Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:45][CH3:46])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[C:43]=1[F:44])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:44][C:43]1[C:39]2[CH2:40][CH2:41][O:42][C:38]=2[C:37]([O:45][CH3:46])=[CH:36][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
After adding 22 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 105 mg of {2-(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 5 ml of methanol and 0.5 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give 5-{(4-fluoro-7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (76 mg) as a light brown solid.
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([C:14]1[C:15](=[O:32])[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([S:24]([NH:27][CH2:28][CH2:29][CH3:30])(=[O:26])=[O:25])=[C:19]([Cl:31])[CH:18]=2)(=[O:13])[O:10]CC)C>C(#N)C>[Cl:31][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([P:9](=[O:8])([OH:13])[OH:10])[C:15](=[O:32])[NH:16]2)=[CH:21][C:20]=1[S:24]([NH:27][CH2:28][CH2:29][CH3:30])(=[O:25])=[O:26]
Reactant: CCCNS(=O)(=O)c1cc2cc(P(=O)(OCC)OCC)c(=O)[nH]c2cc1Cl
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CCCNS(=O)(=O)c1cc2cc(P(=O)(O)O)c(=O)[nH]c2cc1Cl

Procedure:
25.3 mmol of bromotrimethylsilane are added to a suspension of the compound obtained in Example 1 (2.53 mmol) in 30 ml of anhydrous acetonitrile. Stirring is carried out at reflux for 1 hour, followed by evaporation to dryness. The residue is dried in vacuo and taken up in methanol. The suspension is stirred for 30 minutes and becomes increasingly thick. The precipitate is filtered off and rinsed with a small amount of methanol to obtain the title product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:17]=[CH:18][C:19]=1[OH:20].[OH-].[Na+]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:17]=[CH:18][C:19]=1[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
The title compound is prepared in analogy to the procedure of Example XIV from 5.3 g (0.03 mol) of 2-chloromethylquinoline, 6 g (0.03 mol) of methyl 3-chloro-4-hydroxyphenylacetate and 1.2 g (0.03 mol) of sodium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34].C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.ClCCl.CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CCOCCn1c(N2CCCN(CCC3(c4ccncc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.90 g, 1.65 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.49 g, 0.83 mmol), and N,N-diisopropylethylamine (2.1 mL, 11.6 mmol) in acetonitrile (14 mL). Heat to reflux. After 48 hour, add sodium carbonate and stir. After 1 hour, dilute the reaction mixture with dichloromethane, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia and then 50% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Dissolve the residue in dichloromethane, extract with a saturated aqueous sodium bicarbonate solution, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.39 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[C:25]3[C:24]([NH:26][C@H:27]([C:29]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:33](=[O:41])[C:32]5=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]5[N:30]=4)[CH3:28])=[N:23][CH:22]=[N:21][C:20]=3[N:19](COCC[Si](C)(C)C)[CH:18]=2)[CH:14]=[N:13]1)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.N>>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[C:25]3[C:24]([NH:26][C@H:27]([C:29]4[N:34]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:33](=[O:41])[C:32]5=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]5[N:30]=4)[CH3:28])=[N:23][CH:22]=[N:21][C:20]=3[NH:19][CH:18]=2)[CH:14]=[N:13]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCCO[Si](C)(C)C(C)(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cnn(CCCO)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 67.3 %

Procedure:
(S)-2-(1-((5-(1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (124 mg, 0.14 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 2 ml, 14 mmol) according to the method described in Example 27 to give 48 mg (68% yield) of the title compound. Purity 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:23])([CH3:22])[O:14][C:15]=3[C:16]([C:18]([O:20]C)=O)=[CH:17][C:8]=2[N:7]=1.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:22])([CH3:23])[O:14][C:15]=3[C:16]([C:18]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=3)=[O:20])=[CH:17][C:8]=2[N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(NCc3ccccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(F)(F)F)c3)cc3nc(NCc4ccccc4Cl)[nH]c23)O1
Yield: 24.3 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-((2-chlorobenzyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-52, 0.200 g, 0.519 mmol), 3-trifluoromethyl aniline (0.167 g, 1.038 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL). The obtained crude was purified by column chromatography eluting with 0.5% DCM:MeOH to afford 0.0650 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.16 (s, 2H), 7.00 (d, J=6 Hz, 2H), 7.30-7.42 (m, 2H), 7.44-7.64 (m, 6H), 7.72 (d, J=7.8 Hz, 1H), 8.35 (s, 1H), 9.96 (s, 1H), 10.90 (s, 1H); [M+H]+: 515.19.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:20]([N:15]1[C:16](=[O:19])[C:17]2[NH:18][C:10]([C:5]34[CH2:8][CH2:9][C:2]([NH:1][CH2:32][C:28]5[S:27][CH:31]=[CH:30][CH:29]=5)([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)=[N:11][C:12]=2[N:13]([CH2:24][CH2:25][CH3:26])[C:14]1=[O:23])[CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(NCc5cccs5)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 24 h

