Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>CC#N>[CH3:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)NCC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(c1ccccc1)N(C(=O)CCC(=O)O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
25.5 g (255 mmol) of succinic anhydride and 20.3 ml (146 mmol) of NEt3 were added in succession to a solution of 16.3 g of the crude product 7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline from a) in MeCN (300 ml) and the mixture was stirred for 16 h at RT. It was then concentrated to small volume under vacuum. The residue was taken up with DCM (400 ml). It was then washed with a saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (2×400 ml). The collected organic phases were washed with 1N aqueous hydrochloric acid (400 ml) and with brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (gradient heptane/EE 1:1 heptane/EE/AcOH 2:2:1) of the residue and subsequent crystallisation of the residue from EE produced 6.79 g (21 mmol, 24% over 2 stages) of 4-(7-methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]([CH3:55])[CH2:50][CH2:51][CH2:52][NH:53][CH3:54]>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:53]([CH3:54])[CH2:52][CH2:51][CH2:50][N:49]([CH3:55])[CH3:48])=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CNCCCN(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N(C)CCCN(C)C)nc3)cn2)cc1
Yield: 72.2 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-48 and N,N,N′-trimethyl-1,3-propanediamine (67 μl, 0.46 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Step B in Example 1-D-48, amination was carried out, to obtain a crude product of N-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-N,N′,N′-trimethyl-propan-1,3-diamine as a pale yellow solid (162 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-116) as a colorless powder (67 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][Cl:34]>CN(C=O)C.O.CCOCC>[Cl:34][CH2:33][CH2:32][CH2:31][O:14][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:6][C:5]=1[O:4][C:3]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=1[F:1]
Reactant: ClCCCBr
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCCCCl)cc21
Temperature: 80 °C

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.015 g, 0.05 mmol) in DMF (1 mL) was added Cs2CO3. The reaction mixture was stirred for 30 minutes before the addition of 1-bromo-3-chloropropane (0.01 g, 0.08 mmol) and then was heated to 80° C. for 25 hours. After cooling the mixture to room temperature, the reaction mixture was diluted with water and ether and the layers separated. The aqueous layer was extracted with ether and the combined organic layers were washed with 1N NaOH, water, and brine. The crude mixture was dried over Na2SO4 and concentrated under reduced pressure to afford the product with a small impurity. The crude mixture was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:39][CH3:40])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[O:13])[S:10][CH:11]=1.NN>CO>[NH2:17][CH2:16][C@@H:15]([NH:14][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH2:39][CH3:40])[N:4]=[CH:3][C:2]=2[Br:1])[CH:8]=1)=[O:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36]
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CO
Product: CCn1ncc(Br)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (250 mg, 0.39 mmol) was dissolved in MeOH (5 mL) and treated with NH2NH2 (0.5 mL, 15.93 mmol). The mixture was stirred at RT overnight, and concentrated. The residue was purified by column chromatography [silica, 2-10% MeOH in CHCl3 (0.5% NH4OH)] affording the free base of the title compound, which was treated with HCl(aq) in MeOH to give the title compound (144 mg, 51%) as an off white solid: LC-MS (ES) m/z 502 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.93-7.87 (m, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.57-7.51 (m, 2H), 7.43 (t, J=6.6 Hz, 1H), 4.67 (m, 1H), 4.25 (q, J=7.3 Hz, 2H), 3.37-3.11 (m, 4H), and 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:16]=[C:17](\[CH2:21][CH2:22][CH3:23])/[C:18]([OH:20])=[O:19])=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.BrC1C(=O)C2C(=CC=CC=2)C(=O)C=1/C=C(\C)/C(O)=O>CC(C)=O>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH2:21][CH2:22][CH3:23])/[C:18]([OH:20])=[O:19]
Reactant: CCC/C(=C\c1c(Br)c(OC)c2ccccc2c1OC)C(=O)O
Agent: C/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC(C)=O
Product: CCC/C(=C\C1=C(Br)C(=O)c2ccccc2C1=O)C(=O)O

Procedure:
Compound 39b was prepared from 99f (0.078 g, 0.21 mmol) as described above for 39a to give 0.033 g (0.10 mmol, 46%) of the product as a yellow solid following flash chromatography (3:7 acetone:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCCNC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCN(C)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-methyl-propan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 333 (M+, 0.3), 304 (4), 87 (6), 86 (bp), 84 (7), 58 (10).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:33]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:27]5[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.Br[C:36]1[CH:49]=[CH:48][C:39]2[O:40][C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][C:42]=3[C:38]=2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:47][C:44]1[CH:45]=[CH:46][C:41]2[O:40][C:39]3[CH:48]=[CH:49][C:36]([C:9]4[CH:10]=[CH:11][C:12]([C:15]5[CH:16]=[CH:17][C:18]([N:21]6[C:22]7[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=7[C:28]7[C:33]6=[CH:32][CH:31]=[CH:30][CH:29]=7)=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[CH:37][C:38]=3[C:42]=2[CH:43]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)cc2)OC1(C)C
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2oc3ccc(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)cc4)cc3c2c1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 43.7 %

