Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Br.[NH:12]([C:19]1[C:24]([Br:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=2[F:34])[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[NH:12]([C:19]1[C:24]([Br:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:7][CH:9]3[O:11][CH2:10]3)=[CH:29][C:28]=2[F:34])[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)c(F)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(OCC2CO2)ccc1Nc1ncc(Br)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Potassium carbonate (1.1 g, 8.01 mmol) and epibromohydrin (402 mg, 2.94 mmol) were added to a solution of 4-anilino-5-bromo-2-(2-fluoro-4-hydroxyanilino)pyrimidine (Method 5; 1.0 g, 2.67 mmol) in DMF (3 ml), and the suspension was stirred at room temperature for 16 hours. Volatile material was removed by evaporation and the residue was stirred vigorously in water. The solid remaining was collected by filtration and dried under vacuum to give the product (1.1 g, 98%). MS (MH+): 431.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:28]1([CH2:33][C:34](Cl)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:33][C:34]([N:18]([CH:16]2[CH:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CC1CCCC1
Product: CN(C(=O)CC1CCCC1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 88, the title compound 2-cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using cyclopentylacetyl chloride instead of 4-fluorobenzoyl chloride and was obtained as a light yellow oil. MS m/e: 520.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.[CH3:11][Si](C[Mg]Cl)(C)C.C(OCC)C>C1COCC1>[CH2:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH:9]=[CH2:11]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=CCCc1cccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCc1cccnc1
Reaction time: 0.25 h

Procedure:
3-(Pyridin-3-yl)propanal (10 g, 74 mmol) is dissolved in THF (200 ml), and thereto is added a solution of trimethylsilylmethyl magnesium chloride in diethyl ether (100 ml, 100 mmol) under ice-cooling, and the mixture is stirred for 15 minutes. The reaction is quenched with a saturated brine (10 ml), and the mixture is extracted with ethyl acetate (300 ml×2), washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added THF (50 ml) and conc. sulfuric acid (5 ml), and the mixture is heated under reflux for 20 minutes. After being allowed to cool, the reaction solution is neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (200 ml×2). The organic layer is washed with a saturated brine (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(3-butenyl)pyridine (6.5 g) as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]S(O)(=O)=O>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(I)cc(I)c1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)c1cc(I)cc(I)c1

Procedure:
To a solution of 3,5-diiodobenzoic acid (6.8 g, 18.18 mmol) in methanol (200.0 ml) was added CH3SO3H (0.5 ml). The reaction mixture was heated to reflux. After refluxing for 7.5 hours, most of the methanol was removed. Then, water (200.0 ml) was added and a dark-brown solid was collected by filtration. The product was purified by silica gel column chromatography using hexanes/ethyl acetate (8:2) as eluent. The final pure white product was obtained in the amount of 4.2 g (59.2%) by recrystallization from methanol/water:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH2:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH:29][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CNC(=O)OCc3ccccc3)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57012.8 %