Procedure:
To a solution of 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 20) (0.28 mmol) and 37 mg of thiophene-2-carboxaldehyde (0.33 mmol) in CH2Cl2 (5 ml) was added 5 drops of glacial acetic acid and 100 mg of sodium triacetoxyborohydride (0.47 mmol). Complete conversion occurs over 24 h at rt. The reaction mixture was quenched with 2 ml of ethanol and 2 ml of 2N HCl and then concentrated in vacuo to afford a colorless oil which was purified from anhydrous acetonitrile to afford 50.8 mg (40%) as a white solid (MH+=456.29). The following compounds were prepared in an analogous manner:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[NH:12][C:13]1[C:22]2[CH:23]=[CH:24][NH:25][C:26](=[O:27])[C:21]=2[C:20]2[C:15](=[CH:16][CH:17]=[N:18][CH:19]=2)[N:14]=1)[C:5]([O:7]C)=O.[CH2:29]([Mg]Br)[CH3:30]>C1COCC1.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([OH:7])[CH2:30][CH2:29]2)[CH:9]=[C:10]([Cl:28])[C:11]=1[NH:12][C:13]1[C:22]2[CH:23]=[CH:24][NH:25][C:26](=[O:27])[C:21]=2[C:20]2[C:15](=[CH:16][CH:17]=[N:18][CH:19]=2)[N:14]=1
Reactant: COC(=O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Solvent: C1CCOC1
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(C4(O)CC4)cc3Cl)nc3ccncc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,5-dichloro-4-[(10-oxo-9,10-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]benzoate (67 mg, 0.16 mmol) and titanium (IV) isoproxide (46 mg, 0.16 mmol) in THF (4 mL) was added ethylmagnesium bromide (1.29 mL, 1.29 mmol, 1.0 M in THF) dropwise. The solution was stirred at room temperature overnight and extracted with 3:1 CHCl3/iPrOH. Column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[Cl:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C=O.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[Cl:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a suspension of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-chloronitrobenzene (1.50 g) obtained in reference example 3 in 90% formic acid (4.00 g) was added 37% formaldehyde (2.50 g), and the resulting mixture was stirred at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was neutralized with an aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (1.12 g, yield: 98%) as a yellow solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Temperature: 55 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(3-methylthiopropoxy)quinoline (0.95 g, 2.97 mmol) and 2-methylaniline (1.27 g, 11.8 mmol) in toluene was heated to 55° C. and stirred overnight. The solvent was evaporated and the residue was partioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2MeOH 95:5) yielding 0.98 g (80.9%) of the desired product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:14]2C2CCCCO2)=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@H:30]2[CH3:35])[N:9]=1.Cl.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C1COCC1>[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:14]2)=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@H:30]2[CH3:35])[N:9]=1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccccn3)n(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(-c3ccccn3)[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
2,6-Bis-((R)-3-methyl-morpholin-4-yl)-8-pyridin-2-yl-9-(tetrahydro-pyran-2-yl)-9H-purine (33 mg, 69 μmol) was dissolved in 3 mL of THF. 2N aqueous HCl (344 μl, 688 μmol) was added, and the reaction was stirred for 2 hours at room temperature. 100 mg of Na2CO3 and 10 mL of CH2Cl2 were added, and the reaction mixture was stirred for 20 minutes. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (12 g SiO2, heptane/EtOAc in a gradient from 100/0 to 3/2) to give the product as a solid (24 mg, 88%).
Reaction SMILES: N.[Na].[CH2:3]([C@:6]1([CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[CH2:35][CH2:34]2)[C:11](=[O:12])[O:10][C@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)[N:7]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:4]=[CH2:5].[Cl-].[NH4+]>C1COCC1.C(O)C>[C:28]([O:27][C:25]([NH:7][C@@:6]([C:11]([OH:12])=[O:10])([CH2:3][CH:4]=[CH2:5])[CH2:32][CH:33]1[CH2:34][CH2:35][N:36]([C:39]([O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])=[O:40])[CH2:37][CH2:38]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: C=CC[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.33 h

Procedure:
110 ml of ammonia were condensed at −78° C. 1 g of sodium was added in 3 portions at intervals each of 10 min, and the mixture was stirred for 20 min. Then, at −60° C., a solution of 2.76 g of tert-butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]morpholine-4-carboxylate and 2.6 ml of ethanol in 50 ml of THF was added dropwise. The mixture was stirred at −45° C. for 1.5 h and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia was then allowed to evaporate off, and 300 ml of water were added to the residue. The THF was removed in vacuo. The aqueous was adjusted to pH 2 with 1 N HCl and extracted 3 times with 200 ml of ethyl acetate each time. The combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14](N3C=CC=C3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].P(Cl)(Cl)([Cl:26])=O.P(Cl)(Cl)(Cl)(Cl)Cl>CO>[Cl:26][S:14]([C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Temperature: 50 °C

