Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[C:25]([C:38](O)=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:55][C:56]([NH2:59])([CH3:58])[CH3:57].Cl>CN(C=O)C>[C:56]([NH:59][C:38]([C:25]1[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:36])([F:37])[F:35])=[CH:27][C:22]([CH2:21][N:10]2[C:11](=[O:20])[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[CH:23][CH:24]=1)=[O:39])([CH3:58])([CH3:57])[CH3:55]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)NC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
30 mg (0.05 mmol) of the compound from Example 141 were initially charged in 0.75 ml of DMF, and 9 mg (0.074 mmol) of HOBt and 13 mg (0.07 mmol) of EDC were added. After 10 min of stirring at RT, 6 μl (0.06 mmol) of 2-methylpropane-2-amine were added, and the mixture was stirred at RT for 16 h. 50 μl of 1 N hydrochloric acid were then added, and the mixture was directly purified chromatographically [Method 19]. This gave 8.2 mg (24% of theory) of the target compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:55][O:56][C:57](=[O:71])[C:58]1[CH:63]=[CH:62][C:61](CN2C=CC(N)=N2)=[CH:60][CH:59]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[CH3:55][O:56][C:57](=[O:71])[C:58]1[CH:63]=[CH:62][C:61]([CH2:48][N:45]2[CH:46]=[CH:47][C:43]([NH:42][C:40](=[O:41])[C@@H:39]([C:31]3[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:29]([Cl:28])[CH:30]=3)[CH2:49][CH:50]3[CH2:51][CH2:52][CH2:53][CH2:54]3)=[N:44]2)=[CH:60][CH:59]=1
Reactant: COC(=O)c1ccc(Cn2ccc(N)n2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 0 °C

Procedure:
Triphenylphosphine (310 mg, 1.18 mmol) was dissolved in methylene chloride (4 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (238 mg, 1.34 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1; 259 mg, 0.79 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for another 30 min. After such time 4-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (182 mg, 0.79 mmol) and 2,6-lutidine (274 μL, 2.36 mmol) were added dropwise as a solution in methylene chloride (4 mL) and the reaction was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate (80 mL), washed with water (2×20 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) followed by recrystallization from 25% ethyl acetate/hexanes afforded the desired product. The reaction procedure was scaled up by a factor of two according to the same procedure. The combined batches afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (840 mg, 65%) as a beige powder: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.2, found 544.5 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2H, CH2), 1.33-1.80 (m, 8H, 4×CH2), 1.99-2.19 (m, 1H, CH), 3.32 (s, 3H, SO2CH3), 3.82 (s, 3H, CO2CH3), 3.84-3.92 (m, 1H, CH), 5.28 (s, 2H, NCH2), 6.48 (d, J=2.2 Hz, 1H, Ar), 7.29 (d, Jo=8.5 Hz, 2H, Ar), 7.55 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (d, J=2.2 Hz, 1H, Ar), 7.90 (d, Jo=8.5 Hz, 2H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [CH:1]1([CH2:5][CH:6](C(O)=O)[C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CO>[CH:1]1([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCC1)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)CCC1CCC1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
2-Cyclobutylmethyl-malonic acid (1.20 g, 6.9 mmol) was heated at 195° C. for 2 h. After this time, the resulting brown solution was cooled to 25° C. and diluted with a 90/10 methylene chloride/methanol solution (50 mL). The organics were then washed with a saturated aqueous sodium chloride solution, concentrated in vacuo and azeotroped with acetonitrile (2×10 mL) to afford 3-cyclobutyl-propionic acid (770 mg, 85%) as brown oil. The material was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O.[Cu](I)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:27]#[C:26][C:22]2[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:5]=1
Reactant: C#Cc1cccc(O)c1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reaction time: 0.08 h