Procedure:
To a solution of (2S,4S)-1-BOC-2-(aminomethyl)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine (410 mg, 1 mmol) prepared in Step A in DCM (10 ml) was slowly added dropwise benzyl chloroformate (200 mg, 1.2 mmol) at 0° C., and stirred at rt for 3 h. After the reaction finished, the solvent was concentrated in vacuo, the residue was extracted with water and EtOAc, and the organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (310 g, 72%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)O1.I[C:21]1[CH:22]=[N:23][O:24][C:25]=1[CH3:26].CC1C(P(C2C(C)=CC(C)=C(S([O-])(=O)=O)C=2)C2C(C)=CC(C)=C(S([O-])(=O)=O)C=2)=CC(S([O-])(=O)=O)=C(C)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C.Cl>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:25]1[O:24][N:23]=[CH:22][C:21]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: Cc1oncc1I
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])cc1P(c1cc(S(=O)(=O)[O-])c(C)cc1C)c1cc(S(=O)(=O)[O-])c(C)cc1C
Solvent: CC#N
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1oncc1-c1ccc(CC(=O)O)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 0.50 g (1.91 mmol) 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl)phenylacetic acid in 1.90 ml CH3CN and 1.90 ml water was added 0.48 g (2.29 mmol) 4-iodo-5-methyl-isoxazole, 0.08 g (0.12 mmol) TXPTS, 0.01 g (0.05 mmol) Palladium (II) acetate, and 0.54 mL (3.82 mmol) diisopropylamine. After 20 min in the microwave at 120° C., the reaction mixture was cooled, acidified to a pH of 1 with 1N HCl, extracted with CH2Cl2, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo and afforded 0.57 g of ([4-(5-methylisoxazol-4-yl)phenyl]acetic acid that was used without further purification. 1H NMR (CDCl3, 400 MHz) 7.50-7.47 (m, 2H); 7.39-7.33 (m, 3H); 7.32-7.26 (m, 1H); 3.70 (s, 2H). Electrospray mass spec M+H=218.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:22]2[N:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH2:28](B(O)O)[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.[Ag-]=O>[CH:18]1([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][C:10]([NH:9][C@H:8]([C:22]3[N:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[C:5]3[CH:6]=[CH:7][C:2]([CH2:28][CH2:29][CH3:30])=[CH:3][CH:4]=3)=[O:21])=[CH:13][CH:14]=2)[CH2:20][CH2:19]1
Reactant: CCCB(O)O
Reactant: Cn1cc([C@@H](NC(=O)Cc2ccc(C3CC3)cc2)c2ccc(Br)cc2)nn1
Agent: Cl[Pd]Cl
Agent: O=[Ag-]
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1ccc([C@H](NC(=O)Cc2ccc(C3CC3)cc2)c2cn(C)nn2)cc1
Yield: 30.6 %

Procedure:
To a solution of 0.086 g (0.202 mmol) N-[(S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-(4-cyclopropylphenyl)acetamide in 1.0 ml THF was added 0.021 g (0.243 mmol) n-propylboronic acid, 0.017 g (0.020 mmol) PdCl2(dppf)-CH2Cl2 adduct, 0.084 g (0.607 mmol) solid potassium carbonate, and 0.117 g (0.607 mmol) Silver(I) oxide. The reaction mixture was irradiated in the microwave at 150° C. for 30 mins. The resulting solution was diluted with CH2Cl2, washed twice with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to afford 0.024 g (30.6%) 2-(4-cyclopropylphenyl)-N-[(S)-(1-methyl-1H-1,2,3-triazol-4-yl)(4-propylphenyl)methyl]acetamide. 1H NMR (CDCl3, 400 MHz) 7.25 (m, 1H); 7.17-7.02 (m, 8H); 6.68 (d, J=8.24 Hz, 1H); 6.25 (d, J=7.78 Hz, 1H); 4.03 (s, 3H); 3.56 (s, 2H); 2.54 (t, J=7.42 Hz, 2H); 1.90-1.84 (m, 1H); 1.65-1.55-(m, 2H); 0.97-0.90 (m, 5H); 0.69-0.65 (m, 2H). HRMS (ES) [M+1]+ calcd for C24H28N4O: 389.2341. Found: 389.2343.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:19]1([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCc3c(ncnc3Nc3ccccc3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(Nc2ncnc3c2CCNC3)cc1
Reaction time: 24 h
Yield: 110.5 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine (1.5 g, 3.8 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 0.95 g of material as a yellow solid (quant.), which was used as such for the next step.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Cl[CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[K+].O>C1(C)C=CC=CC=1>[C:14]1([CH:13]=[CH:12][CH2:11][N:1]2[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)C1CCNCC1
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(CC=Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
A mixture of 60.0 g of isonipecotamide (4-piperidinecarboxamide), 75.0 g of (3-chloropropenyl)benzene and 72 g of potassium acid carbonate suspended in 700 ml of toluene are heated with stirring at their reflux temperature for a period of 4 hours. The reaction mixture is cooled, water added thereto and filtered. The crude product is washed with water, ether and recrystallized from a 5:1 ethanol/water mixture to yield 99.4 g of 1-(3-phenyl-2-propenyl)-4-piperidinecarboxamide as light beige needles having a m.pt. of 189.5°-191.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10].OS(O)(=O)=O.O=S(=O)=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Nc1ccc(Cl)c(S(=O)(=O)O)c1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
128 parts of p-chloroaniline are added, in portions, at a maximum temperature of 85° C. to 238 parts of 100% sulfuric acid. The mixture is then stirred for 15 minutes at 65° C. until a clear solution forms. This sulfuric acid solution is run into 420 parts of 66% oleum over 30 minutes, while keeping the temperature at 65°-70° C. by cooling with an ice bath. The reaction mixture is stirred for 2 hours at 70° C. to bring the reaction to completion and to give 4-chloroaniline-3-sulfonic acid. The batch is then heated to 160° C. and stirred for 3 hours at this temperature. After cooling to 50° C., the sulfonation mixture is poured into 1100 parts of ice/water, and the resulting clear solution is partially neutralised with 400 parts of a 50% solution of potassium hydroxide. The monopotassium salt of 4-chloroaniline-2,5-disulfonic acid slowly precipitates and is filtered with suction and dried under vacuum, affording 260 parts of 62.0% 4-chloroaniline-2,5-disulfonic acid, corresponding to a yield of 56%, based on p-chloroaniline. The purity is >97% (analysis by HPLC).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[F:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([F:43])=[C:21]([NH:20][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)o1
Yield: 69 %

