Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].O>C(O)(=O)C.[Cl-].[Na+].O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CN(C)S(=O)(=O)c1ccccc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 22 %

Procedure:
2.24 ml (47.4 mmol, 1.3 eq) of fuming nitric acid at 90% were added, over the course of 15 minutes, to a mixture of 7.17 g (35.6 mmol, 1 eq) of 2-hydroxy-N,N-dimethylbenzenesulfonamide in 35.5 ml of acetic acid in a bath at 5° C. The reaction medium was then stirred at ambient temperature. After one and a half hours, the reaction medium was hydrolyzed with water and brine. The reaction medium was then extracted with a 4/1 ethyl acetate/heptane mixture (2×100 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The solid obtained (8.66 g) was combined with GUL1537-178 and was chromatographed on silica gel (prepacked column, eluent heptane/(ethyl acetate+1% methanol), from 20% to 65% of (ethyl acetate+1% methanol)). A fraction enriched in ortho isomer was isolated, that is to say 3.7 g of a yellow solid. This solid was recrystallized from 40 ml of ethanol. 1.93 g of product were obtained in the form of a pale yellow solid. Yield=20%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[CH:37]=2)[NH:32]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]3[CH2:43][CH2:44][N:45]([C:21]([C:20]4[CH:24]=[CH:25][C:17]([O:16][C:13]5[N:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]6[CH:26]=[CH:27][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:4][CH:5]=6)=[CH:11][CH:12]=5)=[CH:18][CH:19]=4)=[O:23])[CH2:46][CH2:47]3)[CH:37]=2)[NH:32]1
Reactant: O=C1CCc2cc(CN3CCNCC3)ccc2N1
Reactant: O=C(O)c1ccc(Oc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(CN3CCN(C(=O)c4ccc(Oc5ccc(NC(=O)c6ccc(C(F)(F)F)cc6)cn5)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-[5-(4-trifluoromethylbenzoylamino)pyridin-2-yloxy]benzoic acid (4.30 g, 10.7 mmol) in DMF (150 mL) were added 1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-ylmethyl)-piperazine (2.6 g, 10.7 mmol), 1-hydroxybenzotriazole monohydrate (1.64 g, 10.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.46 g, 12.8 mmol) under ice cooling, and the resulting solution was stirred for 1 hour under ice cooling and for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. To the residue was added a saturated sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate, to thereby yield 5.24 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C:3]([N:5]1[CH2:10][CH2:9][N:8]2[N:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:7]2[CH2:6]1)=[O:4]>CO.[Pd]>[NH2:14][C:12]1[CH:13]=[C:7]2[CH2:6][N:5]([C:3](=[O:4])[CH:2]([CH3:1])[CH3:17])[CH2:10][CH2:9][N:8]2[N:11]=1
Reactant: CC(C)C(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)N1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 148a (220 mg, 0.924 mmol) in methanol (20 mL) was added Pd/C (22 mg). The system was evacuated and refilled with H2. After stirring at room temperature for 2 h, the mixture was filtered. The filtrate was concentrated under reduced pressure to afford 148b as a yellow solid (190 mg, 98%), which was used in the next step without further purification. MS-ESI: [M+H]+ 209.1
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOCCS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Combine allyl hydroxyethyl ether (1.02 g, 10 mmol), and diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain allyl methanesulfonylethyl ether: Rf=0.80 (silica gel, 20% ethyl acetate/dichloromethane).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:30])(C)(C)C.C(=O)([O-])O.[Na+]>Cl.C(OCC)(=O)C>[NH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29]4)=[O:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[F:30]
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To tert-butyl[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}amino)-2-fluorophenyl]carbamate (3.40 g, 7.67 mmol) was added 4N hydrochloric acid/ethyl acetate (50 mL), and the mixture was stirred at 0° C. overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic layer was concentrated under reduced pressure to give the title compound (1.70 g, 65%) as a purple powder.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH:15]=O)[CH:12]=2)=[CH:5][S:4][N:3]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:26]=[CH:25][C:24]([C@:27]23[CH2:32][C@H:31]2[CH2:30][NH:29][CH2:28]3)=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][C:2]1[C:6]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH2:15][N:29]3[CH2:30][C@H:31]4[C@:27]([C:24]5[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:34])[F:33])=[CH:26][CH:25]=5)([CH2:32]4)[CH2:28]3)[CH:12]=2)=[CH:5][S:4][N:3]=1
Reactant: Cc1nscc1-c1cn(CCC=O)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nscc1-c1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.5 %

