Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>O>[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])=[O:26])=[CH:23][N:22]=1
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCCCOC(=O)c1ccc(N)nc1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To 7 ml of N,N-dimethylformamide were dissolved 0.92 g (4.0 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.72 g (5.2 mmol) of 6-aminonicotinic acid, followed by the addition of 1.30 g (16 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 0.85 g (yield: 78%) of 6,6-difluoro-5-methyl-5-hexenyl 6-aminonicotinate.
Reaction SMILES: Cl.N1C=CC=CC=1N1CCN([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19]2=[O:32])CC1.[Br:33][CH2:34]CCCCBr.BrCCCCBr>>[Br:33][CH2:34][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[C:19]1=[O:32]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Reactant: BrCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 46 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:12][O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[C:3]([F:11])[C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16]
Reactant: O=Cc1cc(Cl)c(F)cc1O
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C=O
Temperature: 140 °C
Yield: 85.5 %

Procedure:
A mixture of 5-chloro-4-fluoro-2-hydroxy-benzaldehyde (0.8 g, 4.6 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.6 g, 9.2 mmol) and K2CO3 (2 g, 14.5 mmol) in DMF (40 mL) was placed in a sealed tube and heated by irradiation in microwave reactor at 140° C. for 12 min. After cooled to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over anhydrous Na2SO4 and concentrated to give the thitle compound as a brown solid (1.08 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[CH2:4][CH2:5]CN=C=NCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:38]3[C:46]4[C:41](=[CH:42][C:43]([C:47]([OH:49])=[O:48])=[CH:44][CH:45]=4)[N:40]([CH3:50])[CH:39]=3)[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=3[O:36][CH3:37])(=[O:28])=[O:27])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.CN(CCO)C>C(Cl)Cl.CN(C=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:38]3[C:46]4[C:41](=[CH:42][C:43]([C:47]([O:49][CH2:5][CH2:4][N:3]([CH3:12])[CH3:2])=[O:48])=[CH:44][CH:45]=4)[N:40]([CH3:50])[CH:39]=3)[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=3[O:36][CH3:37])(=[O:27])=[O:28])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCO
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)OCCN(C)C)ccc12

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (128 mg, 0.67 mmol) was added to a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxylic acid (the product of Example 17, 300 mg, 0.56 mmol), N,N-dimethylaminopyridine (75 mg, 0.61 mmol) and dimethylaminoethanol (0.17 ml, 1.67 mmol) in a mixture of CH2Cl2 (9 ml) and DMF (0.5 ml) at room temperature under a nitrogen atmosphere. After 12 h a fine white precipitate had formed. The product was removed by filtration and washed with cold methanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17].[H][H]>[Ni].C(O)C>[NH2:14][C:11]1[CH:10]=[C:7]2[C:8](=[O:9])[N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:17])[C:6]2=[CH:13][CH:12]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCO
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N(CCO)C2=O

Procedure:
N-(2-Hydroxyethyl)-4-nitrophthalimide (30.0 g.), ethanol (300 ml.), and Raney nickel (3.0 g.) are mixed and hydrogenated at 100°C. and 1500 psi. until hydrogen uptake ceases. The hot solution is filtered to remove the Raney nickel and the solvent evaporated to yield 4-amino-N-(2-hydroxyethyl)-phthalimide, the amine which melts at 171°-173°C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([C:33]([OH:35])=[O:34])[C:24]=1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36]([C:24]3[C:25]([C:33]([OH:35])=[O:34])=[CH:26][C:27]4[C:32]([CH:23]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:37])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc2ccccc2cc1C(=O)O

