Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[F:13].[F:14][C:15]([F:23])([F:22])[C:16]1([C:19](O)=[O:20])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH2:6][NH:7][C:19]([C:16]2([C:15]([F:23])([F:22])[F:14])[CH2:18][CH2:17]2)=[O:20])=[CH:4][C:3]=1[F:13]
Reactant: NCc1cc(F)c(Cl)c([N+](=O)[O-])c1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1cc(F)c(Cl)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-chloro-3-fluoro-5-nitro-benzylamine (761 mg; 3.72 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (573 mg; 3.72 mmol), HBTU (1.41 g; 3.72 mmol), TEA (753 mg; 7.44 mmol) and DMF (10 mL).
Reaction SMILES: C[O-].[Na+:3].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16]>C(O)C>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:13][CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:7][CH:6]=1.[Na+:3]
Reactant: ClCc1ccncc1
Reactant: CC(S)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(SCc1ccncc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium methoxide (5.1 g., 94 mmoles) was dissolved in 50 ml. of absolute ethanol and cooled in an ice bath. A slurry of 4-picolyl chloride hydrochloride (5.0 g., 30.4 mmoles) in 45 ml. of ethanol was added and the chilled reaction mixture stirred for approximately 10 minutes. Finally, 2-mercaptopropionic acid (3.23 g., 30.4 mmoles) dissolved in 5 ml. of ethanol was added over a 10 minute period. The mixture was allowed to warm to room temperature and stirred overnight (approximately 16 hours). The reaction was filtered through filter aid to remove salts, carbon treated and concentrated to crude sodium 2-(4-picolylthio)propionate (approximately 7 g. of oil used directly in the next step).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[O:10]=O.CC1C=C(C)C=C(C)C=1CC1C=C(C)C=C(C)C=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[OH:10]
Reactant: O=O
Reactant: Cc1cc(C)cc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)cc(Cc2c(C)cc(C)cc2C)c1
Solvent: CC(=O)O
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
In a flask, 30 mmol of mesitylene, 4.5 mg (0.02 mmol) of palladium(II) acetate, 323 mg (about 0.14 mmol) of H4PMo11V1O40-nH2O, and 10 ml of acetic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 15 hours. The resulting reaction mixture was analyzed by gas chromatography to find that 8.5 mmol of 1,3,5-trimethyl-2-(3′,5′-dimethylbenzyl)benzene, and 1 mmol of 2,4,6-trimethylphenol were produced.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1[NH2:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=O)C.[NH2:20][NH2:21]>C(O)C>[NH2:16][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][CH3:18])[C:7](=[O:19])[C:6]=1[C:4]([NH:20][NH2:21])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1c(N)c2cccnc2n(CC)c1=O
Solvent: CCO
Product: CCn1c(=O)c(C(=O)NN)c(N)c2cccnc21

Procedure:
A stirred mixture of 2 g. of 4-amino-1-ethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 20 ml. of ethanol containing 5 ml. of hydrazine was heated under reflux for 4 hours. The mixture was cooled and the insoluble material was collected. The filter cake was recrystallized from ethanol to produce 1.1 g. of product, m.p. 275°-277° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:34][C:35](OC2C=CC=CC=2)=[O:36])[C:27](=[CH:32][CH:33]=1)[C:28]([O:30][CH3:31])=[O:29].Cl>O1CCCC1.O>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([NH:34][C:35]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)(=[O:9])=[O:10])=[O:36])[CH:25]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Reactant: NS(=O)(=O)c1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Following the Synthesis Method (B), 938 mg (5.42 mmol) of 3-hydroxybenzenesulfonamide was dissolved in 40 ml of tetrahydrofuran, then 892 μl (5.96 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to as DBU) was added dropwise. The reaction solution was stirred at room temperature for 15 minutes, then 1.66 g (5.42 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate was added and the mixture was stirred at room temperature overnight. An excess amount of water was poured into the reaction solution, then the mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The crude product thus obtained was purified by silica gel column chromatography (0% to 5% methanol/dichloromethane) to obtain 1.23 g (yield 59%) of methyl 4-chloro-2-{[(3-hydroxybenzenesulfonylamino)carbonyl]amino}benzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 3.91 (3H, s), 