Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (216 mg, 0.78 mmol) [prepared according to Example 96], N,N-diisopropylethylamine (0.68 ml, 3.90 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (252 mg, 0.78 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (401 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 545, 547 (M, M+2)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[N:31]1([C:29]([C@@H:25]2[CH2:26][CH2:27][CH2:28][N:23]([C:19]3[N:20]=[C:21]4[NH:22][C:9]([C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[N:8]=5)=[N:15][C:16]4=[CH:17][CH:18]=3)[CH2:24]2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=Cc1cccc(C(F)(F)F)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cccc(C(F)(F)F)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
Into a tube was added 6-(trifluoromethyl)picolinaldehyde (150 mg, 0.47 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (82.2 mg, 0.47 mmol), sodium dithionite (310.7 mg, 1.78 mmol), ethanol (10 mL) and water (1.5 mL). The vessel was sealed and the reaction mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure and water was added to the resulting residue. The mixture was extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound (50 mg, 29%) as a yellow solid. MS (ES+APCI) (M+H) 445.2; LCMS retention time 2.657 min (Method G).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][NH:8][S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCN1CCCC1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
To an ice-cooled solution of 2-pyrrolidin-1-yl-ethylamine (1.00 g, 8.76 mmol) and triethylamine (1.22 ml, 8.76 mmol) in DCM (20 ml) was added portionwise 2-naphthalenesulfonyl chloride (1.98 g, 8.73 mmol). The coolant was removed and the resultant solution was stirred at ambient temperature for 16 h. The organic phase was washed sequentially twice with water (20 ml) and brine (20 ml), and dried over anhydrous magnesium sulfate. The filtrate was evaporated at reduced pressure to obtain the title compound as a white solid (1.81 g, 68%). 1HNMR 8.45 (1H, d, 1.5), 7.99-7.83 (4H, m), 7.66-7.61 (2H, m), 5.80-5.20 (1H, br s), 3.06-3.02 (2H, m), 2.53 (2H, m), 12.36-2.32 (4H, m), 1.74-1.65 (4H, m). Microanalysis found C 62.96 H 6.74; N 9.11. C16H20N2O2S requires C 63.13 H 6.62 N 9:20.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Br.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][CH:28]=2)=[O:9])[CH:3]=1
Reactant: NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=C(O)c1cccnc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCCOc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
868 mg of nicotinic acid, 954 mg of N-hydroxybenzotriazole and triethylamine (1.23 ml) were added to a dimethylformamide solution (50 ml) containing 2.0 g of 6-[4-(4-aminobutoxy)phenyl]pyridazin-3(2H)-one hydrobromide. 1.35 g of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide was added to the mixture at 0° C., and the resulting mixture was stirred at room temperature for 6 hours and then poured into ice water, and precipitated crystal was collected by filtration. The crystal was recrystallized from ethanol to obtain 1.75 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butoxy)phenyl]pyridazin-3(2H )-one.
Reaction SMILES: ClC1C=CC([C@H]2CC[C@H](C3C=CC(Cl)=C([N+]([O-])=O)C=3)N2C2C=CC(NC(C)(C)C)=C(F)C=2)=CC=1[N+]([O-])=O.[C:38]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C@@H:53]([C:54]3[CH:55]=[CH:56][C:57]4[N:61]=[C:60]([C@@H:62]5[CH2:66][CH2:65][CH2:64][N:63]5[C:67](=[O:77])[C@@H:68]([NH:72][C:73]([O:75][CH3:76])=[O:74])[CH:69]([CH3:71])[CH3:70])[NH:59][C:58]=4[CH:78]=3)[CH2:52][CH2:51][C@@H:50]2[C:79]2[CH:80]=[CH:81][C:82]3[N:86]=[C:85]([C@@H:87]4[CH2:91][CH2:90][CH2:89][N:88]4[C:92](=[O:102])[C@@H:93]([NH:97][C:98](=[O:101])[O:99][CH3:100])[CH:94]([CH3:96])[CH3:95])[NH:84][C:83]=3[CH:103]=2)=[CH:45][C:44]=1[F:104])([CH3:41])([CH3:40])[CH3:39].[C:105](OC(=O)C)(=[O:107])[CH3:106].N1C=CC=CC=1>>[C:105]([N:42]([C:38]([CH3:41])([CH3:39])[CH3:40])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C@@H:53]([C:54]3[CH:55]=[CH:56][C:57]4[N:61]=[C:60]([C@@H:62]5[CH2:66][CH2:65][CH2:64][N:63]5[C:67](=[O:77])[C@@H:68]([NH:72][C:73]([O:75][CH3:76])=[O:74])[CH:69]([CH3:71])[CH3:70])[NH:59][C:58]=4[CH:78]=3)[CH2:52][CH2:51][C@@H:50]2[C:79]2[CH:80]=[CH:81][C:82]3[N:86]=[C:85]([C@@H:87]4[CH2:91][CH2:90][CH2:89][N:88]4[C:92](=[O:102])[C@@H:93]([NH:97][C:98](=[O:101])[O:99][CH3:100])[CH:94]([CH3:96])[CH3:95])[NH:84][C:83]=3[CH:103]=2)=[CH:45][C:44]=1[F:104])(=[O:107])[CH3:106]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(NC(C)(C)C)c(F)c3)cc2[nH]1)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)Nc1ccc(N2[C@@H](c3ccc(Cl)c([N+](=O)[O-])c3)CC[C@@H]2c2ccc(Cl)c([N+](=O)[O-])c2)cc1F
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc([C@H]3CC[C@H](c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)N3c3ccc(N(C(C)=O)C(C)(C)C)c(F)c3)cc2[nH]1)C(C)C