Procedure:
A solution of 4-(difluoromethoxy)phenyl iodide (4.70 g) in deoxygenated dimethylformamide was treated with trans-dichlorobis(triphenylphosphine) palladium(II) (244 mg) and copper(II) iodide 66 mg) followed by triethylamine (7.52 mL), stirred under a nitrogen atmosphere for 5 min., treated with 3-hydroxyphenyl acetylene (2.467 g), stirred under nitrogen atmosphere for 16 h, poured into ethyl acetate and was washed with 0.05 N HCl and water. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed, silica gel, 40% ethyl acetate/hexane as eluent, to afford 3-((4-(difluoromethoxy)phenyl)ethynyl)phenol as a tan solid, 5.40 g; 1H NMR (DMSO-d6): δ 9.64 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.27 (t, J=73.7 Hz, 1H), 7.17 (d, J=8.8 Hz, 2H), 7.16 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), and 6.77 (m, 1H); MS (ES neg) m/z 260.
Reaction SMILES: [OH:1][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:3].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:25]([O:3][C:2]([CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:8][CH:7]=1)=[O:1])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Reactant: CCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=CC(=O)OCCCCC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 250-mL round-bottom flask were added 2-methyl-acrylic acid 6-[4-(2-hydroxycarbonyl-vinyl)-phenoxy]-hexyl ester (4.98 g, 15.0 mmol), 1-pentanol (1.785 mL, 16.5 mmol) and 4-dimethylaminopyridine (DMAP,92 mg, 0.75 mmol) as solids and a stirbar. The flask was purged with N2, followed by the addition of CH2Cl2 (35 mL). The suspension was stirred at room temperature for 20 min to give a white slurry. The flask was cooled in an ice bath and N,N′-dicyclohexylcarbodiimide (DCC, 3.25 g, 15.75 mmol) was introduced. The mixture quickly became a light yellow solution, which was then removed from the ice bath and stirred at room temperature. After 20 h, the resulting white slurry was loaded on a SiO2 column (˜100 g) for quick purification. The product was eluted off with 10% EtOAc in hexanes. The fractions with the desired product were combined, concentrated and then dried in vacuo to a clear oil, which turned into a white solid (Addition Monomer 6) upon cooling (5.45 g, 90%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=2[CH:4]=[C:3]([C:14]([O:16]C)=[O:15])[N:2]=1.[OH-].[Na+]>CO.O>[CH:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1
Reactant: COC(=O)c1cc2oc3ccccc3c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2oc3ccccc3c2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Methyl benzofuro[3,2-c]pyridine-3-carboxylate (2.02 g, 8.89 mmol) is dissolved in MeOH (50 ml) and water (10 ml). 2M NaOH (5.3 ml, 10.67 mmol) is added dropwise, and the reaction stirred overnight at rt. When the reaction is complete by TLC, the volatiles are removed in vacuo. The solid residue is suspended in water (40 ml) and the pH is adjusted to 3 with concentrated HCl. The white slurry is filtered, and the cake is dried first in a stream of air and then in a vacuum oven overnight, affording 1.84 g (97%) of benzofuro[3,2-c]pyridine-3-carboxylic acid as a pale yellow solid. 1H NMR (DMSO-d6) δ 7.56 (t, J=8 Hz), 7.68 (t, J=7 Hz), 7.877 (d, J=8 Hz), 8.38 (m), 9.51 ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13](CC#N)=[CH:12][CH:11]=2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[K+].[CH2:27]([OH:29])[CH3:28]>>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:28][C:27]([OH:25])=[O:29])=[CH:12][CH:11]=2)=[C:4]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1
Reactant: CCO
Reactant: [OH-]
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Agent: [K+]
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1
Temperature: 80 °C

Procedure:
A mixture of the product from step (iv) (51.7 g) and 5 M KOH (517 g) in ethanol (204 g) was heated at 80° C. for 4 hours. After the solvent was evaporated under reduced pressure, the residue was diluted with water (259 mL) and washed with t-butyl methyl ether (390 g) at 25° C. The solution was cooled to 5° C. and the pH of the solution was adjusted to pH 5 with conc. HCl. The resulting precipitate was collected by filtration, washed with a solution of water (200 mL) and MeCN (200 g) and dried to afford the subtitle compound as a solid, 57.0 g; containing 4.5% weight of water; 1H NMR DMSO-d6: 7.12 (d, 2H), 7.02 (d, 2H), 6.32 (t, 1H), 5.94 (brs, 2H), 3.71 (s, 2H), 3.46 (s, 2H), 3.27-3.23 (m, 2H), 2.00 (s, 3H), 1.48-1.41 (m, 2H), 1.27-1.21 (m, 2H), 1.18-1.13 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:22]([N:24]=CN(C)C)=[N:23][C:18]3=[CH:17][CH:16]=2)=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:10]=1.C(O)(=O)C.Cl.[OH-].[Na+]>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]2[N:20]=[C:19]3[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)=[C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:10]=1
Reactant: CC(C)Cn1c(N=CN(C)C)nc2ccc(-c3c(-c4ccccc4)nc(-c4c(F)cccc4F)n3C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccccc4)nc(-c4c(F)cccc4F)n3C)nc21
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Heat N′-{5-[2-(2,6-difluorophenyl)-3-methyl-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl}-N,N-dimethylformamidine (0.02 g, 0.04 mol) in 1:1 glacial acetic acid:concentrated HCl (0.6 mL) at 100° C. for 30 min. Cool to RT. Add CH2Cl2 and water, neutralize with 5N NaOH to about pH=7 with rapid stirring. Extract the aqueous phase 3× with CH2Cl2, combine organic layers, wash with saturated aqueous NaCl and dry over Na2SO4. Filter and concentrate to give the title compound (0.02 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH:21]=[CH:20][CH:19]=[N:18]4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>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.O>[N:17]1([C:13]2[CH:12]=[C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:24]5[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=5)=[CH:3][C:4]4=[N:10][CH:9]=3)[CH:16]=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=[N:18]1
Reactant: Clc1ccn2c(-c3cccc(-n4cccn4)c3)cnc2c1
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: c1cncc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1

