Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:17]1)[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(NC2CCN(CC(=O)OCC)CC2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCCn1c(NC2CCN(CC(=O)O)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of 5.5 parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetate, 15 parts of a sodium hydroxide solution 1N, 100 parts of water and 16 parts of ethanol was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was taken up in water, washed with dichloromethane and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (80:20 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1 part (19.1%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetic acid; mp. 227.3° C. (compound 182).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18](O)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[CH3:24][NH:25][CH3:26]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([N:25]([CH3:26])[CH3:24])=[O:19])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (60 mg) was reacted with dimethylamine Hydrochloride similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3,N3-dimethyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 41.3 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3,N3-dimethyl-5,6-dihydroimidazo[1,2-d][1,4]benz oxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 401 (M)+. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.24 (s, 1H), 7.02 (d, J=10.5 Hz, 1H), 6.58 (s, 1H), 5.51 (s, 1H), 4.61-4.48 (m, 2H), 4.39-4.12 (m, 2H), 3.01 (s, 3H), 2.88 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:53])[CH:26]([C:28]1[CH:33]=[CH:32][C:31](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:30][CH:29]=1)[CH3:27]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:53])[CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:32][CH:33]=1)[CH3:27]
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.086 g, 0.29 mmol), triethyl amine (3 mL), copper(I)iodide (0.026 g, 0.14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained as a brown oil (0.067 g, 54%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[CH2:16][CH2:17][C:18]4[NH:19][C:20](=[O:23])[CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[K+].[Br-]>CO.C(Cl)(Cl)Cl>[O:23]=[C:20]1[NH:19][C:18]2[CH2:17][CH2:16][N:15]3[C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[CH:3]=[O:2])=[N:11][CH:12]=[C:13]([C:14]=23)[CH:22]=[CH:21]1
Reactant: COC(OC)c1cccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)c1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)c1

Procedure:
1-(3-Dimethoxymethyl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (31a) was isolated during flash silica gel column chromatography as a by-product in the form of a white solid: mp=182-185° C.; Rf=0.15 (5% MeOH/CHCl3); IR (KBr) 2361, 1653, 1458, 1091, 1046 cm−1; 1H NMR (DMSO-d6) δ 3.31 (s, 6H), 3.52-3.54 (m, 2H), 4.45-4.46 (m, 2H), 5.50 (s, 1H), 7.36 (t, 1H, J=7.8 Hz), 7.58-7.60 (m, 2H), 7.81-7.92 (m, 4H), 8.43-8.45 (m, 1H). HRMS calcd for C19H19N3O3 337.1426 (M+), found 337.1415. Anal. (C19H19N3O3) C, H, N, O.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:9][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:8][CH:7]=1
Reactant: Nc1cc(Cl)ccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-Bromo-5-chloroaniline (CAS#823-57-4; 5 g), 4-fluorophenylboronic acid (3.56 g) and cesium carbonate (31.6 g) were combined in THF (70 ml) and water (35 ml). The mixture was degassed by bubbling argon through the solution. After addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (886 mg) the reaction mixture was stirred 1 h at 80° C. in a sealed tube. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2SO4, evaporated and purified by chromatography (silica gel, 0% to 30% EtOAc in heptane). The product was finally bulb-to-bulb distilled at 0.3 mbar and 120-130° C. oven temperature to give the title compound (5.07 g) as a light yellow liquid.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8](O)([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8](=[CH2:12])[C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CC(O)(C(N)=O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: C=C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
To a solution of 0.05 moles of p-carboxy-α-hydroxyhydratropamide in 50 cc. of acetic acid is added 5 cc. of concentrated sulfuric acid. The mixture is heated on the steam-bath for 1/2 hour, then concentrated in vacuo. Addition of water to the residue and filtration gives p-carboxyatropamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](OC)=[O:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.CO>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CCC(CNC(=O)OC(C)(C)C)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCC1CCc2cc(CO)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
In dichloromethane (10 ml), (2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (0.47 g) was dissolved, followed by the dropwise addition of diisobutylaluminum hydride (a 0.95M hexane solution, 3.6 ml) at an external temperature of −78° C. The resulting mixture was stirred for 90 minutes without changing the temperature. Methanol was added to the reaction mixture, followed by heating to room temperature. The insoluble matter was filtered off through Celite. The filtrate was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1), whereby colorless crystals (0.31 g, 72%) were obtained. A portion of the crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:37]=[C:36]3[C:32]([CH2:33][NH:34][C:35]3=[O:38])=[CH:31][CH:30]=2)O1>>[O:38]=[C:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:37]=2)[CH2:33][NH:34]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc3c(c2)C(=O)NC3)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)C(=O)NC4)ccn2c1=O
Yield: 87.8 %