Procedure:
A mixture of 9-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)-9H-carbazole (1.75 g, 4.42 mmol), 2,8-dibromodibenzo[b,d]furan (2.52 g, 7.74 mmol), tetrakis(triphenylphosphine) palladium(0) (0.25 g, 0.22 mmol), potassium carbonate (1.83 g, 13.26 mmol), 1,4-dioxane (40.00 mL), and water (8.00 mL) was degassed with bubbling argon for 30 minutes. The reaction mixture was then heated to 80° C. and was stirred overnight (16.5 hours), maintaining an argon atmosphere. Consumption of the starting material was confirmed by thin-layer chromatography and the reaction was cooled to room temperature. The product was extracted with dichloromethane, dried, and purified by silica gel column chromatography with dichloromethane in hexanes as the eluent. The product fractions were then dried and the product was collected to yield Compound 15 (1.09 g, 44%). Confirmed by LCMS (APCI): calculated for C36H22BrNO (M+H): 564. Found: 564.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][C:23]1[N:24]=[C:25]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[S:26][C:27]=1[C:28](O)=[O:29]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28]([C:27]4[S:26][C:25]([C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[N:24][C:23]=4[CH3:22])=[O:29])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1nc(-c2cccnc2)sc1C(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2sc(-c3cccnc3)nc2C)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-4-methyl-2-(pyrid-3-yl)thiazole-5- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 4-methyl-2-(pyrid-3-yl)thiazole-5-carboxylic acid using method D. NMR; δH CDCl3 9.18,(1H, b), 8.72,(1H, b), 8.27,(1H, d), 7.84,(2H, d), 7.59,(1H, s), 7.55,(1H, dd), 7.45-7.40,(4H, m), 7.30,(1H, d), 6.27,(1H, t), 3.36,(2H, m), 2.83,(3H, s), 2.25,(3H, s), 1.09,(1H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.41 min, MH+483.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.OCC[O:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:2][CH:1]=[O:5])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCOc1ccc(O)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCc1ccc(O)cc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of oxalyl chloride (2.0 ml) and dichloromethane (20 ml), previously cooled to -78° in a dry ice/acetone bath, is added dropwise over 5 min a solution of DMSO (3.4 ml) and methylene chloride (5 ml). The mixture is stirred at -78° for 5 min and then allowed to warm to 0° in an ice bath. To the mixture is added dropwise a solution of 4-(2-hydroxyethoxy)-phenol (1.54 g) in methylene chloride (15 ml) over 10-15 min. The mixture is stirred at 0° for 30 min. triethyl amine (7 ml) is added dropwise and the mixture allowed to warm to 20°-25°. The mixture is diluted with methylene chloride (25 ml) and washed with hydrochloric acid (5%, 50 ml), twice with water (50 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave an oil that is flash chromatographed on silica gel (25 g) eluting with ethyl acetate/hexane (33/67) to give 4-hydoxyphenylacetaldehyde which is carried on immediately by the addition of 2,6-bis(1-pyrrolidinyl)-4-(1-piperazinyl)pyrimidine (PREPARATION A-22, 0.79 g) and methanol (10 ml). To the mixture is added sodium cyanoborohydride (0.16 g) and the mixture is stirred at 20°-25° for 18 hr. The mixture is treated with aqueous hydrochloric acid (10%, 10 ml) HCl at 0° and the methanol removed at reduced pressure. The residue is distributed between ethyl acetate (50 ml) and water (40 ml). The aqueous phase is brought to pH 8 with aqueous potassium hydroxide (45%) at 0° and then extracted methylene chloride (2×50 ml). The combined extracts are dried over sodium sulfate and the solvent removed at reduced pressure to give a foam that is flash chromatographed on silica gel (35 g) eluting with hexane/ethyl acetate (33/67) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH:6]([C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]2[C:18](=[O:40])[CH:19]([NH:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:4]2[S:3]1.O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CC(C)=O>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[NH2:20][CH:19]1[C:18](=[O:40])[N:5]2[CH:6]([C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]([CH3:41])([CH3:1])[S:3][C@H:4]12
Reactant: CN(Cc1ccccc1)C(=O)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CN(Cc1ccccc1)C(=O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.3 %

Procedure:
To a solution of 2,2-dimethyl-6-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam (200 mg) in acetone (2 mL) was added p-toluenesulfonic acid monohydrate (70 mg). The solution was stirred at room temperature for 11/2 hours and the acetone was removed in vacuo. Trituration of the residue with ether and vacuum drying gave partially impure 6-Amino-2,2-dimethyl-3-(N-methyl-N-benzylcarbamoyl)penam p-toluenesulfonic acid salt (200 mg).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:19][C:20]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[Br:30]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OCC)(=O)C>[Br:30][CH2:29][C:28]1[C:20]([Cl:19])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)O)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(CBr)c1Cl
Temperature: 85 °C