Procedure:
7-Chloro-3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridine (Intermediate AA) (1 eq, 0.214 mmol, 70 mg) and 3-pyridine boronic acid (1 eq, 0.214 mmol, 26.1 mg) are dissolved in DME (3 ml), EtOH (1 ml) and water (1.5 ml) and Na2CO3 (2 eq, 0.427 mmol, 53.0 mg) is added. Pd(PPh3)4 (0.06 eq, 0.01 mmol, 15 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 3-(3-pyrazol-1-yl-phenyl)-7-pyridin-3-yl-imidazo[1,2-a]pyridine as a light brown solid; [M+H]+=338
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[CH3:9][C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][N:2]([CH3:3])/[CH:4]=[CH:9]/[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccncc1C#N
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccncc1C#N
Temperature: 35 °C

Procedure:
940 ml of DMF dimethyl acetal are added to a solution of 200 g of 4-methylnicotinonitrile in 940 g of DMF, and the mixture is heated under reflux at 120-110 for 3 days. The mixture is cooled to 35° C., poured into 10 liters of ice-water and cooled at 4° C. for 16 h. The precipitate is filtered off, washed with water and dried, giving 263 g of 4-((E)-2-dimethylaminovinyl)nicotinonitrile; M˜173.22 g/mol; M+H found 174, NMR corresponds.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1>>[CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH:20][C:29](=[O:30])[CH2:28][N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(NC2CCCCCCC2)=N3)CC1
Yield: 61.6 %

Procedure:
Prepared from N2-cyclooctyl-4H-benzo[d][1,3]oxazine-2,6-diamine (150 mg, 0.55 mmol) and and 4-methylpiperazin-1-acetic acid (95 mg, 0.60 mmol) according to the procedure described for example 93. Obtained the title compound as a brown solid (140 mg, 62%), MS (ISP) m/e=414.4 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][C:25]1([CH3:31])[CH2:30][CH2:29][CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC1(C)CCCNC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: CC1(C)CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3,3-dimethylpiperidine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 40-65% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (33 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 6H) 1.45 (s, 6H) 1.50 (t, J=6.06 Hz, 2H) 1.80 (br. s., 2H) 3.51 (s, 2H) 3.65 (t, J=5.05 Hz, 2H) 6.33 (d, J=2.02 Hz, 1H) 7.39 (s, 1H) 7.60 (d, J=8.34 Hz, 2H) 8.00 (d, J=8.34 Hz, 2H) 8.08 (d, J=2.02 Hz, 1H) 10.85 (s, 1H). ESI-MS: m/z 408.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:8])=[CH:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:7][C:6]1[CH:5]=[C:4]([Cl:8])[S:3][C:2]=1[Cl:1]
Reactant: Cc1cc(Cl)sc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)c(Cl)s1
Yield: 91.1 %

Procedure:
To a stirred solution of 2,5-dichloro-3-methylthiophene (25.8 g, 154 mmol) in carbon tetrachloride (47 mL) was added N-bromosuccinimide (27.5 g, 154 mmol) and benzoyl peroxide (310 mg, 1.28 mmol). The mixture was heated at reflux temperature for 8 hours. After cooling, the insolubles were filtered off. The filtrate was washed with aqueous sodium sulfite solution, dried over MgSO4, and concentrated in vacuo. The residue was fractionally distilled under reduced pressure (bp 80° C., 0.5 mmHg) to give the subtitle compound (34.5 g, 91% yield).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[C:11](=[O:20])[N:12]([CH3:19])[C:13](=[O:18])[N:14]([CH3:17])[C:15]=1[NH2:16]>CN(C)C1C=CC=CC=1>[N:12]1([C:11](=[O:20])[C:10]2[NH:9][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[N:16][C:15]=2[N:14]([CH3:17])[C:13]1=[O:18])[CH3:19]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: O=C1CCCC(=O)O1
Solvent: CN(C)c1ccccc1
Product: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O

