Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=3)([OH:21])[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1cccc(Cl)c1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 3-chlorophenyl magnesium bromide in tetrahydrofuran (0.5 M, 50 mL, 25 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (20 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(3-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][NH2:40].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:22]1[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:40][O:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][O:33]3)=[CH:13][N:14]=2)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:21]1
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (2.25 g, crude) in DMF (23 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (776 mg), HOBt (1.03 g), and EDCI (1.19 g) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluted with AcOEt to give tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate (2.51 mg) as pale yellow form.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Cl)c3)nc2n(CC)c1=O
Yield: 42.1 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.50 g (17.7 mmol) of 5,6-diamino-1,3-diethyluracil and 3.55 g (19.4 mmol) of 3-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.57 g (yield 42%) of Compound 132 as white plates.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:35])[N:11]([CH3:34])[C:12]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[N:13][C:14]=1[C:15]1[O:19][N:18]=[C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:16]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:17]2[N:16]=[C:15]([C:14]3[N:13]=[C:12]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[N:11]([CH3:34])[C:10](=[O:35])[C:9]=3[OH:8])[O:19][N:18]=2)=[CH:22][CH:23]=1
Reactant: Cn1c(N2CCOCC2)nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(N2CCOCC2)nc(-c2nc(Cc3ccc(F)cc3)no2)c(O)c1=O
Yield: 80.9 %

Procedure:
A yellow solution of 5-(benzyloxy)-6-(3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)-3-methyl-2-morpholinopyrimidin-4(3H)-one (0.216 g, 0.45 mmol) in TFA (10 mL) was stirred 8 h at room temperature. The reaction mixture was then concentrated and the resulting yellow oil was dissolved in MeOH and concentrated to give pale yellow slurry which was triturated with water and filtered to afford the title compound (0.141 g, 80% yield) as a pale off-white solid. 1HNMR (500 MHz, CDCl3) δ: 9.62 (1H, s), 7.30 (2H, dd, J=8.4, 5.4 Hz), 7.01 (2H, t, J=8.6 Hz), 4.15 (2H, s), 3.85-3.83 (4H, m), 3.58 (3H, s), 3.19-3.17 (4H, m). HRMS (M+H) calcd for C18H19N5O4F: 388.1421. found: 388.2924. Anal calcd for C18H18N5O4F: C, 55.81; H, 4.68; N, 18.08; F, 4.90. found: C, 56.16; H, 4.96; N, 17.40; F, 4.94.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.O>CN(C=O)C>[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH2:29]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OC1CCCNC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCC(O)C4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 73.8 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 3-hydroxypiperidine(168 mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetatediisopropylether to give (E)-N-[4-(3-hydroxypiperidinomethyl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 67) (174 mg) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C@@H:9]([CH3:31])[CH2:10][O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:5]1>C(Cl)Cl>[CH3:2][O:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C@@H:9]([CH3:31])[CH2:10][OH:11])[CH2:5]1
Reactant: CO[C@@H]1CCN([C@@H](C)COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Product: CO[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Hydrogen chloride (2N in Et2O, 1.1 mL, 2.2 mmol) was added to a solution of (R)-3-methoxy-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (420 mg, 1.05 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h, diluted with DCM (20 mL), and washed with 2×20 mL saturated aqueous K2CO3. The aqueous layer was back extracted with DCM (10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield (S)-2-((R)-3-methoxypyrrolidin-1-yl)propan-1-ol as a brown oil (75 mg). 1H NMR (DMSO-d6): 4.31 (t, 1H), 3.82 (m, 1H), 3.47 (m, 1H), 3.18 (m, 1H), 3.15 (s, 3H), 2.77 (dd, 1H), 2.58 (m, 1H), 2.47 (m, 2H), 2.27 (m, 1H), 1.88 (m, 1H), 1.59 (m, 1H), 0.97 (d, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][O:2]1.O=P(Cl)(Cl)Cl.C(#N)C.O.[CH2:21]([Cl:23])Cl>CN(C=O)C.C(O)=O>[Cl:23][C:21]1[C:9]2[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:1][O:2][C:3]=1[CH:4]=[O:11]
Reactant: ClCCl
Reactant: O=C1COCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=CO
Solvent: CC#N
Product: O=CC1=C(Cl)c2ccccc2CO1
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To commercially available isochroman-4-one (900 mg, 6.07 mmol) in DCM (18 ml), DMF (0.706 ml) and POCl3 (1.699 ml, 18.23 mmol) were added in sequence under Nitrogen at r.t. The mixture was refluxed for 6 h and kept at r.t overnight. The reaction mixture was diluted with DCM (15 ml), washed with water and sat NaCl, then anhydrified over Na2SO4 and evaporated in vacuo. The resulting crude was purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give 4-chloro-1H-isochromene-3-carbaldehyde (Intermediate G20.1, 716 mg, 60.6% yield)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5](N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:24]#[N:25].[K+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([C:24]#[N:25])=[CH:4][CH:3]=1
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCc2c(Cl)ccc(C#N)c2CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-amine, (10 g, 47.5 mmol) in acetic acid (34 ml) and water (20 ml) was stirred, treated with sulfuric acid (7.5 ml), cooled to 5° C. and treated with a solution of sodium nitrite (3.65 g, 53 mmol) in water (7.5 ml) added below the surface over 20 minutes. The mixture was added dropwise under the surface of a stirred mixture prepared from cupric sulfate pentahydrate (14.2 g, 57 mmol) in water (35 ml), potassium cyanide (15.4 g, 240 mmol), ice (24 g), sodium bicarbonate (31.8 g, 380 mmol) in water (36 ml) and toluene (35 ml) at 50°-55° C. The mixture was stirred for 15 minutes at 50° C. and for 1 hour at 25° C., treated with a solution of sodium bicarbonate (70 g) in water (700 ml) to pH 8 and then with 10% sodium hydroxide (300 ml). The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous sodium hydroxide and brine, dried with magnesium sulfate and concentrated. The residual oil was treated with ethereal hydrogen chloride to give 8.3 g (68%) of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile; mp 288°-290° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: CC(C)(C(=O)O)c1ccc(Br)nc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(Br)nc1
Yield: 93 %