7.02 (1H, m), 7.09 (1H, m), 7.34 (1H, t), 7.57 (2H, m), 7.89 (1H, d), 8.38 (1H, d), 10.94 (1H, s). Next, the 1.23 g (3.2 mmol) of the compound thus obtained was dissolved in 20 ml of methanol, then 10 ml of 2N sodium hydroxide aqueous solution was added dropwise. The reaction solution was stirred at room temperature for 15 minutes, then an excess amount of water was added and the mixture was made acidic with hydrochloric acid. This was then stirred to cause crystals to precipitate which were then obtained by filtration and dried to obtain carboxylic acid. The product thus obtained was dissolved in 50 ml of tetrahydrofuran (hereinafter referred to as THF), then 434 mg (2.68 mmol) of CDI was added under ice cooling and the mixture was stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate, then concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to obtain 230 mg (yield 20%: 2 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 7.12 (2H, s), 7.24 (1H, d), 7.48 (1H, t), 7.58 (2H, s), 7.85 (1H, d), 10.28 (1H, s), 11.63 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:27]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])=[O:29])[NH:10][C@H:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[C@:12]2([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)N2CCC[C@H]2CO)[C@@H](c2cccc(Cl)c2)[C@]1(C#N)c1ccc(Cl)cc1
Yield: 11.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with (S)-1-pyrrolidin-2-yl-methanol (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3S,4S,5S)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-pyrrolidine-3-carbonitrile (12.0 mg, 11.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([OH:15])[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C=O)c(O)c2)c(OC)c(OC)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Yield: 92.5 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (743 mg, 2.14 mmol) was dissolved in acetone (50 ml) and after adding thereto anhydrous sodium carbonate (593 mg, 4.30 mmol) and benzyl bromide (477 mg, 2.79 mmol), the solution was stirred at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (864 mg, 1.98 mmol, 93%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:27][CH:28]=1>CN(C)C=O>[OH:32][C:29]([C:26]1[N:27]=[CH:28][C:23]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: O=C1CN(CCN2CCOCC2)c2nc(Br)cnc2N1
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCN2CCOCC2)CC(=O)N3)cn1
Temperature: 100 °C
Yield: 27 %

Procedure:
6-Bromo-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.228 g, 0.666 mmol) and 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (0.220 g, 0.733 mmol) were combined in dimethylformamide (3 mL). Solution was purged with nitrogen gas followed by the addition of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.109 g, 0.133 mmol). Solution was heated to 100° C. for 2 h. Solution was condensed under reduced pressure and the resulting oil purified via reverse-phase-preparative HPLC (5-60% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min) and desired fractions were loaded onto a Strata-XC ion exchange column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol and was concentrated under reduced pressure and dried to afford the title compound (0.070 g, 0.18 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.33 (br. s., 1H), 9.05 (d, J=1.56 Hz, 1H), 8.27 (dd, J=8.59, 2.34 Hz, 1H), 8.06 (s, 1H), 7.72 (d, J=8.59 Hz, 1H), 5.27 (s, 1H), 4.29 (s, 2H), 3.71 (t, J=6.44 Hz, 2H), 3.54 (t, J=4.49 Hz, 4H), 2.62 (t, J=6.44 Hz, 2H), 2.40-2.48 (m, 4H), 1.46 (s, 6H); MS (ESI) m/z 399.2 [M+1]+; mp 239-241° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH3:11])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)[CH3:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH3:11])[CH2:12][CH2:13][CH2:14][O:15][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C@H:22]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])[CH2:23][CH2:24]3)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: CN(CCCO)c1nc(Cl)c(C#N)cc1F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)c(C#N)cc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 2-chloro-5-fluoro-6-[(3-ydroxypropyl)(methyl)amino]nicotinonitrile (Example 311) (0.50 g, 2.