Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].C(N(CC)CC)C.Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.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>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:21][N:22]=[C:23]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[CH:36][CH:37]=3)[N:24]=2)[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: C#Cc1cccc(C(=O)OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 120 °C
Yield: 57.3 %

Procedure:
To a nitrogen de-gassed solution of methyl 3-ethynylbenzoate (I31) (0.105 g, 0.655 mmol) in dry DMF (6 mL) were added triethylamine (0.308 mL, 2.18 mmol) followed by tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I3) (0.250 g, 0.546 mmol), triphenylphosphine (0.021 g, 0.082 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.038 g, 0.055 mmol) and Cu(I)I (0.016 g, 0.082 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I32) (0.182 g, 57% yield) as an orange solid; 1H NMR (400 MHz, d6-DMSO) δ 10.28 (brs, 1H), 8.78 (s, 1H), 8.16-8.03 (m, 2H), 7.90 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 3.90 (s, 3H), 3.50-3.41 (m, 4H), 3.11-2.99 (m, 4H), 1.42 (s, 9H). LCMS Method C: rt 6.82 min; m/z 582.2 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:6])[CH2:3][OH:4].[F:12][C:13]1[N:18]=[C:17](F)[C:16]([F:20])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:8]([O:7][C@@H:5]([CH3:6])[C@H:2]([NH:1][C:15]1[C:16]([F:20])=[CH:17][N:18]=[C:13]([F:12])[N:14]=1)[CH2:3][OH:4])([CH3:10])([CH3:9])[CH3:11]
Reactant: Fc1ncc(F)c(F)n1
Reactant: C[C@H](OC(C)(C)C)[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](OC(C)(C)C)[C@@H](CO)Nc1nc(F)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a round bottom flask containing (2R,3S)-2-amino-3-(tert-butoxy)butan-1-ol (1.25 g, 7.75 mmol) and a stir bar was added acetonitrile (50 mL) followed by the addition of 2,4,5-trifluoropyrimidine (1.04 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol). The resulting reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Reaction mixture was then partitioned between EtOAc and water. Aqueous layer extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a viscous yellow oil of (2R,3S)-3-(tert-butoxy)-2-((2,5-difluoropyrimidin-4-yl)amino)butan-1-ol (1.56 g, 5.67 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) δ 1.15 (s, 9H) 1.32 (d, J=6.26 Hz, 3H) 3.45 (br. s., 1H) 3.67 (d, J=11.35 Hz, 1H) 3.85-3.92 (m, 1H) 4.27 (d, J=11.74 Hz, 1H) 6.29 (d, J=5.48 Hz, 1H) 7.87 (d, J=2.35 Hz, 1H). LCMS m/z 276.4 (M+H)+, Rt 0.71 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.Cl.[CH3:16][C:17]1([NH2:20])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:20][C:17]1([CH3:16])[CH2:19][CH2:18]1)[C:8]([CH3:13])=[N:7]2
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(F)c(Br)c2nc1NC1(C)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To a 15-mL glass reaction vial was added 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (2.02 g, 7.33 mmol), 1-methylcyclopropanamine hydrochloride (ChemBridge, San Diego, Calif.) (1.420 g, 13.20 mmol) and DIEA (5.10 mL, 29.3 mmol) in DMSO (6 mL). The reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was cooled to RT and poured over ice water. The precipitated orange solid was filtered, washed with water (2×5 mL), ether (2×5 mL). The orange solid was dried overnight to afford 1.77 g of 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclopropyl)quinoxalin-2-amine (610a). The filtrate was extracted with EtOAc (2×10 mL). The organic extracts were washed with water and dried over Na2SO4, and concentrated in vacuo to give the crude material as an orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography (with a gradient of 0-20% EtOAc in hexanes) to provide 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclopropyl)quinoxalin-2-amine (610a) (474 mg) as an orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, dd, J=9.1, 5.8 Hz), 7.17 (1H, t, J=8.7 Hz), 5.29 (1H, br. s.), 2.49 (3H, s), 1.61 (3H, s), 0.86 (3H, d, J=4.7 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −103.55 (1F, s). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Br:10]Br>O>[Br:10][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Solvent: O
Product: O=c1[nH]c(Cl)c(Br)c(=O)[nH]1
Yield: 61.1 %