Procedure:
Methyl 8-(3-oxoisoindolin-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (106.5 mg, 0.41 mmol). The precipitate was rinsed with DCM and dried in a vacuum stove to afford the title compound as a yellow solid (116 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16](C=O)=[CH:15][CH:14]=2)[N:8]=1.O1CCN(C2CCC=CC2)CC1.[C:34]12(CS(O)(=O)=O)[C:41](C)(C)[CH:38](C[CH2:40]1)[CH2:37][C:35]2=[O:36].Cl>C(OCC)(=O)C.O.C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([CH:40]=[C:34]3[CH2:41][CH2:38][CH2:37][C:35]3=[O:36])=[CH:17][CH:18]=2)[N:8]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: Cc1cc(-c2cccc(-c3ccc(C=O)cc3)n2)c(C)[nH]1
Agent: C1=CCC(N2CCOCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(-c2cccc(-c3ccc(C=C4CCCC4=O)cc3)n2)c(C)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask equipped with Dean-Stark trap topped with a condenser and N2 inlet were added 552 mg (2.0 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-formylphenyl)-pyridine, 20 mL benzene, 0.384 mL (2.4 mmol) 4-morpholino-1-cyclohexene, and 10 mg camphorsulfonic acid. The solution was refluxed with removal of water for 13 hours cooled, and 25 mL 3N hydrochloric acid added. The mixture was stirred at room temperature for 1 hour then diluted with ethyl acetate and water. The organic layer was separated, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated. The crude oil solidified on standing, 460 mg (˜100%), and was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[OH:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22]([C:21]1[CH:27]=[CH:28][C:29]2[O:30][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[O:18][C:19]=2[CH:20]=1)=[O:23])[CH3:26]
Reactant: Clc1cccc(C(Cl)(Cl)c2cccc(Cl)c2)c1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Product: CCOC(=O)c1ccc2c(c1)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2

Procedure:
This compound was prepared from bis-(3-chloro-phenyl)-dichloromethane and ethyl 3,4-dihydroxybenzoate according to Example 269d; yellow viscous oil, MS: m/e=415 ([M+H]+).
Reaction SMILES: OS(O)(=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3:11].N#N.[AlH3].[CH3:15][N:16]([CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=2)[NH:22][CH:21]=1)[CH3:17].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C1COCC1.CO.CCOCC.O>[AlH3:11].[CH:37]([C:36]([NH2:16])=[O:41])=[O:38].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH3:15][N:16]([CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=2)[NH:22][CH:21]=1)[CH3:17]
Reactant: [Al+3]
Agent: CN(C)CCc1c[nH]c2ccc(Cc3ccccc3)cc12
Agent: N#N
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C=O
Reaction time: 1 h

Procedure:
A solution of AlH3 was prepared by addition of c.H2SO4 (1.59 g) dropwise to a cooled (ice-bath) suspension of LiAlH4 (1.226 g) in dry THF (82 mL) over 20 min. The mixture was them left to stand under dry N2 for 1 hr to allow the solids to settle. A solution of the glyoxamide (0.59 g, 1.926 mmol) in THF (110 mL) was prepared, and in a N2 atmosphere, the AlH3 solution (55 mL) was added over 5 min. The mixture was stirred for 16 hr and then H2O was added dropwise to quench excess reagent, and the THF was evaporated in vacuo. The residue was partitioned between 1M HCl/CH2Cl12 and after re-extraction of the aqueous layer (2×; CH2Cl2), the combined organic layers were washed with 1M HCl and then saturated aqueous NaCl, dried (MgSO4) and evaporated to a solid. Chromatography (silica gel; CH2Cl2 /EtOH containing 2% concentrated aqueous NH3 ; 0-12%), gave the free base: 1-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane, as a gum, 0.246 g (46%). This was treated with oxalic acid (0.07 g) in MeOH (2 mL) and Et2O added until crystallisation commenced. The product: 1-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane oxalate, was obtained as white granular crystals, 0.191 g (27%), m.p.158°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5](O)=[O:6].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:69][O:70][C:71](=[O:75])[CH2:72][CH2:73][NH2:74].C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[CH3:69][O:70][C:71](=[O:75])[CH2:72][CH2:73][NH:74][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH:12]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:2]([F:1])[CH:3]=1
Reactant: CCCCCCC(Oc1ccc(C(=O)O)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC(=O)CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 101.9 %