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.25 9, 1.14 mmol) in THF (9 mL) were added PPh3 (0.54 g, 2.05 mmol) and ADDP (0.52 g, 2.05 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.41 g, 81%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.29 (d, 1H), 7.04 (d, 1H), 6.73 (d, 1H), 6.66 (dd, 1H), 4.16 (q, 2H), 3.99 (t, 2H), 3.82 (t, 2H), 3.51 (qt, 1H), 3.25 (d, 3H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.12 (qt, 2H), 1.82-1.72 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=O)[O:11]CCC2C=CC(Br)=CC=2C)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][CH3:31])[C:27]([CH2:32][CH2:33][OH:34])=[C:26]([CH2:35][CH3:36])[CH:25]=1.N(C1C=C(C=CC=1)C#N)=C=O>>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[O:34][CH2:33][CH2:32][C:27]2[C:26]([CH2:35][CH3:36])=[CH:25][C:24]([Br:23])=[CH:29][C:28]=2[CH2:30][CH3:31])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1cc(Br)cc(CC)c1CCO
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Agent: N#Cc1cccc(N=C=O)c1
Product: CCc1cc(Br)cc(CC)c1CCOC(=O)Nc1cccc(C#N)c1
Yield: 86 %

Procedure:
Using a procedure analogous to that used to prepare 30C, 37C (280 mg, 1.95 mmol) was reacted with 3-isocyanatobenzonitrile to yield 37D (670 mg, 86%) as an yellow oil. 1H NMR (400 MHz, CD3OD) δ ppm 1.22 (t, J=7.58 Hz, 6 H) 2.73 (q, J=7.58 Hz, 4 H) 3.06 (t, J=8.1 Hz, 2 H) 4.21 (t, J=8.1 Hz, 2H) 7.19 (s, 2 H) 7.32-7.39 (m, 1 H) 7.40-7.50 (m, J=8.08, 8.08 Hz, 1 H) 7.66 (d, J=8.34 Hz, 1 H) 7.86 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:10][C:9]([CH3:11])=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2]
Reactant: COC(=O)CCCCC=C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)=CCCCCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a stirred solution of 7-methyl-oct-6-enoic acid methyl ester (3.29 g, 19.4 mmol) in toluene (180 mL) was added DIBAL-H (48.5 mL, 1 M solution in hexane, 48.5 mmol) dropwise at 0° C. under N2. After stirring at 0° C. for 30 min, the reaction was quenched by MeOH (12 mL). Saturated aqueous sodium potassium tartrate (120 mL) was added to the reaction mixture. After stirring for 1 h, the organic layer was separated and the aqueous phase was extracted with ether. The combined organic layers were washed with water and brine and dried. Evaporation of the solvent gave 7-methyl-oct-6-en-1-ol (2.70 g, 98%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.11 (1H, m), 3.63 (2H, m), 1.99 (2H, m), 1.68 (3H, s), 1.59 (3H, s), 1.53 (2H, m), 1.25–1.45 (4H, m); 13C NMR (75 MHz, CDCl3) δ 131.52, 124.69, 63.25, 33.00, 29.95, 28.25, 26.02, 25.69, 17.98.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([NH:19][C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[CH:23][N:24]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C>O1CCOCC1>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[O:21][C:20]([NH:19][C:12]3[C:11]4[CH2:10][CH:9]([NH2:8])[CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:24][CH:23]=2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(-c2cnc(Nc3cccc4c3CC(NC(=O)OC(C)(C)C)CC4)o2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnc(Nc3cccc4c3CC(N)CC4)o2)cc1
Reaction time: 0.75 h

Procedure:
Hydrogen chloride in dioxane (4N, 7 mL, 28 mmol) was added to a suspension of 199 mg (0.474 mmol) of the product of Example 20G in 1 mL dioxane. After stirring 45 minutes, the mixture was quenched with 3N NaOH solution, then diluted with EtOAc and poured into water. The separated organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was triturated with Et2O and the solid was collected by vacuum filtration. The result was 92 mg (61%) of the title compound as a pale pink solid. 1H NMR (DMSO-d6) δ 9.02 (br s, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.28 (s, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.08 (t, J=7.8 Hz, 1H), 6.83 (d, J=7.1 Hz, 1H), 3.05-2.70 (m, 4H), 2.31 (m, 4H), 1.85 (m, 3H), 1.42 (m, 1H); MS (ESI+) m/z 320 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15]2[N:19]3[N:20]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:23][C:18]3=[CH:17][N:16]=2)[C@H:3]1[CH3:31].FC1C=CC=C(F)C=1C1C=CC2N(C(NC3C=NC=CC=3N3CCCC(NC(=O)OC(C)(C)C)C3C)=NC=2)N=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15]2[N:19]3[N:20]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:23][C:18]3=[CH:17][N:16]=2)[C@H:3]1[CH3:31]
Reactant: C[C@H]1[C@H](N)CCCN1c1ccncc1Nc1ncc2ccc(-c3ncccc3F)nn12