Procedure:
Starting from 4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-N-tert-butyl-2-fluoroaniline, the initial product of the sequence outlined above was methyl {(2S)-1-[(2S)-2-{6-[(2R,5R)-1-[4-(tert-butylamino)-3-fluorophenyl]-5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-benzimidazol-6-yl}pyrrolidin-2-yl]-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (ACD Name v12). The N-acetyl group was added by reaction with acetic anhydride/pyridine to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73-0.90 (m, 12H), 1.13 (d, J=5.20 Hz, 9H), 1.37-1.44 (m, 4H), 1.62-1.72 (m, 2H), 1.92-2.02 (m, 9H), 2.10-2.26 (m, 5H), 2.51-2.58 (m, 2H), 3.52 (s, 6H), 3.73-3.85 (m, 4H), 3.98-4.12 (m, 2H), 5.09-5.17 (m, 2H), 5.36-5.48 (m, 3H), 6.08-6.18 (m, 3H), 6.74-6.87 (m, 1H), 7.08 (dd, J=13.72, 8.29 Hz, 3H), 7.20 (s, 1H), 7.24-7.31 (m, 4H), 7.40 (d, J=8.24 Hz, 1H), 7.48 (d, J=8.13 Hz, 1H), 12.01 (s, 1H), 12.17 (s, 1H); MS (ESI+) m/z 964 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1>CC(O)C.CS(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH:36][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]5[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=5)[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: OCc1cccc(OCC2CO2)c1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: OCc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)c1
Yield: 35 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 14 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 35% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28].CO>>[NH2:28][C:17]1[C:18]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[C:12]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CSC[C@@H](O)CNCc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reactant: N
Solvent: CO
Product: CSC[C@@H](O)CNCc1cn(COCc2ccccc2)c2c(N)ncnc12
Temperature: 25 °C
Yield: 72 %

Procedure:
The product from Example 2.4 (0.124 g, 0.305 mmol) was stirred in a solution of 7M NH3-MeOH (25 ml) for 24 h in a sealed tube at 135° C. (oil bath). After cooling to rt the solvent was evaporated and the residue chromatographed on silica gel (CH2Cl2-7M NH3 in MeOH, 98:2) to give (S)-1-((4-amino-5-(benzyloxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-3-(methylthio)propan-2-ol (0.085 g, 72%) as a colourless gum. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.47 (s, 1H), 7.28 (m, 5H), 5.66 (s, 2H), 4.58 (s, 2H), 3.97 (d, J=13.8 Hz, 1H), 3.91-3.83 (m, 2H), 2.84 (dd, J=12.1, 3.5 Hz, 1H), 2.62 (dd, J=12.1, 8.4 Hz, 1H), 2.56 (d, J=6.4 Hz, 2H), 2.09 (s, 3H). 13C NMR (CD3OD) δ 152.8, 151.6, 149.4, 137.7, 133.5, 129.5, 129.3, 129.2, 116.0, 114.3, 78.6, 71.4, 70.3, 54.6, 43.3, 40.4, 16.2. +ESMS Found 388.1813 (M+H)+ C19H26N5O2S requires 388.1807.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15](F)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C-:22]#[N:23].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([C:22]#[N:23])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 20 h