Procedure:
To a stirring and refluxing solution of 6-chloropyrimidine-2,4(1H,3H)-dione (10.0 g, 68.25 mmol) in water (100 mL) was added bromine (4 mL, 79.84 mmol)) over 10 min. The colorless precipitate that formed was collected by filtration, washed with water (50 mL×2), and dried in a vacuum oven at 50° C. overnight, to obtain 9.4 g of the title compound as a white solid. HPLC/MS: retention time=1.05 min, [M+H]30 =225.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([Br:41])=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[CH:35]=[CH:34]2>>[Br:41][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:26][CH:27]=3)[N:3]=2)=[C:38]2[C:33]=1[CH:34]=[CH:35][N:36]([CH3:40])[C:37]2=[O:39]
Reactant: Cn1ccc2c(Br)ccc(N)c2c1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4ccn(C)c(=O)c34)n2)cc1)OCC
Yield: 62.8 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (166.9 mg, 0.3939 mmol) and 8-amino-5-bromo-2-methylisoquinolin-1(2H)-one (Compound 123A, 120 mg, 0.47 mmol). The crude material was adsorbed onto a pre-filled silica gel loading cartridge and purified using an ISCO Combiflash system eluting first with 0-100% EtOAc:CH2Cl2 and then 15% MeOH:EtOAc. The desired fractions were pooled together and concentrated in vacuo. The material was further purified by trituration in CH2Cl2 and heptane to afford the title product (158.3 mg 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (br s, 1H), 9.90 (s, 1H), 8.82 (br s, 1H), 8.50 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58 (br d, J=5.6 Hz, 2H), 7.25 (dd, J=8.6, 2.3 Hz, 2H), 6.82 (d, J=7.6 Hz, 1H), 3.90-4.03 (m, 4H), 3.55 (s, 3H), 3.21 (d, J=21.2 Hz, 2H), 1.19 (t, J=6.9 Hz, 6H). MS (ES+): m/z 640.03/642.05 (96/100) [MH+]. HPLC: tR=3.90 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Cl)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)c2ccc(F)cc2)cc1Cl
Temperature: 0 °C

Procedure:
Chloro-2,4-Dimethoxy-benzene (5.00 g, 29.0 mmol) and AlCl3 (4.63 g, 1.2 eq.) were dissolved in 290 ml of CH2Cl2 and cooled down to 0° C. 4-Fluoro-benzoyl chloride (3.47 mL, 1.0 eq.) was slowly added via dropping funnel and the mixture allowed to react for 2 additional h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents left 8.41 g of the title compound used crude for the next step.
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:5]([C:2]4([OH:1])[CH2:4][CH2:3]4)=[O:7])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C1(O)CC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3(O)CC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-hydroxycyclopropanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (53.4% yield). 1H NMR (500 MHz, CDCl3) δ8.07, 8.03, 7.01, 3.98-3.73, 3.58, 1.53, 1.16, 1.02, 0.76, 0.48, 0.10. MS (ES+) m/z 360 (M+1).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH:24]([CH3:25])[CH2:23][C:22]2[C:17](=[N:18][C:19]([N:31]3[CH2:36][CH2:35][CH:34]([O:37][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=4[F:45])[CH2:33][CH2:32]3)=[C:20]([NH:26][CH2:27][CH:28]([F:30])[F:29])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:30][CH:28]([F:29])[CH2:27][NH:26][C:20]1[N:21]=[C:22]2[CH2:23][CH:24]([CH3:25])[NH:15][CH2:16][C:17]2=[N:18][C:19]=1[N:31]1[CH2:32][CH2:33][CH:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=2[F:45])[CH2:35][CH2:36]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Reaction time: 3 h