Procedure:
In the same manner as in Example 55 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (57.2 mg, 0.405 mmol), tetrahydrofuran (5 mL), thionyl chloride (70.0 μL, 0.807 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (114 mg, 69%) was obtained as a pale-brown solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][OH:15])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=CNc1cccc(C(=NO)C(=O)O)n1
Solvent: ClCCl
Product: O=CNc1cccc(C(=NOC(=O)C(Cl)Cl)C(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
A mixture of 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), dichloroacetyl chloride (7.6 g.) and methylene chloride (100 ml.) was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with diethyl ether and dried to give 2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (4.6 g.), mp 88° to 90° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@@H:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:25][C:20]1[C:19]([OH:22])=[CH:18][CH:17]=[C:16]2[C:21]=1[N:13]([CH2:12][C@@H:11]([NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:23])[N:14]=[CH:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)c(Br)c21)NC(=O)OCc1ccccc1

Procedure:
A solution of benzyl (S)-2-(6-hydroxy-1H-indazol-1-yl)-1-methylethylcarbamate (3.00 g, 9.23 mmol) from Step A in tetrahydrofuran (30 mL) was cooled in an ice bath, small portions of N-bromosuccinimide (1.64 g, 9.23 mmol) were added and the mixture was stirred for a few minutes followed by the addition of a saturated aqueous solution of sodium sulfite (150 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried over magnesium sulfate, filtered, and evaporated to a white solid (3.76 g): mp 40° C.; LC/MS m/z 404/406.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[C:7](\[CH3:13])/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH3:16]
Reactant: CCO
Reactant: C/C(=C\C(N)C(=O)O)CP(=O)(O)O
Agent: Cl
Product: CCOC(=O)C(N)/C=C(\C)CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are placed in 50 ml of ethanol and the whole is saturated with hydrogen chloride gas for21/2 hours at 50°. After concentration, the residue is dissolved in 20 ml of ethanol, 20 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/ethanol (1:3) yields E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 193°-194°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH3:19])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O.O>[N:1]1([CH2:6][CH2:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[C:11]=2[CH3:19])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]c2ccccc2c1C(=O)CCn1ccnc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(=O)CCn2ccnc2)c2ccccc2n1C
Reaction time: 1 h

