Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[O:21][C:20]([C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=O)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[N+]=[N-].O.[OH-].[Na+]>O1CCCC1>[NH2:7][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[O:21][C:20]([CH2:22][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: [N-]=[N+]=NC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCN(Cc2ccc(CN3CCCCC3)o2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
In 100 ml of dry tetrahydrofuran was suspended 1.1 g (28.8 mmol) of lithium aluminum hydride, and under nitrogen stream a solution of 2.28 g (7.2 mmol) of Compound v in 50 ml of dry tetrahydrofuran was added dropwise at room temperature. After completion of dropwise addition, the mixture was heated under reflux for 20 hours. The reaction mixture was ice-cooled and 2.2 ml of water, 1.1 ml of 20% aqueous sodium hydroxide solution and 5.5 ml of water were serially added gradually. The mixture was stirred at 0° C. for 30 minutes. The insolubles were then filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to vacuum distillation (160°-180° C./1 mmHg) to give 1.82 g (91.5%) of 2-(4-amino-piperidinomethyl)-5-piperidinomethylfuran (Compound w) as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][C:8](=[O:26])[C@@H:9]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][O:4][CH2:3]1.C(N(CC)CC)C>C(Cl)Cl.B(F)(F)F.CCOCC>[CH2:19]([O:18][C:16](=[O:17])[NH:15][C@H:9]([C:8]12[O:4][CH2:5][C:2]([CH3:1])([CH2:3][O:26]1)[CH2:6][O:7]2)[CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a solution of 2(S)-benzyloxycarbonylamino-4,4-dimethylpentanoic acid 3-methyl-oxetan-3-ylmethyl ester (21.5 g, 59 mmol) in dry DCM (50 ml) was added BF3.Et2O (0.4 ml, 3.2 mmol). After 5 h, triethylamine (0.9 ml, 6.4 mmol) was added and stirring was continued for 30 min at room temperature. The solvent was evaporated using a rotavap and the resulting oil was redissolved in ethyl acetate and was washed with 50 ml of 3% NH4Cl solution followed by brine. The ethyl acetate layer was dried over MgSO4, the solvent was evaporated and the residue was purified with column chromatography using silica gel and 20:80 EtOAc:Hexane as eluent to give [3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]carbamic acid benzyl ester (15.5 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[O:11]1[C:16]2([CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:24]=[C:25]([CH2:30][CH2:31][OH:32])[CH:26]=[C:27]([F:29])[CH:28]=3)[CH2:18][CH2:17]2)[CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:29][C:27]1[CH:26]=[C:25]([CH2:30][CH2:31][OH:32])[CH:24]=[C:23]([CH2:22][N:19]2[CH2:18][CH2:17][C:16]3([O:11][CH2:12][CH2:13][N:14]([S:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)(=[O:9])=[O:8])[CH2:15]3)[CH2:21][CH2:20]2)[CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)s1
Reaction time: 1 h

Procedure:
A solution of 5-methylthiophene-2-sulfonyl chloride (0.15 g) in DCM (3 mL) was added dropwise to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g) and N-ethyl-N-isopropylpropan-2-amine (0.14 mL) in DCM (20 mL). The resulting mixture was stirred for 1 h and the solvent evaporated. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogen carbonate solution (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 47.5:47.5:5 ethyl acetate:isohexane:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow gum. Yield 0.21 g.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[CH2:86]([CH2:88][NH2:89])[OH:87]>>[OH:87][CH2:86][CH2:88][NH:89][C:40]([C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][NH:9][CH:10]=3)[CH:3]([CH3:5])[CH3:4])[CH:31]=2)[CH:36]=1)=[O:41]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: NCCO
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NCCO)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.0 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with ethanolamine (0.26 mL) in a similar manner as described in Example 24-(i) to give the titled compound (1.74 g) as a colorless powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C[O-].[Na+].CO.[H][H]>[Ni].CO>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1)[CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN(CCC)CCCCNCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 98.7 %