Procedure:
Prepared in a similar manner to Example 35a from 2-(6-Bromopyridin-3-yl)-2-methylpropanoic acid (example 40b) and isobutyl amine. Yield: 93%. MS+H (300).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1N
Reactant: Clc1cccc(C[Zn+])c1
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: N#Cc1cc(Cc2cccc(Cl)c2)ccc1N

Procedure:
From 9 (488 mg, 2 mmol) and 3-chlorobenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method as 10a; white powder (269 mg, 55%): mp 84.5-85.5° C.; 1H NMR (CDCl3) δ 3.82 (s, 2H, CH2), 4.30 (br s, 2H, NH2), 7.02 (d, J=8.4 Hz, 1H, H-3), 7.12-7.22 (m, 5H, aromatic protons).
Reaction SMILES: COC1C=CC(CC(O)=O)=CC=1.[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([C:37]([O-:39])=[O:38])[S:35]C=2)=[CH:28][CH:27]=1.[OH-].[Na+]>O1CCOCC1.CO>[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]1[S:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=1[C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1ccc(-c2csc(C(=O)[O-])c2)cc1
Agent: COc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)sc2-c2ccccc2Cl)cc1
Temperature: 55 °C

Procedure:
5-(2-Chlorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid is prepared, according to the procedure used in stages 1A)-1E), from (4-methoxyphenyl)acetic acid and methyl 2-chlorobenzoate. In the final stage of this procedure, 5 g of methyl 542-chlorophenyl)-4-(4-methoxyphenyl)-2-thiophenecarboxylate and 1.11 g of sodium hydroxide pellets are added to 30 ml of methanol and 3 ml of dioxane. The reaction medium is heated at 50-60° C. for 5 hours. It is evaporated to dryness, water is added and the impurities are extracted with ether. The aqueous phase is acidified and the expected compound is extracted with ether. After drying and evaporating, 3.5 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:17]([OH:19])=O.[CH3:20][CH:21]([CH3:45])[CH2:22][NH:23][C@H:24]1[CH2:29][C@@H:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:27][N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:17]([N:23]([CH2:22][CH:21]([CH3:45])[CH3:20])[C@H:24]1[CH2:29][C@@H:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:27][N:26]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:25]1)=[O:19]
Reactant: COCCCCn1c(C(=O)O)cc2c1C(=O)CCC2
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
1-(4-Methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (210 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (292 mg) and N,N-diisopropylethylamine (550 μl) were dissolved in 1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (244 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue m was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (245 mg).
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH3:10][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35]3)(=[O:33])=[O:32])=[CH:30][C:17]=2[N:16]=1)([CH3:14])[CH2:12][CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH3:14][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[CH:37][C:36]([C:39]([NH2:3])=[O:41])=[CH:35]3)(=[O:33])=[O:32])=[CH:30][C:17]=2[N:16]=1)([CH3:10])[CH2:12][CH3:13]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(N)=O)c3)ccc2n1CC1CCOCC1
Yield: 56.7 %