Procedure:
Benzoyl peroxide (1.33 g) was added to a suspension of 2-chloro-3-methylbenzoic acid (25 g) and N-bromosuccinimide (28.7 g) in chlorobenzene (250 mL) and the resulting mixture was heated to 85° C. for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous brine (3×100 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated. The beige solid was recrystallised from ethyl acetate (˜75 mL)/isohexane (˜250 mL) to give the subtitled compound as a white solid. Yield 25.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][C:10]=2[Cl:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:10]1[N:11]=[C:12]([N:14]2[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]2)[S:13][C:9]=1[C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][N:25]=2)[CH:3]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2sc(N3CCCNC(=O)C3)nc2Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccnc(Nc2cc(C)cc(-c3sc(N4CCCNC(=O)C4)nc3Cl)c2)n1
Temperature: 80 °C
Yield: 23.9 %

Procedure:
A sealed tube was charged with a stir bar, 4-[5-(3-amino-5-methylphenyl)-4-chloro-1,3-thiazol-2-yl]-1,4-diazepan-2-one (45 mg, 0.134 mmol), 2-chloro-4-methoxypyrimidine, (20 mg, 0.138 mmol), potassium carbonate (37 mg, 0.268 mmol), Pd2(dba)3 (13 mg, 0.013 mmol), and dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (X-Phos, 31.8 mg, 0.067 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed t-amyl alcohol (450 μl) was added, the tube was sealed and heated at 80° C. for 16 h with stirring. The reaction mixture was then cooled and filtered through a celite plug, which was rinsed with 10% isopropanol in CHCl3. The eluent was concentrated and purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water (30-100%), providing 4-(4-chloro-5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one (19 mg, 0.032 mmol, 29.1%) as a TFA salt. APCI: [M+H]+ m/z 440.1. 1H NMR (500 MHz, dmso) δ9.65 (s, 1H), 8.19 (d, J=5.7, 1H), 7.90 (s, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 6.98 (s, 1H), 6.29 (d, J=5.7 Hz, 1H), 4.15 (s, 2H), 3.93 (s, 3H), 3.76 (s, 2H), 3.23 (s, 2H), 2.28 (s, 3H), 1.77 (s, 2H). rhSYK activity=+++.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:29](/[CH:30]=[CH:31]/[CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:29]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:11]3[CH:12]=[C:13]([C:16]([N:18]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3cccc(Cl)c3)c(/C=C/CN3CCCCC3)c2c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3cccc(Cl)c3)c(CCCN3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
In a 15 mL sealed tube were added compound of Example 72i.e. (E)-2-(3-chlorophenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (160 mg, 0.299 mmol), trifluoroacetic acid (0.069 ml, 0.896 mmol), and triethylsilane (0.143 ml, 0.896 mmol) in chloroform (5 ml) and the mixture was heated to 80-100° C. overnight, cooled down to room temperature and assayed for conversion by HPLC/LCMS. LC indicated homogenous peak but LCMS indicated the presence of both olefin and saturated compounds. Then 140 μL of TFA and 280 μL of triethylsilane were added and the mixture was heated to 100° C. for 5 days and cool down to room temperature. Saturated sodium bicarbonate was slowly added and the separated organic layer was washed with brine and dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was dissolved in DMF and purified on a reverse-phase Zorbax SB-C18 column 21.2×100 mm and was eluted with MeOH-water-0.1% TFA. Isocratic 30% for 3 minutes then Gradient: 30% to 100% MeOH over 14 minutes. LCMS m/z 537.3 (M+H)+, ret. time=2.55 min.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:4].[OH-].[Na+]>CO>[C:23]([O:22][C:20]([N:6]1[CH2:7][C@@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OCC(Cl)(Cl)Cl)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ((2S,4S)-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (360 mg, 0.83 mmol) in MeOH (20 mL) was added aq. 1N NaOH (1.66 mL, 1.66 mmol). The reaction was stirred at RT for 16 h then was concentrated. The residue was acidified with aq 2N HCl to pH 3, extracted with EtOAc (2×25 mL). The organic phases were joined, dried over Na2SO4, filtered and concentrated. The crude residue was used without further purification in the next step. MS (UPLC): 421 [M+H]+, 419 [M−H]−; tR (HPLC conditions f): 1.00 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(OC(=O)C)(=[O:19])C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Product: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Temperature: 80 °C
Yield: 73 %

Procedure:
4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol) was heated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20 mL) and aqueous 1 N NaOH (15 mL). The resulting black solution was concentrated to a volume of 15 mL, and the solid was filtered off, rinsed with CH2Cl2 and dried under vacuum to provide the title compound (1.29 g, 73%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H), 7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4, 2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:24])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>CN(C(OC)OC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:24])[C:10]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]1)=[CH:10][N:11]([CH3:16])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1
Agent: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1 mmol of tert-butyl 4-[2-(2,4-dichlorophenyl)-2-oxoethyl]piperazinecarboxylate was heated to 80 °C. in neat N,N-dimethylformamidedimethyl acetal for six hours. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether to obtain tert-butyl 4-{2-(2,4-dichlorophenyl)-1-[(dimethylamino)methylene]-2-oxo-ethyl}piperazinecarboxylate.