Procedure:
To 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 mmol) and 2,3-naphthalenedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL) was added HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by preparative hplc (Gilson) to yield 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-naphthalenecarboxylic acid. This compound was dissolved in 3 mL of DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol) to which was added HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and purified by preparative hplc (Gilson) to give 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-naphthalenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This compound was then dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and it was heated at 60° C. for 1 h. The solution was applied to an amine column which was rinsed with 10 mL of dioxane:MeOH (3:1) to afford 2.7 mg (3.4%) of the above named product. LC-MS m/z 798 (M+H)+, 1.42 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].Cl>C(Cl)Cl>[CH3:36][S:37]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CCOc3ccc(N)cc3)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To the above amine (1.50 g, 3.59 mmol) in CH2Cl2 (30 mL) at 0° C. under nitrogen was added pyridine (0.58 mL, 7.18 mmol) and methanesulfonyl chloride (0.42 mL, 5.38 mmol). After stirring for 2 hours, the mixture was partitioned between 10% aqueous NaHCO3 and 4:1 CH2Cl2 /isopropanol. The organic phase was dried and concentrated to afford a residue which was treated with ethanolic HCl to give 0.85 g (48%) of the title compound as a hydrochloride: mp: 170°-175° C.; 1H NMR (DMSO-d6): δ10.12 (s, 1H), 9.45 (s, 1H), 7.45 (d, J=8.56 Hz, 2H), 7.25 (d, J=8.59 Hz, 2H), 7.16 (d, J=8.96 Hz, 2H), 6.97 (d, J=8.97 Hz, 2H), 4.37 (m, 2H), 3.60-3.25 (m, 10H), 3.05 (s, 3H), 2.87 (s, 3H), IR (KBr): 3010, 2580, 2460, 1640, 1610 cm-1 ; MS (m/z) 497 (MH+, 10 %) 198 (35), 79 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C([Li])(C)(C)C.CN([CH:24]=[O:25])C>CCOCC>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:24]=[O:25])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Temperature: -75 °C
Reaction time: 0.83 h

Procedure:
To a solution of [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (15 g, 56.1 mmol) in ether (450 mL), at −75° C. a solution of tert-butyl lithium (99 ml of 1.7 N solution in hexanes, 168 mmol) is added. The mixture is stirred for 50 minutes at −75° C., and then for 30 minutes at −30° C. To the obtained beige suspension, DMF (22.5 ml) is added during 15 minutes, and then the mixture is allowed to warm to ambient temperature. The mixture is poured on water and extracted with diethyl ether (500 mL). After washing the organic layer with brine (3 times 500 mL), and drying (sodium sulfate), removal of the solvent leaves the crude aldehyde, which is recrystallized, from toluene/hexane. Yield of the title compound: 9.9 g (81.8%) yellowish plates, mp=103° C. 1H-NMR (CDCl3, 300 MHz) δ 2.36 (s, 6H, N(CH3)2); 2.65-2.75 (m, 2H, CH2); 2.96-3.03 (m, 2H, CH2NMe2); 7.08 (d, 1H, 3J=2.7 Hz, H-2); 7.33 (d, 1H, 3J=8.4 Hz, H-7); 7.70 (dd, 1H, 4J=1.7 Hz, H-6); 8.13 (d, 1H, H-4); 8.74 (br s, 1H, NH); 10.02 (s, 1H, CHO). 13C-NMR (CDCl3, 75 MHz) δ 23.91 (CH2); 45.76 (CH3); 60.40 (CH2N); 111.85 (C-7); 116.68 (C-3); 122.87 (C-6); 123.61 (C-2); 124.04 (C-4); 127.68 (C-9); 129.35 (C-5); 140.06 (C-8); 192.56 (CHO).
Reaction SMILES: [Br:1]C1C=C(C(F)(F)F)C=CC=1N1CCOC2C=C(S(Cl)(=O)=O)C=CC1=2.Cl[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]1[CH2:42][CH2:41][O:40][C:39]2[CH:43]=[C:44]([S:47]([O:50][C:51]3[C:56]([F:57])=[C:55]([F:58])[C:54]([F:59])=[C:53]([F:60])[C:52]=3[F:61])(=[O:49])=[O:48])[CH:45]=[CH:46][C:38]1=2>>[Br:1][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]1[CH2:42][CH2:41][O:40][C:39]2[CH:43]=[C:44]([S:47]([O:50][C:51]3[C:56]([F:57])=[C:55]([F:58])[C:54]([F:59])=[C:53]([F:60])[C:52]=3[F:61])(=[O:49])=[O:48])[CH:45]=[CH:46][C:38]1=2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br