Agent: CC1C(NC(=O)OC(C)(C)C)CCCN1c1ccncc1Nc1ncc2ccc(-c3c(F)cccc3F)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1[C@@H](N)CCCN1c1ccncc1Nc1ncc2ccc(-c3ncccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-(4-((trans)-3-amino-2-methyl-1-piperidinyl)-3-pyridinyl)-2-(3-fluoro-2-pyridinyl)imidazo[1,5-b]pyridazin-7-amine (enantiomer 1) (Example 54). tert-Butyl (1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting enantiomer) (53 mg, 0.09 mmol) in 2 mL of DCM was treated with 0.5 mL of TFA and stirred at RT for 1 h. Volatiles were removed under reduced pressure. The residue was treated with 10 mL of 1 N NaOH, and the mixture was extracted with 3×15 mL of EtOAc. The combined organic extracts were washed with 2×5 mL of water followed by 2×5 mL of brine, dried over sodium sulfate and concentrated to give the title compound (39 mg, 96% yield) as an orange amorphous solid. MS (ESI, pos. ion) m/z: 436.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.47 (1 H, s), 8.00-8.17 (2 H, m), 7.63 (1 H, tt, J=8.5, 6.5 Hz), 7.39 (1 H, s), 7.30 (2 H, m), 7.16 (1 H, d, J=5.1 Hz), 6.70 (1 H, d, J=9.4 Hz), 3.37 (3 H, br.), 2.78 (2 H, m), 2.56 (1 H, m), 2.36 (1 H, m), 1.76 (1 H, m), 1.59 (2 H, m), 1.23 (1 H, m), 0.84 (3 H, d, J=6.3 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −113.35. The relative stereochemistry was confirmed by 1H-NMR studies.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62](Br)=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:48]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([C:47]1[CH:48]=[C:49]([NH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([B:25]([OH:27])[OH:26])=[CH:61][C:60]=2[CH3:66])=[O:55])[CH:50]=[CH:51][CH:52]=1)[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Yield: 64 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 39D (1.07 g, 1.84 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 39E (640 mg, 64%) as a tan foam. 1H NMR (400 MHz, CD3OD) δ ppm 1.14 (t, J=7.15 Hz, 3 H) 2.65-2.86 (m, 2 H) 2.99 (t, J=7.15 Hz, 2 H) 4.05 (q, J=7.15 Hz, 2 H) 4.19-4.35 (m, 2 H) 4.93-5.14 (m, 3 H) 6.98 (d, J=7.70 Hz, 1 H) 7.12-7.33 (m, 8 H) 7.34-7.45 (m, 2 H) 7.45-7.59 (m, 1 H) 9.14 (s, 1 H)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C1(P([CH:25]2[CH2:30][CH2:29]CCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=2[O:10][CH3:11])[CH2:30][CH2:25]1
Reactant: COc1ccc(C#N)nc1Br
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)nc1C1CC1
Temperature: 130 °C

Procedure:
In a microwave vial, 6-bromo-5-methoxypyridine-2-carbonitrile (5-2, 300 mg, 1.41 mmol, 1.0 equiv), potassium cyclopropyl(trifluoro)borate (521 mg, 3.52 mmol, 2.5 equiv), tricyclohexylphosphine (158 mg, 0.56 mmol, 0.4 equiv), palladium(II) acetate (63.2 mg, 0.28 mmol, 0.2 equiv) and tripotassium phosphate (1046 mg, 4.93 mmol, 3.5 equiv) were suspended in toluene (15 mL) and water (0.75 mL). The reaction mixture was heated in a microwave reactor for 60 minutes at 130° C. and then filtered, rinsing with EtOAc. The filtrate was concentrated and the residue purified by normal phase column chromatography (10-35% EtOAc in hexanes) to afford the product (5-5). ESI+ MS [M+H]+ C10H11N2O: 175.1 found, 175.2 required.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[N:38]1([C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(CCCCNC(=O)OCc2ccccc2)C(=O)N2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a cold (0° C.), nitrogen-blanketed mixture of 2-[[(4-methylphenyl]sulfonyl]amino]6-[[(phenylmethoxy)carbonyl]amino]hexanoic acid (18.00g, 44.43 mmol), triethylamine (5.80 mL, 41.43 mmol) and piperidine (4.10 mL, 41.43 mmol) in anhydrous dimethylformamide (80 mL) was added dropwise diphenylphosphoryl azide (8.90 mL, 41.43 mmol). The mixture was stirred at about 0° C. for about 1 hour and at ambient temperature for about 2 hours before it was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was extracted three additional times with ethyl acetate. The combined extracts were then washed with saturated sodium bicarbonate solution, 1N hydrochloric acid and brine prior to drying and solvent concentration. There was isolated in sufficiently pure state 20.90g (100%) of the title compound of as pale yellow oil; 1H NMR (CDCl3) δ 7.62 (d, J=8.2 Hz, 2H), 7.30-7.22 (m, 5H), 7.19 (d, J=8.1 Hz, 2H), 5.94 (d, J=8.9 Hz, 1H), 5.09-5.07 (m, 1H), 5.03 (s, 2H), 3.90-3.88 (m, 1H), 3.43-3.36 (m, 1H), 3.09-2.91 (m, 5H), 2.32 (s, 3H), 1.43-1.23 (m, 10H), 1.09-0.97 (m, 2H); 13C NMR (CDCl3) ppm 168.28, 156.09, 142.87, 136.43, 136.30, 128.98, 127.95, 127.43, 126.96, 65.81, 52.08, 45.70, 42.67, 40.14, 32.58, 28.72, 25.49, 24.65, 23.64, 21.71, 20.93; IR (KBr, cm-1) 3316, 2938, 2860, 1718, 1634, 1526, 1452, 1416, 1340, 1246, 1162, 1092; MS m/z (MH+) calcd 502.2376, obsd 502.2363.