Procedure:
4.0 g (13.91 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 24 ml of methanol were charged in a 100 ml three-necked flask. 400 mg (10 wt %) of the Raney nickel prepared in Example 1 was then slowly added to the mixture. After the addition of 2.58 g (13.35 mmol, 0.96 equivalents) of a 28% sodium methoxide/methanol solution, the atmosphere in the flask was replaced with nitrogen and then with hydrogen. The mixture was then stirred at room temperature for five days using a hydrogen balloon. After completion of the reaction, the reaction solution was filtered through celite. After concentration, the resulting residue was added to 50 ml of water. The product was extracted with 100 ml of chloroform three times. The chloroform layer was washed twice with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 4.0 g of 4-[(4-dipropylaminobutyl)amino]methylbenzylamine (5a) as a colorless oily substance (yield: 99%, GC: 96.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1>C1(C)C=CC=CC=1.C(O)(=O)C.[Fe]>[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1nc2ccccc2[nH]1
Agent: [Fe]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(N)cc1-c1nc2ccccc2[nH]1
Temperature: 125 °C
Yield: 71.6 %

Procedure:
Iron powder (3.0 g, 50.9 mmol) was added to a solution of nitrobenzimidazole 7 (4.30 g, 16.9 mmol) in toluene (30 ml) and acetic acid (30 ml), and the reaction mixture was heated at 125° C. for about 1 h (completion of the reaction was monitored by TLC). The resulting crude mixture was filtered through a cotton wool plug (to remove iron particles). The crude solution was evaporated to dryness, diluted with EtOAc, washed with saturated NaHCO3 (until the pH=7), and the aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated at reduced pressure to give 8 (2.70 g, 73%) a brown solid: 1H NMR(C2D6SO) δ 12.55 (s, 1H), 7.73 (d, 1H), 7.57 (d, 1H), 7.16 (broad m, 2H), 7.09 (d, 1H), 7.01 (app d, 1H), 6.70 (dd, 1H) 5.15 (broad s, 2H), 2.39 (s, 3H); MS (ES, positive mode): 224 [M++1].
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=3)[C:4]=2[CH:3]=1.CCN(CC)CC.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29].CCOC(C)=O.C(Cl)Cl>CN(C1C=CN=CC=1)C.C1COCC1.C(Cl)Cl.CCCCCC>[Br:17][C:13]1[CH:12]=[C:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[N:19]=[CH:18][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Yield: 5.7 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)-amino]pyrido[3,4-d]pyrimidine (J Med Chem, 1996;39:1823) (250 mg, 0.82 mmol), Et3N (excess, 2.0 mL) and DMAP (catalytic) in THF (30 mL) under nitrogen was added methacryloyl chloride (3×1.1 mol eq., total of 264 μL), the reaction conditions and work up were followed as above to give after column and preparative layer chromatography on silica gel eluting with EtOAc/CH2Cl2 (1:1), N-[4-[(3-bromophenyl)amino]-pyrido-[3,4-d]pyrimidin-6-yl]-2-methylacrylamide (18 mg, 6%) as a cream powder, mp (CH2Cl2/hexane) 177-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[Cl:12][C:13]1[CH:14]=[C:15](I)[N:16]2[C:21]=1[CH:20]=[N:19][C:18]([S:22][CH3:23])=[N:17]2.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:16]2[C:21]=1[CH:20]=[N:19][C:18]([S:22][CH3:23])=[N:17]2
Reactant: CSc1ncc2c(Cl)cc(I)n2n1
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(Cl)c3cnc(SC)nn23)cn1
Temperature: 60 °C
Yield: 81 %