Procedure:
A mixture of 31.3 g glutaric anhydride, 25 g 5.6-diamino-1,3-dimethyl uracil, and 300 ml N,N-dimethyl-aniline was heated under reflux for 4 hours. Upon cooling, the product crystallized from the dark, clear reaction mixture. The crystals were collected by filtration, washed with benzene, then with methanol, and dried affording 187 g light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:20][C:5]2[N:6]=[C:7]([NH:18][NH2:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[Cl:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+].C(Cl)Cl>C(O)(=O)C>[Cl:1][C:2]1[S:20][C:5]2[N:6]3[C:23]([CH2:22][Cl:21])=[N:19][N:18]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2sc(Cl)cc2C(c2ccccc2Cl)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: ClCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.7 g of 7-chloro-5-(o-chlorophenyl)-2-hydrazino-3H-thieno[2,3-e]-1,4-diazepine are introduced, with cooling at 15° C., into 15 ml of glacial acetic acid and a solution of 0.25 g of chloroacetyl chloride in 5 ml of glacial acetic acid is slowly added dropwise thereto. The mixture is then stirred for a further 2 hours, treated with 0.3 g of sodium acetate and stirred for 1 hour. The solution is poured on to ice-water, neutralized and shaken out with methylene chloride. After evaporation of the solvent, the residue is refluxed with 30 ml of absolute xylene for 1 hour. After evaporation of solvent, the residue is recrystallized from ethyl acetate containing active carbon to yield 2-chloro-9-chloromethyl-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 101°-103° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)OC(C)(C)C)CC3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.2 %

Procedure:
tert-Butyl 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarboxylate (375 mg, 0.787 mmol) was taken up in CH2Cl2 (12 mL) before adding TFA (3 mL). The reaction was stirred at room temperature overnight. The reaction was evaporated to dryness, and the residue was azeotroped with DCE (3×) to provide 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclopropanecarboxylic acid (TFA salt) (421 mg, 100%) as a yellow solid. MS ESI: [M+H]+ m/z 421.0. 1H NMR (600 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.21 (s, 1H), 8.80 (d, J=4.8, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.44 (s, 1H), 7.25 (d, J=4.9, 1H), 7.12 (s, 1H), 2.29 (s, 3H), 1.81-1.62 (m, 4H). rhSYK activity=+++
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)([CH3:4])[CH3:3].Cl.Cl.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C@H:27]([NH2:29])[CH3:28])[CH:23]=[N:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH:27]([NH:29][C:15]([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[CH:6]=3)[CH:11]=2)=[O:17])[CH3:28])[CH:23]=[N:22]1
Reactant: Cc1c([C@@H](C)N)cnn1C
Reactant: CC(C)(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(C)NC(=O)c2ccc3cc(C(C)(C)O)ccc3c2)cnn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a DMF (3 ml) solution of 6-(1-Hydroxy-1-methyl-ethyl)-naphthalene-2-carboxylic acid (U.S. Pat. No. 4,638,087, published 20 Jan. 1987, 95 mg, 0.413 mmol), Amine 9 (1-(5-Methyl-1H-pyrazol-4-yl)ethanamine dihydrochloride, 95 mg, 0.352 mmol), HBTU (188 mg, 0.495 mmol) and triethylamine (0.173 ml, 1.24 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with sat. NaHCO3 aq and water, and the product extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (Ethylacetate:Hexane=2:1) to give the title product as a white solid (84.4 mg, 58.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.46-1.49 (3H, d), 1.50-1.53 (6H, s) 2.22-2.24 (3H, s) 3.67-3.68 (3H s) 5.13-5.20 (2H, m) 7.38-7.39 (1H, s) 7.69-7.72 (1H, d) 7.81-8.00 (4H, m) 8.39-8.40 (1H, s) 8.68-8.72 (1H, d). MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=C([CH:19]=[CH:20][CH:21]=2)C(O)=O)[CH2:9][CH2:8]1>C(Cl)Cl.CN(C=O)C>[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:1]([CH:19]=[CH:20][CH:21]=2)[C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoic acid (0.28 g) in methylene chloride (10 ml) which contained DMF (2 drops). The reaction mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated and azeotroped with toluene to give 3-morpholinobenzoyl chloride (0.3 g); Mass M+H 222.