. for 1 hour, then cooled to room temperature. The reaction was filtered, diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (7:3 ethyl acetate:hexanes, then 100% ethyl acetate) to afford 1-{6-[3-amino-5-(morpholin-4-yl)phenyl]pyridin-2-yl}cyclobutanol as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.66-7.58 (m, 1H), 7.56 (d, J=7.5, 1H), 7.36-7.23 (m, 2H), 7.01 (s, 1H), 6.90 (s, 1H), 6.34 (s, 1H), 5.81 (s, 1H), 3.90 (m, 4H), 3.23 (m, 4H), 2.64-2.54 (m, 4H), 2.14-2.08 (m, 1H), 1.96-1.92 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CC#N>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:6]1[CH2:7][CH2:8][C:9]2[NH:1][N:2]=[CH:3][C:4]=2[CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1n[nH]c2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCc2[nH]ncc2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (300 mg) in MeCN (10 mL) was added Cs2CO3 (1.49 g) followed by benzyl bromoacetate (0.253 mL). The reaction mixture was stirred at RT overnight and evaporated to dryness. The residue was taken up in EA and washed with water and brine. The aq. layers were extracted with EA, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 10 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 15 for 7CV, 15 to 25 over 3CV, 25 for 5CV) to afford (1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)acetic acid benzyl ester (218 mg, pale yellow oil). LC-MS (B): tR=0.50 min; [M+H]+: 272.12. 1H-NMR (CDCl3): 7.40-7.33 (m, 5H); 7.30 (s, 1H); 5.21 (s, 2H); 3.73 (s, 2H); 3.52 (s, 2H); 3.50 (s, 1H); 2.98 (t, 2H, 6.0 Hz); 2.85 (t, 2H, 5.8 Hz).
Reaction SMILES: [CH2:1]([S:5]([N-:8][Si](C)(C)C)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([NH:20][C@H:21]([C:32](F)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C1C=CC=CN=1)C>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:5]([NH:8][C:32](=[O:33])[C@H:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)F
Agent: CN(C)c1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
A solution of N-butanesulfonyl-N-trimethylsilylamide (0.75 g, 3.6 mmol), t-butoxycarbonyltryptophan fluoride (0.92 g, 3.01 mmol), and dimethylaminopyridine (37 mg, 0.3 mmol) in tetrahydrofuran (10 ml) is stirred at room temperature for 2 hours. The mixture is diluted with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material is chromatographed on silica gel with ethyl acetate/hexane (1:1) and trace of acetic acid to give N-butanesulfonyl-(t-butoxycarbonyl)tryptophanamide.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:13])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.C(N(CC)CC)C.[C:27]1([N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[F:19][C:2]([F:18])([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:13][C:34]([N:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:35])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(OC(=O)N(c2ccccc2)c2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2 g (0.0069 mol) of methyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate (example 4 of U.S. Pat. No. 4,655,816) in 20 mL of acetonitrile was added 0.7 g of triethylamine. A solution of 1.6 g (0.0069 mol) of diphenylcarbamyl chloride in 20 mL of acetonitrile was added to the above mixture and the resulting mixture was stirred at room temperature over the weekend. The precipitate formed was filtered off and the filtrate was concentrated in vacuo. The residue was slurried with ether. The insoluble material was filtered. The ether filtrate was concentrated and the residue was recrystallized from cyclohexane to give a white solid, mp 114-116° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][N:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C1CC2CCN1CC2
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)[C@@H]1CC2CCN1CC2

Procedure:
Quinuclidine-2-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-quinuclidine-2-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2I)[CH:10]([CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:10]([CH3:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1I
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
rac-4-(2-Iodo-5-methanesulfonyl-benzoyl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.78 mmol) was poured into morpholine (5.0 ml) and the reaction mixture was stirred for 15 h at 100° C. before being concentrated in vacuo. The residue was then purified by column chromatography (SiO2, 20 g, dichloromethane/methanol=0-5%) to give the title compound as a colorless foam (322 mg, 88%). MS (m/e): 468.3 (M+H+).