Procedure:
2-Methoxypyridine-5-boronic acid (116 mg, 0.758 mmol), Tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) and 5-Chloro-7-iodo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.152 g, 0.467 mmol) were placed in a vial, followed by 1,4-Dioxane (3.00 mL) and 2.00 M of Sodium carbonate in Water (1.00 mL, 2.00 mmol). The sample was frozen, placed under vacuum, sealed, warmed, refrozen, evacuated, then placed under nitrogen and heated in a 60° C. block. When complete, the sample was partitioned between EtOAc and water (30 mL each), the aq. extracted (EtOAc 3×20 mL) and the comb. organics washed with brine. Purification (ISCO, 12 g, 0-30% EtOAc:Hex) afforded 5-Chloro-7-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.116 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:22]([O:26][C:27](=[O:38])[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1)([CH3:25])([CH3:24])[CH3:23].CCOC(C)=O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:22]([O:26][C:27](=[O:38])[NH:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:10]=2)=[CH:34][CH:35]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)cc1
Reactant: Oc1cccc(Oc2ccnc(Cl)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(COc2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reaction time: 0.33 h

Procedure:
Under an atmosphere of argon, 3-(2-chloro-pyrimidin-4-yloxy)-phenol (177 mg; 0.8 mmol; Stage 5.1) is dissolved in DMF (4 mL), followed by addition of Cs2CO3 (1.30 g; 4.0 mmol) and stirring is continued for 20 min. (4-Chloromethyl-benzyl) -carbamic acid tert-butyl ester (203 mg; 0.8 mmol) and tetrabutyl ammonium iodide (20 mg) are added, and the reaction is continued for another 1 h 50 min. The reaction mixture is poured onto brine, taken up into EtOAc, washed with water and brine and dried (Na2SO4). After filtration, the solvent is removed under reduced pressure and the crude product is purified by flash chromatography over silica gel (eluting with Hexane/EtOAc 80:20) to give the title compound of Stage 5.2 as an oil; ES-MS: [M+H]+; m/z=442; Rf (Hexane/EtOAc 1:1)=0.50; HPLC: AtRet=5.29 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([O:44][CH2:45][CH3:46])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:45]([O:44][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH3:43])[CH3:46]
Reactant: CCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3,4-diethoxyphenyl borate (134 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-(3,4-diethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 51) (214 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH2:19])[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.Cl[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][N:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][N:24]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(-c3nc(N)sc3C)cn2)cc1
Reactant: Fc1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3nc(Nc4cc(F)ccn4)sc3C)cn2)cc1
Yield: 70.2 %

Procedure:
According to Scheme 3 Step 2: A solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-amine (0.47 mmol, 140 mg), 2-chloro-4-fluoropyridine (0.47 mmol, 61 mg), Xantphos (70 μmol, 40.5 mg), Pd(OAc)2 (46 μmol, 10.5 mg) and cesium carbonate (0.93 mmol, 304 mg) in dioxane (6.5 mL) was microwaved at 135° C. for 2 hours under nitrogen. After evaporation of the solvent, the resulting crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (80:20) as eluent to afford N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-4-fluoropyridin-2-amine (0.33 mmol, 132 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1>[Pd].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:7]([N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2C#N)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ncn(-c2ccc(N)cc2C#N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Step G (2): 10% Palladium on carbon (5.06 g) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrobenzonitrile (10.9 g, 47.6 mmol) dissolved in methanol (100 mL). The flask was repeated evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 16 h under the hydrogen atmosphere. Purged with nitrogen gas. Filtered the crude reaction mixture through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford 5-amino-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (6.59 g, 70% yield) as a brown solid. LC-MS (M+H)+ 200.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.29-2.37 (m, 3 H) 5.99 (s, 2 H) 6.94 (dd, J=8.85, 2.44 Hz, 1 H) 7.00 (d, J=2.44 Hz, 1 H) 7.37 (d, J=8.54 Hz, 1 H) 8.69-8.81 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(F)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)c(Cl)c1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoate (174 mg, 0.524 mmol) in THF (1967 μl)/H2O (656 μl) was added LiOH (37.7 mg, 1.573 mmol) and the reaction was allowed to stir for 2 h. THF was removed by rotovap before the solution was diluted in EtOAc (10 mL) and aqueous phase was acidified to pH 3 using a 1N aqueous HCl solution. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product, (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid, was obtained as a yellow gum (0.183 mg, 99%).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1>C(O)C.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH2:11]1
Reactant: CCC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(=O)N1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 111.7 %