Procedure:
A solution of N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole (100 mg, 0.32 mmol) and 6 N sodium hydroxide (1 mL) in methanol (1.5 ml) was refluxed for approximately 6 h. Evaporation of solvents and drying in vacuo resulted in an oil. Phosphorus oxychloride (258 ml, 2.52 mmol) and phosphorus pentachloride (131 mg, 0.63 mmol) were added to the oil and the resulting brown suspension was heated at 50° C. for 3 h. The resulting clear brown solution was carefully added to about 20 mL of crushed ice and then extracted with ethyl acetate (3×25 mL). The combined organic layers was washed with brine (2×5 mL), dried (MgSO4) and evaporated to leave an oily residue. Flash chromatography over silica gel using 2% ethyl acetate/hexanes yielded (53 mg, 59%) of the pure ulfonyl chloride as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])O.[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:14][C:13]=2[F:19])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.6 %

Procedure:
4-(4-amino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester (11.5 g) was dissolved in acetone (340 ml) and water (170 ml). To the reaction mixture was added sodium hydrogencarbonate (17.3 g), then benzyl chloroformate (9.79 ml) while stirring in an ice water bath, followed by stirring for 15 min. The reaction mixture was allowed to warm up to room temperature, then stirred for 2 hr. To the reaction mixture cooled in an ice water bath was further added benzyl chloroformate (2.45 ml), followed by stirring for 18 hr. The reaction mixture was concentrated under reduced pressure, and to the resultant residue were added ethyl acetate (500 ml) and brine (200 ml), and liquid-liquid separation was carried out. The separated organic layer was washed with water (100 ml) and brine (200 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the resultant solid was suspended in ethyl acetate (50 ml) and hexane (30 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as a pale yellow solid (9.6 g, 70.6%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:16]([N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 140 °C
Yield: 80 %

Procedure:
To a stirred solution of ethyl chloroacetate (1.0 g, 8.16 mmol) in EtOH (5.0 mL), dibenzylamine (2.09 g, 10.6 mmol) was added and the mixture heated at 140° C. in a microwave reactor for 20 min. After evaporation of the solvent, the crude was dissolved in CH2Cl2 and washed with a 1.0 M KOH solution and brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (98:2), gave the title compound (1.85 g, 80%), as a white solid. MS (ESI) m/z: 284 [M−H]+[1H NMR as previously reported in literature: Synthesis, 1985, 9, 850-855].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.Cl.[Cl:35][C:36]1[N:40]([CH3:41])[N:39]=[CH:38][C:37]=1[NH2:42].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.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]>[Cl:35][C:36]1[N:40]([CH3:41])[N:39]=[CH:38][C:37]=1[NH:42][C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:31][CH2:32][CH2:33]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:6]=2[N:7]=1
Reactant: Cn1ncc(N)c1Cl
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4cnn(C)c4Cl)nc(OC4CCC4)c23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 5-chloro-1-methyl-1H-pyrazol-4-amine hydrochloride (1 equiv) and cesium carbonate (5 equiv) in 1,4-dioxane (0.09 M) was added tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv) and (dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine) (0.2 equiv). The reaction was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound (23% yield). MS (ESI) m/z 582.4 [M]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:25]([C:27]1[N:31]([CH2:32][CH3:33])[N:30]=[CH:29][C:28]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:26].O>ClCCl>[CH2:32]([N:31]1[C:27]([C:25](=[O:26])[NH:15][C:13]2[CH:12]=[CH:11][N:10]3[CH:16]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[N:14]=2)=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:29]=[N:30]1)[CH3:33]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(CC)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Reaction time: 8 h

Procedure:
2-Phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 648 mg, 3.08 mmol) and triethylamine (519 mg, 715 μA, 5.13 mmol) were combined with dichloromethane (15 ml) to give a light brown solution. Ethyl 5-(chlorocarbonyl)-1-ethyl-1H-pyrazole-4-carboxylate (1.6 g, 2.57 mmol) was diluted in dichloromethan and was added dropwise at 0° C. The reaction was stirred overnight. The reaction mixture was poured into 20 mL water and extracted with dichloromethan (2×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 50% to 100% EtOAc in heptane). The obtained product contained the imide (2 acid chlorides added to amine) as an impurity, but was used in the next step (where the title compound and the impurity give the same product). The title compound was obtained as a light brown solid (510 mg, 49.1%).