Procedure:
A mixture of 3-(1H-imidazol-yl)-1-(2-methyl-1H-indol-3-yl)-1-propanone (148 mg), and potassium carbonate (0.7 g) in dimethylsulphoxide (5 ml) was stirred for 1 h and treated with iodomethane (0.10 g). The mixture was stirred for a further 4 h then diluted with water and extracted with ether (200 ml total). The combined organic extracts were washed with water, dried and evaporated to give the title compound which was crystallised from ethyl acetate to give a solid (80 mg), m.p. 151°-152°; λmax (EtOH) 246.5 nm (ε12,940), λmax 268.5 nm (ε8,740), λmax 306.5 nm (ε12,215).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]([C:9]1[S:10][C:11]([C:14]2[N:18]3[N:19]=[C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[CH:12][CH:13]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:32]=[C:28]1[CH2:29][CH2:30][CH2:31][N:27]1[CH2:26][CH2:25][CH2:24][NH:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3[S:10][C:9]([C:7]([NH2:6])=[O:8])=[CH:13][CH:12]=3)=[CH:15][N:16]=2)[N:19]=1
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cnc4ccc(NCCCN5CCCC5=O)nn34)s2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(-c2cnc3ccc(NCCCN4CCCC4=O)nn23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To 50 mg (0.094 mmol) of N-(2,4-dimethoxybenzyl)-5-(6-((3-(2-oxopyrrolidin-1-yl)propyl)amino)imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxamide dissolved in 1 mL DCM was added 5 mL of TFA. The resulting solvent was stirred at rt for 0.5 hr and then concentrated. It was purified in the PREP HPLC to obtain 26 mg (72%) of the desired product. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.04 (quin, J=7.39 Hz, 4H) 2.33-2.41 (m, 2H) 3.45-3.60 (m, 6H) 6.76 (d, J=9.85 Hz, 1H) 7.64-7.72 (m, 2H) 7.75 (d, J=4.04 Hz, 1H) 7.94 (s, 1H); LRMS (ESI) m/e 385.0 [(M+H)+, calcd for C18H20N6O2S 384.0].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.CC(=C)C.S(=O)(=O)(O)O>[C:2]([O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:7])([CH3:3])[CH3:1]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 72 h

Procedure:
The benzyloxycarbonyl-L-proline thus obtained (180 g.) is dissolved in a mixture of dichloromethane (300 ml.), liquid isobutylene (800 ml.) and concentrated sulfuric acid (7.2 ml.). The solution is shaken in a pressure bottle for 72 hours. The pressure is released, the isobutylene is allowed to evaporate and the solution is washed with 5% sodium carbonate, water, dried over magnesium sulfate and concentrated to dryness in vacuo, to obtain benzyloxycarbonyl-L-proline tert.butyl ester, yield 205 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[C:7]([O:11]CC2C=CC(OC)=CC=2)[N:6]=[CH:5][C:4]=1[C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[OH:11][C:7]1[N:6]=[CH:5][C:4]([C:21]2[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=2)=[C:3]([O:2][CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: COc1ccc(COc2ncc(-c3ccn(C)n3)c(OC)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(-c2ccn(C)n2)cnc(O)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A mixture of 4-methoxy-2-((4-methoxybenzyl)oxy)-5-(1-methyl-1H-pyrazol-3-yl)nicotinonitrile obtained in Step C (0.81 g) and trifluoroacetic acid (2.6 g) was stirred at room temperature for 15 min, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent (5 mL) of isopropyl ether/ethyl acetate=1/1, and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (0.57 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[CH:33]2)[CH:20](N1C(=O)CCC1=O)O>C(O)CO>[CH3:17][NH:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:19]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:20][N:1]=3)[N:4]=2)=[CH:13][N:12]=1)=[O:15]
Reactant: CNC(=O)c1ccc(-c2cnc(N)nn2)cn1
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Solvent: OCCO
Product: CNC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(3-amino-1,2,4-triazin-6-yl)-N-methylpyridine-2-carboxamide (Step 1, 6.5 g, 0.022 mol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (8.71 g, 0.0273 mol, Example 1, Step 7) in 1,2-ethanediol (100 mL) was stirred at 120° C. overnight. The reaction mixture was concentrated. The mixture was neutralized to pH=10 with methylamine in THF solution (2.0M), and then purified by flash chromatography on a silica gel column with 5% MeOH in dichloromethane to afford the desired product which was contaminated with some starting material. The product was dissolved in 10% MeOH in dichloromethane, and concentrated to a volume of about 2 mL. The resulted solid was filtered, washed with MeOH (2 mL) to afford the pure product (4.50 g, 50%). The product was treated with 2N HCl (aqueous) and acetonitrile, and dried by lyophilization to give the desired product as the HCl salt. LCMS (M+H)+: m/z=396.4. 1H-NMR (400 MHz, DMSO-d6): 9.40 (s, 1H), 9.27 (s, 1H), 9.20 (d, J=5.5 Hz, 1H), 9.10 (d, J=8.0 Hz, 1H), 8.64 (d, J=8.0 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.20 (d, J=8.0, Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 5.5 Hz, 1H), 4.76 (s, 2H), 2.81 (s, 3H).