Procedure:
1-[1-(diphenylmethyl)azetidin-3-yl]-4-propionylpiperazine (0.22 g, 0.59 mmol) was dissolved in a mixture of ethanol (9 mL) and acetic acid (0.2 mL) and to the resultant solution was added palladium hydroxide on carbon (83 mg). The mixture was stirred under hydrogen (5 bar) at RT for 23 h and then the catalyst was filtered off by means of a phase separator column then washing with ethanol. The solvent was removed by evaporation and the residue was dissolved in methanol (1 mL). The solution was filtered through a cation exchange column (Isolate SCX-2, 10 g). The column was washed with THF and then the product was eluted with ammonia-saturated methanol. The solvent was removed by evaporation and there was obtained 0.13 g (100%) of the title compound as an oil. 1H NMR (500 MHz, CD3OD): 1.1 (t, 3H), 2.3-2.5 (m, 6H), 3.4 (m, 1H), 3.6 (m, 4H), 3.9-4.0 (m, 4H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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].O>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2
Reactant: Clc1ncccn1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: O=C1CCc2cc(-c3ncccn3)ccc21
Temperature: 95 °C
Reaction time: 2 h
Yield: 179.4 %

Procedure:
To a 500 mL round-bottomed flask was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 12.9 g, 35.0 mmol), 2-chloropyrimidine (4.00 g, 35.0 mmol) and 400 mL of dimethoxyethane. Dry nitrogen gas was bubbled through the solution for 10 minutes. Aqueous sodium carbonate (2M in water, 140 mmol) was added followed by Pd(dppf)Cl2 catalyst (100 mg, 0.12 mmol). The reaction mixture was degassed for another 15 minutes. The reaction was heated to 95° C. (silicon oil bath temperature) for 2 hours. A second aliquot of 2-chloropyrimidine (1 g, 8.73 mmol) and Pd(dppf)Cl2 (100 mg, 0.12 mmol) were added to the reaction and heating was continued for another 2 hours. The reaction was cooled to room temperature overnight and 200 mL of water was added. The mixture was filtered through a Celite® pad and the organic phase was separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous MgSO4 and evaporated to afford 13.2 g of an orange brown solid. This material was triturated with hexane to give 6.72 g of a light brown solid (SM-1b). The filtrate was concentrated and purified by silica chromatography (ethyl acetate/heptanes) on a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) to afford another 600 mg of product (7.32 g, 98%). MS (ES+) 211.2 (M+H)+. 1H NMR (CDCl3) δ 2.77 (t, 2H), 3.24 (t, 2H), 7.28 (d, 1H), 7.87 (d, 1H), 8.48 (d, 1H), 8.57 (s, 1H), 8.87 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: CCOC(=O)Cl
Product: CCOC(=O)n1cc(F)c(N)nc1=O
Yield: 25.6 %

Procedure:
Using the procedure of Example 2, 4-amino-5-fluoro-pyrimidin-2-ol (0.25 g, 1.9 mmol), BSA (1.41 mL, 5.8 mmol) and ethyl chloroformate (0.277 mL, 2.9 mmol) were reacted, and the resulting material was purified via reverse phase chromatography (gradient, CH3CN/H2O) to give ethyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.098 g, 25.6%) as a white solid: mp 190-193° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.04-8.01 (m, 2H), 4.27 (q, J=7.25 Hz, 2H), 1.26 (t, J=7.25 Hz, 3H); ESIMS m/z 200 ([M−H]−).