Procedure:
Perfluorophenyl 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate was prepared from INTERMEDIATE C according to the procedure used to prepare INTERMEDIATE F. MS (ESI, positive) m/z: 625.8 (M+Na).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.Cl.Cl.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:48][CH2:47][C:43]1[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cn1ccnc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1ccnc1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 1.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), C-(1-methyl-1H-imidazol-2-yl)-methylamine dihydrochloride (13.91 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((1-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (4.9 mg, 0.001 mmol, 13% yield): LCMS=525.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.24 (2 H, m), 7.70 (4 H, t, J=8.03 Hz), 7.52-7.64 (3 H, m), 7.00 (1 H, d, J=1.25 Hz), 6.88 (1 H, d, J=1.51 Hz), 5.18 (1 H, s), 4.40-4.58 (2 H, m), 3.60 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.0 min.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:34]2[CH2:39][CH2:38][CH2:37][C:36]([NH:41]C(=O)OC(C)(C)C)([CH3:40])[CH2:35]2)=[C:27]2[CH2:33][CH2:32][CH2:31][C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:34]2[CH2:39][CH2:38][CH2:37][C:36]([NH2:41])([CH3:40])[CH2:35]2)=[C:27]2[CH2:33][CH2:32][CH2:31][C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A mixture of tert-butyl {1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-methylpiperidin-3-yl}carbamate (8.4 mg, 0.012 mmol), DCM (0.12 mL) and TFA (0.12 mL, 1.6 mmol) was stirred at room temperature for 30 min. The solution was then concentrated under reduced pressure and the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a white powder (3.5 mg, 59%). LCMS calc. for C24H27F2N6OS (M+H)+: m/z=485.2. Found: 485.2.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:19]([O:16][C:15]1[CH:17]=[CH:18][C:10]([CH:9]=[O:8])=[CH:11][C:12]=1[O:13][CH3:14])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Triethylamine (2.8 liters, 20.1 moles) was added dropwise to a solution of vanillin (2.00 kg., 13.15 moles) and acetic anhydride (2.6 liters, 27.5 moles) in methylene chloride (11.3 liters) maintaining temperature below 25° C. After adding 4-dimethylaminopyridine (20 g.) the solution was stirred at room temperature for 30 minutes. The reaction mixture was washed twice with water, followed by 20% (w/w) hydrochloric acid and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to 8 liters. Hexane (15 liters) was added slowly while removing remaining methylene chloride. After cooling, 2.45 kg. (96% yield) product was filtered off. Recrystallization of a small sample from anhydrous ether gave the acetate as fine yellow needles, M.P. 76°-78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(OC(F)(F)F)cc1

Procedure:
Example 35 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-(trifluoromethoxy)benzene (20.6 μl) to give the title compound (0.0371 g). LC-MS (System A): Rt 2.57 mins, Mass Spectrum m/z 478 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: C#CCOc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of CuI and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[I:12]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:12])=[C:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: ClI
Reactant: Cc1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(Cl)nn2c1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Added to a solution of 7.00 g (41.8 mmol) of 6-chloro-2-methylimidazo[1,2-b]pyridazine (CAS 14793-00-1) in 300 ml of chloroform, cooled to 0° C., are 10.2 g (62.7 mmol) of iodine monochloride in solution in 20 ml of methanol. The reaction is then left at ambient temperature for 16 hours then poured over a mixture of a 5% sodium thiosulphate solution and of sodium hydrogen carbonate. The product is extracted with dichloromethane, the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].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>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](=[O:38])[NH:22][CH2:21][C:19]2[N:20]=[C:15]3[CH:14]=[CH:13][N:12]([S:2]([C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=4)(=[O:3])=[O:4])[C:16]3=[N:17][CH:18]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (34.0 g, 100 mmol, Example #5, Step C), (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambient temperature for about 45 min. The reaction was washed with saturated aqueous NaHCO3 (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was purified by chromatography on silica gel (330 g) using 33-100% EtOAc in heptane to give (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (53 g, 96%) as a pale-yellow foam: LC/MS (Table 1, Method b) Rt=2.40 min; MS m/z: 528 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]([C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)#[CH:25]>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:25]#[C:24][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#Cc1ccsc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ccccc2)cc1C#Cc1ccsc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and 3-ethynyl-thiophene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 95:5; yield (60 mg, 45%); 1H NMR δ (CDCl3): 7.78 (d, J=8.10 Hz, 2H), 7.60 (m, 1H), 7.46-7.29 (m, 4H), 7.22 (m, 1H), 6.77 (s, 1H), 4.05 (s, 3H); LCMS m/z: 264.