Procedure:
5.0 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine and 1.5 g of potassium cyanide in 50 ml of dimethylformamide were heated at 50° C. for 4 hours and then stirred at 23° C. for 20 hours. The mixture was then poured into 200 ml of water. The aqueous phase was extracted three times with 100 ml of tertbutyl methyl ether each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=9:1). Yield: 2.7 g (53%) of a yellow oil which slowly crystallized.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41].CCN(C(C)C)C(C)C.Cl[CH2:52][CH:53]1[CH2:55][O:54]1>CN(C=O)C>[Cl:40][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@@H:2]([N:1]3[CH2:55][CH:53]([OH:54])[CH2:52]3)[C@H:3]([OH:41])[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH2:33][CH3:34])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:20]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]2[N:18]=1
Reactant: ClCC1CO1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N4CC(O)C4)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (29 mg, 0.046 mmol) was dissolved in DMF (1 ml) in a 4 ml vial. DIPEA (0.25 ml, 1.431 mmol) was added and the mixture warmed to 70° C. A solution of 2-(chloromethyl)oxirane (100 μl, 1.279 mmol) in DMF (1 ml) was added slowly. The reaction mixture was kept at 70° C. for 30 minutes. The crude reaction mixture was filtered through a MCX cartridge (Waters, 5 g adsorbent). The cartridge was washed with MeOH and the product eluted with a 1:1 mixture of (CH3CN+2 molar solution of NH3 in MeOH). Evaporation to dryness gave 30 mg of (+/−)-2-((2-chloro-5-cyano-3-((3R,4R)-3-hydroxy-4-(3-hydroxyazetidin-1-yl)piperidin-1-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile. The crude was used “as is” in the following deprotection
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br.[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1>>[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[CH:24]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: Br
Product: CCCCCCCCc1noc(-c2ccc(CNCc3cccc(-c4ccccc4)c3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,1′-biphenyl-3-ylmethylamine hydrobromide gave the title compound as an oil. M+(LC/MS(ESI)): 454.6 HPLC (Condition A), Rt: 4.52 min (HPLC purity: 81%).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH2:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([NH:28][CH2:16][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1)[CH3:27]
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: CC(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(NCc1nc2ccccc2n1COCC[Si](C)(C)C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-2-carbaldehyde in CH2Cl2 with 1-pyridin-2-yl-ethylamine and NaBH(OAc)3 gave (1-pyridin-2-yl-ethyl)-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-2-ylmethyl]-amine as a pale green oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18][O:19][CH2:20]Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:18][O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2,4-di-tert-butylphenol (20.6 g, 0.1 mol) in dry THF (50 mL) is added with stirring to a suspension of NaH (2.4 g, 0.1 mol) in dry THF (150 mL). After 1 h of stirring, the mixture is cooled to 0° C., and chloromethyl methyl ether (7.6 mL, 0.1 mol) is added. The reaction mixture is stirred at room temperature for 2 h, quenched with water (500 mL) and extracted with Et2O (2×100 mL). The combined organic phase is dried over MgSO4 and evaporated under reduced pressure. The residue is used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:14]([CH2:15][C:16]#[N:17])[C:13](=[O:18])[C:12]3[CH:19]=[CH:20][CH:21]=[N:22][C:11]=3[S:10]2)=[CH:4][CH:3]=1.CN(C=O)C.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:14]([CH2:15][C:16]3[NH:30][N:29]=[N:28][N:17]=3)[C:13](=[O:18])[C:12]3[CH:19]=[CH:20][CH:21]=[N:22][C:11]=3[S:10]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1Cc1nnn[nH]1

Procedure:
A mixture of 658 mg (2 mmol) of [2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetonitrile and 8 ml of DMF was put in a 50 ml flask. To the mixture were then added 1.30 g of sodium azide and 1.07 g of ammonium chloride with stirring. The mixture was then stirred at a temperature of 120° C. for 4 hours. The resulting reaction mixture was allowed to cool, poured into water, and then extracted with ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then washed with cold ethanol to obtain 512 mg of 2,3-dihydro-[2-((4-chlorophenyl)imino]-3-(1H-tetrazol-5-ylmethyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.NC1C=CC(O)=CC=1>C(O)(=O)C>[OH:36][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: Nc1ccc(O)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccc(O)cc1
Yield: 41 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (500 mg, 2.14 mmol), triethyl orthoformate (5 ml), 4-aminophenol (444 mg, 4.07 mmol), and acetic acid (0.5 ml) were used to give 283 mg (0.88 mmol, 41% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)=[O:8].[C:25]1([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=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>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][CH:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([NH:37][C:33]4[N:32]=[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:36]=[CH:35][N:34]=4)[CH:3]=[N:4][CH:5]=3)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: CC1CCN(Cc2ccc(NC(=O)c3cncc(Br)c3)cc2)CC1
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1CCN(Cc2ccc(NC(=O)c3cncc(Nc4nccc(-c5ccccc5)n4)c3)cc2)CC1
Temperature: 150 °C
Yield: 41.8 %

Procedure:
A mixture of 5-bromo-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide (45.6 mg, 0.1 mmol) and 4-phenylpyrimidin-2-amine (25.7 mg, 0.15 mmol), KOBut (22.4 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 2 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder (20 mg, 38%). MS (ESI+) m/z 479.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[Na].Cl[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CN(C)CCO
Agent: [Na]
Product: CN(C)CCOc1ccnc(N)c1
Temperature: 25 °C
Yield: 537.6 %

Procedure:
2-Dimethylaminoethanol (34.8 g, 39.0 mmol) was treated with sodium (2.7 g, 11.7 mmol) in a sealed tube and stirred at ambient temperature until homogeneous. 4-Chloropyridin-2-amine (5 g, 3.9 mmol) was added and reaction heated to 150° C. and stirred in sealed tube for 8 hours. The mixture was cooled to ambient temperature before concentrating and triturating with dichloromethane (50 mL) four times. The combined triturates were concentrated and purified by column chromatography to give 4-(2-(dimethylamino)ethoxy)pyridin-2-amine as a yellow solid (3.8 g).