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (135 mg, 0.210 mmol) and Pd(OH)2 on carbon (14.7 mg, 0.021 mmol) in THF (1.05 mL) was purged and stirred under hydrogen atmosphere for 3 h. The reaction mixture was filtered through Celite™ and the solvent was removed to give the title compound as a TFA salt (107 mg, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: COc1ccccc1CCCCC(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1CCCCC(=O)Nc1cc(C2CCNCC2)ccc1F
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Into a solution of tert-butyl 4-(4-fluoro-3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate (48.4 mg, 0.100 mmol) in CH2Cl2 (2.0 mL) was added trifluoroacetic acid (114 mg, 1.0 mmol) at room temperature. The reaction mixture was stirred for 30 min and concentrated in vacuo. The residue was dissolved in CHCl3/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOH solution. The organic layer was separated and the aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford afford N-[2-fluoro-5-(4-piperidinyl)phenyl]-5-(2-methoxyphenyl)pentanamide (38.0 mg, 95%): 1H NMR (400 MHz, CD3OD) δ 8.30-8.12 (m, 1H), 7.64-7.41 (m, 1H), 7.24-7.07 (m, 2H), 7.06-6.92 (m, 1H), 6.92-6.74 (m, 3H), 3.80 (s, 3H), 3.25-3.06 (m, 2H), 2.80-2.49 (m, 5H), 2.48-2.24 (m, 3H), 1.89-1.71 (m, 4H), 1.71-1.46 (m, 4H); ESMS m/e: 385.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:28][C:27]=1[F:26])=[O:34]
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1F

Procedure:
In analogy to example 74, step 6, from 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and 3-fluoro-4-methoxycarbonylphenyl boronic acid was prepared the title compound as a yellow oil, MS (ESI+): m/z=468.1977 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:42]([NH:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(CC)CC>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:11]([NH:50][NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NNCc1ccccc1)C(C)(C)C
Yield: 50 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using N-(methoxycarbonyl)-(L)-tert-leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.56 g, 8.24 mmol), EDAC (1.74 g, 9.08 mmol), HOBT (1.22 g, 9.03 mmol), NMM (0.995 mL, 9.05 mmol), benzylhydrazine×2HCl (1.61 g, 8.25 mmol) and Et3N (2.53 mL, 18.0 mmol) which gave the title compound (1.21 g, 50%) as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>O1CCOCC1.CCOC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCC(O)CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(NCC(O)CO)nc1
Temperature: 80 °C

Procedure:
A mixture of 3-amino-1,2-propanediol (4.93 g, 54.1 mmol) and 6-chloronicotinonitrile (1.50 g, 10.8 mmol) was prepared in anhydrous dioxane (20 mL), and then stirred at RT for hours and 80° C. for additional hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with a half saturated solution of brine (2×50 mL) and brine (50 mL). The aqueous layers were extracted with EtOAc (2×50 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by trituration in hot MTBE (10 mL) and filtration, the title compound was obtained as a white powder (970 mg, 46%). UPLC/MS, M+(ESI): 193.9, M−(ESI): 192.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1>C(Cl)Cl>[CH3:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)[N:3]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5]=2[CH:10]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C)sc3n2)CC1
Yield: 22 %