Procedure:
3-[5-(3-methyl-4-isothiazolyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep 0.126 mmol) was dissolved in 1,2-Dichloroethane (DCE) (1 ml). (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P4, 28.6 mg, 0.126 mmol) and ACETIC ACID (0.022 ml, 0.378 mmol) were added and the mixture was stirred at rt for 15 minutes. Then it was cooled at 0° C. and SODIUM TRIACETOXYBOROHYDRIDE (29.4 mg, 0.139 mmol) was added. The mixture was stirred at 0° C. for 3 hours. The mixture was treated with NaHCO3 aqueous saturated solution (5 mL) and extracted with DCM (3×5 mL). The organic were filtered on a separatory cartridge, combined and dried to afford a crude that was submitted to LC preparative purification. Fraction collected was dried (rotary) to afford the title compound as a white solid (8.7 mg, 14% yield).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][OH:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[Br:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(CCO)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CCOCc2ccccc2)c1Br
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Sodium hydride (50% in oil) (1.7 g, 0.036 mol) was suspended in dry tetrahydrofuran (75 ml) in argon atmosphere. 2-(2-bromo-3-methylphenyl)-1-ethanol (7.0 g, 0.033 mol) solved in tetrahydrofuran (25 ml) was added dropwise during 30 min at room temperature. Benzyl bromide (6.2 g, 0.036 mol) was added and the reaction mixture was stirred at room temperature over night. Water (1.0 ml) was added carefully and the solvent was evaporated under reduced pressure. The residue was partitioned between water and diethyl ether and the water layer was extracted twice with diethyl ether. The ether extracts were combined, washed twice with water, and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane:methylene chloride (7:3) as eluent gave 7.5 g (74.3%) of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:46])([F:45])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]6[CH2:41][CH2:40][N:39](C([O-])=O)[CH2:38][CH2:37]6)=[O:35])[CH:32]=5)[NH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:36]1([C:34]([C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:46])([F:8])[F:45])=[N:11][N:12]=4)[N:15]=3)[CH2:20][CH2:21]2)=[O:35])[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]1
Reactant: O=C([O-])N1CCN(C(=O)c2ccc3[nH]cc(C4CCN(c5ccc6nnc(C(F)(F)F)n6n5)CC4)c3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1)N1CCNCC1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
TFA (1 mL) was added in one portion at ambient temperature to a stirred solution of tert-butyl [4-[3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]-1H-indole-5-carbonyl]piperazine-1-carboxylate (190 mg, 0.32 mmol) in DCM (2 mL). The resulting solution was stirred for 1 hour then applied to an SCX column and eluted with MeOH followed by 2M ammonia in MeOH. Pure fractions were combined and concentrated by evaporation then triturated with ether to give a solid which was collected by filtration and air dried to give 6-[4-[5-(piperazin-1-ylcarbonyl)-1H-indol-3-yl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (156 mg, 99%) as a colourless solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH2:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22](Br)[C:23]#[CH:24]>CC(C)=O>[CH2:24]([NH:21][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:23]#[CH:22]
Reactant: CCCCCCCCCCCCCCN
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCNCCCCCCCCCCCCCC

Procedure:
5 g (47 mmol) of anhydrous sodium carbonate are added to a solution of 10.0 g (47 mmol) of n-tetradecylamine in 100 ml of absolute acetone, and the suspension is heated to reflux. At that temperature 5.9 g (50 mmol) of propargyl bromide in 50 ml of acetone are then added dropwise and the mixture is subsequently heated at reflux for 2 hours. After aqueous working-up, the product is obtained in the form of a brown oil having a purity of >90%.
Reaction SMILES: I[Si](C)(C)C.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]2/[CH:36]=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])(=[O:18])=[O:17])(=[O:9])=[O:8].N>C(Cl)(Cl)Cl>[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2/[CH:36]=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])(=[O:17])=[O:18])(=[O:9])=[O:8]
Reactant: COC(=O)/C=C/c1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Agent: C[Si](C)(C)I
Agent: N
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Temperature: 20 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Methyl(E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]-acrylate can be obtained in the following way: 40 μl of iodotrimethylsilane are added dropwise to a solution, maintained under an atmosphere of argon, of 150 mg of methyl(E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1-tert-butoxycarbonylindazol-3-yl]acrylate in 10 ml of chloroform, and the mixture is stirred at a temperature in the region of 20° C. for 16 hours. 5 ml of an aqueous solution containing 5% of aqueous ammonia are then added and the medium is extracted with dichloromethane. The pooled organic extracts are washed with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The white foam thus isolated is recrystallized from 8 ml of acetonitrile. 19 mg of methyl(E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]-acrylate are thus obtained in the form of a white solid melting at 253° C. (analysis C18H17N3O6S2 % calculated C, 49.65; H, 3.93; N, 9.65; O, 22.04; S, 14.73. % found C, 49.14; H, 3.92; N, 9.47; S, 14.23).
Reaction SMILES: [H-].[K+].[CH2:3]([O:5][P:6]([CH2:11][S:12]([O:15][CH2:16][CH3:17])(=[O:14])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].Cl[CH2:19][C:20]1[C:25]([CH2:26]Cl)=[CH:24][CH:23]=[CH:22][N:21]=1>CS(C)=O>[CH2:3]([O:5][P:6]([O:8][CH2:9][CH3:10])([C:11]1([S:12]([O:15][CH2:16][CH3:17])(=[O:13])=[O:14])[CH:19]=[C:20]2[C:25]([CH:24]=[CH:23][CH2:22][NH:21]2)=[CH:26]1)=[O:7])[CH3:4]
Reactant: ClCc1cccnc1CCl
Reactant: CCOP(=O)(CS(=O)(=O)OCC)OCC
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)C1(S(=O)(=O)OCC)C=C2C=CCNC2=C1
Temperature: 90 °C

Procedure:
To an ice bath chilled solution of 35% potassium hydride in mineral oil (5.0 mmol) stirring under argon DMSO (7 ml) is added a solution of diethoxyphosphinyl methanesulfonic acid, ethyl ester (2.5 mmol) [prepared as described in J. C. Carretero, et. al., Tetrahedron, Vol. 43, pp. 5125-5134 (No. 21) 1987] in DMSO (5 ml). On completion of a dropwise addition, the resulting solution is stirred at room temperature for one hour. A solution of 2,3-bis(chloromethyl)pyridine (2.5 mmol) [prepared as described in K. Tsuda, et. al., Chem. Pharm. Bull., Vol.1, pp. 142, 1953] in DMSO (2 ml) is added slowly and the reaction mixture is then heated at 90° C. for 1 hour. After cooling, the reaction mixture is concentrated under reduced pressure and the desired product is purified by flash chromatography using a 5-15% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH2:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
[8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.067 g, 56%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.6 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.67 (t, J=7.4 Hz, 1H), 7.47 (t, J=8.0 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 6.99-6.91 (m, 3H), 6.57 (s, 1H), 3.17-3.12 (m, 4H), 2.97 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@@H:10]3[CH2:14][CH2:13][N:12]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[CH3:18])=[O:22])[CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Reactant: Cc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)N1CC[C@@H](Nc2nc3ccc(Cl)cc3o2)C1
Yield: 61.4 %