Procedure:
Following the same procedure in Example 24, Step A, using DIPEA (105 uL, 78 mg, 0.60 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.20 mmol) (see following Steps B and C for preparation), HATU (114 mg, 0.30 mmol) and saturated ammonia in DMF (5 mL). The crude product was purified by reversed HPLC using CH3CN/H2O (30-60%) to give 52 mg (45%) of a white solid as the title compound. 1H NMR (400 MHz, CD3OD) δ 0.78 (t, J=7.52 Hz, 3 H), 1.41-1.57 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.42 Hz, 2 H), 2.20-2.37 (m, 1 H), 3.22-3.38 (m, 2 H), 3.90 (dd, J=11.82, 3.22 Hz, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.94 (d, J=8.8 Hz, 1 H), 8.01 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.36 (d, J=1.56 Hz, 1 H), 8.79 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=460.3.
Reaction SMILES: CO[C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH3:32][NH:33][CH3:34].CO.C[Al](C)C.CCCCCC.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[CH3:32][N:33]([CH3:34])[C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: CNC
Reactant: COC(=O)CCc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(c2-c2ccnc4cc(CCC(=O)N(C)C)ccc24)CCC3)n1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-propionic acid methyl ester (0.30 g, 0.73 mmol) and 2M dimethylamine in methanol (1.05 mL, 2.1 mmol) in dichloromethane (1 mL) is added 2 M trimethylaluminum in hexane (1.64 mL, 3.25 mmol). The solution is heated at 40° C. for 48 h. The mixture is diluted with dichloromethane (150 mL), treated with saturated potassium sodium tartrate (30 mL), and stirred 18 h. The organic portion is separated and; washed with water and brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (10% methanol in dichloromethane) to yield the title compound, 0.29 g (89%), as a yellow foam.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:20](OC)=[O:21])=[CH:16][NH:17][C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28][CH2:27]1)=[O:25]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[CH:16][NH:17][C:18]=3[CH3:19])[C:20](=[O:21])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:24]([N:26]1[CH2:27][CH2:28][CH:29]([O:32][CH3:33])[CH2:30][CH2:31]1)=[O:25]
Reactant: COC(=O)c1c[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
Hydrazine hydrate (0.023 mL, 0.31 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-5-methyl-1H-pyrrole-3-carboxylate (62) (0.117 g, 0.28 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.022 g, 19.65% yield); 1H NMR (400.132 MHz, DMSO) δ 1.21 (1H, m), 1.34 (1H, m), 1.62 (1H, m), 1.77 (1H, m), 2.25 (3H, s), 2.96 (1H, m), 3.15-3.36 (6H, m), 3.82 (1H, s), 4.05 (2H, s), 7.07-7.15 (2H, m), 7.19 (1H, m), 7.33 (1H, s), 11.22 (1H, s), 12.15 (1H, s); m/z (LC-MS, ESI+), RT=1.39 min (M+H=399.15).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:28](=[CH:29][CH:30]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:27])[C@@H:18]([NH:22][C:23](=[O:26])[O:24][CH3:25])[CH:19]([CH3:21])[CH3:20])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]3[C:63](=[CH:64][CH:65]=2)[C:45]2[NH:46][C:47]([C@@H:49]4[C@@H:54]5[CH2:55][C@@H:51]([CH2:52][CH2:53]5)[N:50]4[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:48][C:44]=2[CH2:43][CH2:42]3)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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:59]([O:58][C:56]([N:50]1[C@H:49]([C:47]2[NH:46][C:45]3[C:63]4[C:41]([CH2:42][CH2:43][C:44]=3[N:48]=2)=[CH:40][C:39]([C:2]2[CH:3]=[C:4]3[C:28](=[CH:29][CH:30]=2)[C:8]2[NH:9][C:10]([C@@H:12]5[CH2:16][CH2:15][CH2:14][N:13]5[C:17](=[O:27])[C@@H:18]([NH:22][C:23]([O:24][CH3:25])=[O:26])[CH:19]([CH3:21])[CH3:20])=[N:11][C:7]=2[CH:6]=[CH:5]3)=[CH:65][CH:64]=4)[C@@H:54]2[CH2:55][C@H:51]1[CH2:52][CH2:53]2)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2c([nH]1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2
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: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c4-5)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 39.7 %

Procedure:
Methyl (S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (482 mg, 1.02 mmol) and (1R,3S,4S)-tert-butyl 3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (552 mg, 1.12 mmol) were combined in DME (12 mL). Pd(PPh3)4 (118 mg, 0.102 mmol) and K2CO3 (2M H2O, 1.68 mL, 3.36 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (307 mg).