Procedure:
1.67 g of 2-chloro-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine and 3 g of ethyl piperidine-4-carboxylate are heated at 130° for 3 hours. After cooling, the residue is dissolved in methylene chloride and the solution is worked up in the customary manner. 0.5 g of ethyl 1-[6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine-2-yl]-piperidine-4-carboxylate is obtained.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.Cl.CC[O:32]CC>ClCCl>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH:11]=[O:32]
Reactant: N#Cc1cc2c(cc1I)CCC2
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cc2c(cc1I)CCC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 6-iodoindane-5-carbonitrile (36.5 mg, 0.136 mmol) in dichloromethane (1.0 mL) under N2 at −78° C. was added a solution of 1N DIBALH in toluene (272 μL, 0.272 mmol) dropwise. The reaction was stirred at −78° C. for 15 min. Keeping the temperature at −78° C., another two portions of DIBALH (100 μL each) were added until the starting material disappeared by TLC. The reaction mixture was poured into 2N HCl (45 mL) and diluted with Et2O. The mixture was stirred for 0.5 h. The Et2O layer was separated. The aqueous layer was extracted with Et2O (2×). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford 6-iodoindane-5-carbaldehyde (27 mg, 73%). 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H,), 2.19-2.13 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([SH:33])[CH3:32]>CC(C)=O>[CH2:31]([S:33][C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:21])[F:22])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:32]
Reactant: CCS
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1SCC
Yield: 57.8 %

Procedure:
This material was pepared as described in Example 11: 3.36 g (0.009 mol) of product of Example 27, 0.86 g (0.006 mol) of K2CO3 and 12 ml (0.180 mol) of ethanethiol in 25 ml of acetone were reacted affording an orange oil which was kugelrohr distilled at 33 Pa, pot temperature 79° to give 2.11 g (58.8%) of product as a clear oil, nD25 1.4507.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:14]Br>C(OCC)C>[Br:14][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3](=[O:11])[C:2]([F:12])([F:13])[F:1]
Reactant: BrBr
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Solvent: CCOCC
Product: O=C(C(Br)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1,1,1-trifluoro-3-phenylpropanone (0.50 mL, 3.2 mmol) was dissolved in 5 mL of diethyl ether and the mixture was cooled to 0° C. Bromine (0.16 mL, 3.2 mmoL) was added and the mixture was stirred for 18 h and allowed to warm to rt. The solvent was removed to provide a 2:1 mixture of Example A176a as a starting material which was used in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)O)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: CC(C)(O)c1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
Ethyl 5-(2-hydroxypropan-2-yl)isoxazole-3-carboxylate (0.436 g, 2.189 mmol) was dissolved in methanol (20 ml). A solution of cesium carbonate (1.426 g, 4.38 mmol) in 20 ml of water was added and the reaction mixture was stirred at RT for 18 h. Solvents were evaporated and the residue was taken into a mixture of ethyl acetate and water, pH was adjusted to 2.5 with 10% citric acid solution and the layers were separated. Water layer was extracted three times with ethyl acetate and the combined organic layers were dried with Na2SO4, filtered and evaporated affording 0.246 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49 (s, 6H), 5.75 (m, 1H), 6.60 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([CH3:34])[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)=[CH:23][CH:22]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:34])=[CH:22][CH:23]=3)[S:28][CH:29]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: Cc1ccc(-c2nc(C=O)cs2)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1csc(-c2ccc(C)cc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 2-(p-tolyl)thiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 425.01 g/mol.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:35])[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.5 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.18 mmol) in dichloromethane (2 mL) was added formaldehyde (37% solution in water) (80 μL, 1.06 mmol) and sodium triacetoxyborohydride (113 mg, 0.53 mmol). The reaction was stirred (rt) for 17 h. The mixture was diluted with dichloromethane and was washed with H2O (1×10 mL). The organic phase was washed with brine, and was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water to obtain 13 mg (17%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.88 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.37-7.28 (m, 5 H), 7.14 (dd, 1 H), 6.58 (s, 1 H), 5.65 (s, 2 H), 3.11-2.97 (m, 1 H), 2.85 (d, 2 H), 2.18 (s, 3 H), 2.04-1.94 (m, 4H), 1.77-1.61 (m, 2 H); ES-MS m/z 438.3 [M+H]+, HPLC RT (min) 2.11.