Procedure:
Combine 3-Fluoro-4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid (0.033 g, 0.07 mmol), PyBOP (0.044 g, 0.084 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.0195 g, 0.14 mmol) and triethyl-amine (0.04 mL, 0.28 mmol) in N,N-dimethyl-formamide (1.5 mL). Stir for sixteen hours at room temperature. Dilute reaction with ethyl acetate and water. Wash organic layer with water two times then wash with saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter and concentrate under reduced pressure. Purify on silica gel chromatography (30-80% Ethyl acetate/hexanes gradient) to provide 0.04 g of title compound (99%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH:31]([CH3:32])[CH2:30][O:29][C:28]4=[O:33])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:35][O:36][CH3:37]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([N:14]([CH2:35][O:36][CH3:37])[C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH:31]([CH3:32])[CH2:30][O:29][C:28]4=[O:33])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC1COC(=O)N1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cccc(Cl)c1)c1nccc(-c2ccnc(N3C(=O)OCC3C)c2)n1
Reaction time: 5 h

Procedure:
Potassium t-butoxide (0.235 g, 2.1 mmol) is added at room temperature to a solution of 3-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-4-methyl-oxazolidin-2-one (0.5 g, 1.3 mmol). After stirring the mixture for 10 minutes chloromethylmethylether (0.17 g, 2.1 mmol) in THF (3 ml) is added. The mixture is stirred for additional 5 hours at this temperature. Dilution with ethyl acetate, washing with brine, drying over magnesium sulfate, filtering and evaporation of the solvent gives the title compound in form of a slightly colored oil; 1H-NMR (DMSO): 8.70 (s, 1H); 8.51 (d, 1H); 8.48 (d, 1H); 7.68 (d, 1H); 7.47–7.23 (m, 5H); 5.39 (s,2H); 4.87–4.74 (m,1H); 4.50 (dd, 1H); 4.08 (dd,1H); 3.25 (s,3H); 1.33 (d,3H).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:21][CH:20]3[N:22]([CH3:23])[CH:17]([CH2:18][CH2:19]3)[CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(Cl)(OCC1C=CC=CC=1)=O.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CO.Cl.[OH-].[Na+].[OH-].[OH-].[Pd+2]>[CH3:23][N:22]1[CH:20]2[CH2:19][CH2:18][CH:17]1[CH2:16][CH:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[CH2:21]2
Reactant: CN1C2CCC1CC(N1CCN(Cc3ccccc3)CC1)C2
Agent: [Pd+2]
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Solvent: CO
Product: CN1C2CCC1CC(N1CCNCC1)C2
Temperature: 0 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
A solution of 1-benzyl-4-(N-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine hydrochloride (14.8 g, 36.4 mmol) in methanol (150 ml) and 6N HCl (32 ml) was hydrogenated at a pressure of 2.0 atm (30 psi) in the presence of 20% palladium hydroxide on carbon (1.5 g) for 12 h. The mixture was then filtered through a pad of celite. The celite pad was washed with MeOH (50 ml) The filtrate and the washings were combined and concentrated to afford a yellow viscous oil. This oil was dissolved in 2N NaOH (150 ml) and to the solution was dropwise added CBZCl (10.4 g, 72.8 mmol) under ice bath cooling. The mixture was stirred at 0° C. for 5 h. To the mixture was dropwise added 2N HCl at 0° C. to pH 1. The aqueous solution was washed with EtOAc (50 ml×2) to remove bis-(benzyloxycarbonyl)piperazine. The aqueous layer was concentrated in vacuo to give a Z-protected compound. This was dissolved in MeOH (150 ml) and 6N HCl (32 ml) was hydrogenated in the presence of 20% palladium hydroxide on carbon (1.5 g) for 12 h. The mixture was basified with 6N NaOH to pH10. The mixture was filtered through a celite pad and the pad was washed with MeOH (50 ml). The filtrate and the washings were combined and concentrated. The residue was dried azeotropically with EtOH and then toluene. The residue was dissolved in EtOH (150 ml) and insoluble inorganic material was filtered off. The filtrate was concentrated in vacuo to give a white solid and the solid was washed with EtOH-Et2O (1:50) to give the title compound as a white solid (6.4 g, 84%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[CH:48][C:47]([Cl:52])=[CH:46][N:45]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:44]([Cl:43])=[N:45][CH:46]=[C:47]([Cl:52])[CH:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cc(Cl)cnc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(Cl)cnc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,5-dichloro-3-(chloromethyl)pyridine and isolated as light-yellow gum. MS(m/e): 442.3 (MH+).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[C@@H:4]12[O:9][C@@H:8]1[CH2:7][CH:6]([C:10]([O:12][CH3:13])=[O:11])[CH2:5]2>CCOCC.[Cu]I>[CH2:1]([C@H:8]1[C@H:4]([OH:9])[CH2:5][C@@H:6]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1)[CH3:2]
Reactant: [Li]CC
Reactant: COC(=O)C1C[C@@H]2O[C@@H]2C1
Agent: [Cu]I
Solvent: CCOCC
Product: CC[C@@H]1C[C@H](C(=O)OC)C[C@H]1O
Temperature: -25 °C
Reaction time: 1 h