Procedure:
A mixture of 32.9 mg (0.12 mmol) (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride, 19.6 mg (0.144 mmol) 2-methyl-benzoic acid, 53.9 mg (0.168 mmol) TBTU and 77.5 mg (0.6 mmol) DIPEA in 2 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated, taken up in methanol and formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 26.2 mg (61%) of the title compound. (MH+) 356.1.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccnc(Nc2ccccc2)n1
Reactant: O=C1CCCC(=O)O1
Product: O=C(O)CCCC(=O)NCc1ccnc(Nc2ccccc2)n1
Yield: 51.4 %

Procedure:
By an analogous process to Method 13, 2-anilino-4-aminomethylpyrimidine (Method 12)(4.8 g, 24 mmol) was treated with glutaric anhydride (2.74 g, 24 mmol) to give the title compound (3.88 g, 51.7%) as a pale brown solid. NMR: 1.75 (m, 2H), 2.25 (t, 4H), 4.23 (d, 2H), 6.68 (d, 1H), 6.93 (t, 1H), 7.27 (t, 2H), 7.76 (d, 2H), 8.4 (d, 2H), 9.53 (s, 1H): m/z 315.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:7]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[N:15][CH:16]=2)[CH:8]=1.[Cl:33][C:34]1[N:39]=[C:38](Cl)[C:37]([Cl:41])=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:29]([O:28][C:26]([NH:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:36]2[C:37]([Cl:41])=[CH:38][N:39]=[C:34]([Cl:33])[N:35]=2)=[CH:8][C:7]=1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH:14]=[N:15][CH:16]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CN)ccc2NC(=O)OC(C)(C)C)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CNc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Yield: 41.5 %

Procedure:
To a solution of tert-butyl [5-(2-{5-(aminomethyl)-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.81 g, 1.8 mmol) and 2,4,5-trichloropyrimidine (0.45 g, 2.4 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.30 g, 9.37 mmol). The resultant mixture was stirred overnight at 45° C. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water, and then dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (0.44 g, 40%). LCMS for C28H35Cl2N6O4 (M+H)+: m/z=589.1, 591.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: COc1cccc(CCN)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Yield: 95 %

Procedure:
To a solution of 3-methoxyphenethylamine (1.93 mL, 13.2 mmol) and 2,4,5-trichloropyrimidine (1.59 mL, 13.9 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (5.5 g, 40 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a yellow gel (3.74 g, 95%). LCMS for C13H14Cl2N3O (M+H)+: m/z=298.0, 300.0.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)CCC.O>C1(C)C=CC=CC=1.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>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCOC(=O)c1ncsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ncsc1-c1nccs1

Procedure:
To a solution of ethyl 5-bromo-1,3-thiazole-4-carboxylate in toluene were added 2-(tributylstannyl)-1,3-thiazole and PdCl2(PPh3)2, followed by heating under reflux for 6 hours. Water was added thereto and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2,5′-bi-1,3-thiazole-4′-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:22]1[S:26][C:25]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(#N)C>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:22]3[S:26][C:25]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:24][CH:23]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OC
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1)C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 1.70 g. (6.32 mmol.) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 2.30 g. (6.32 mmol.) of dimethyl N-(5-bromothien-2-ylcarbonyl)-L-glutamate, 44 mg. of palladium chloride, 130 mg. of triphenylphosphine, 25 mg. of cuprous iodide, and 1.13 mL. of triethylamine in 30 mL. of acetonitrile was heated at reflux for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue column chromatographed (Waters 500) eluting with 1:19 methanol:methylene chloride to yield dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6yl}ethynyl)thien-2ylcarbonyl]-L-glutamate, m.p. 228°-230° C. Anal. Calc. for C26H27N5O7S: C, 56.41; H, 4.92; N, 12.65; S, 5.79. Found: C, 56.64; H, 4.77; N, 12.88; S, 5.58.