Procedure:
To a suspension of copper(I) iodide (4.95 g, 26.0 mmol) in 50 ml ether at −25° C. was added ethyllithium (1.7M, 30.6 ml, 52.0 mmol) dropwise. The solution was stirred for 1 hr at −25° C. followed by dropwise addition of an ether solution (50 ml) of methyl (1S,5R)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (1.848 g, 13 mmol) maintaining at −25° C. The reaction was allowed to warm to rt until TLC showed complete reaction. Cooled in ice and quenched with NH4Cl (sat)(5 ml) and stirred for 10 minutes. Filtered thru celite and washed with ether (3×10 ml) and the combined filtrates were washed with brine and dryed over sodium sulfate. Silica gel chromatagraphy on a 25 g Biotage SNAP column with 10-50% MTBE/Hexane afforded title compound. 1H NMR (500 MHz, CDCl3) δ 0.96 (t, J=7.3 Hz, 3H), δ 1.24-1.48 (m, 2H), δ 1.54-1.77 (m, 3H), δ 1.83-1.90 (m, 1H), δ 2.12-2.29 (m, 2H), δ 3.02 (m, 1H), δ 3.69 (s, 3H), δ 3.98 (m, 1H)
Reaction SMILES: [ClH:1].Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.[Br:30][C:31]1[C:32]([C:38]2[S:42][C:41]3[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:40]=3[CH:39]=2)=[N:33][C:34]([Cl:37])=[N:35][CH:36]=1.NCCCN1CCN(C)CC1>>[ClH:37].[ClH:1].[ClH:37].[Br:30][C:31]1[C:32]([C:38]2[S:42][C:41]3[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:40]=3[CH:39]=2)=[N:33][C:34]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[N:35][CH:36]=1
Reactant: COc1cccc2cc(-c3nc(Cl)ncc3Br)sc12
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: COc1cccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Br)sc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 5-bromo-2-chloro-4-(7-methoxy-benzo[b]thiophen-2-yl)-pyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a yellow solid. ES+(m/z) 476 (79Br) and 478 (81Cl) [M+H].
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:8][C@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:17])[CH3:16]
Reactant: O[C@@H](CC1CCCC1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CC1CCCC1)c1ccccc1
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of 406 mg (2.13 mmol) of (S)-2-cyclopentyl-1-phenylethanol (from Step C) in 9 mL of pyridine was treated with 1 mL of acetic anhydride. After stirring for 6 h, the reaction was concentrated. Flash chromatography on silica gel using 93:7 v/v hexanes/EtOAc afforded 495 mg (100%) of the title compound: RF: 0.75 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.10-1.21 (m, 2H), 1.44-2.04 (m, 9H), 2.05 (s, 3H), 5.75 (dd, J=8.0, 6. 1, I H), 7.25-7.34 (m, 5H).