Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([CH3:21])[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:22](Cl)=[O:23].[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][CH2:32][NH:33][C:22]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([CH3:21])[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc2nccc(Oc3ccc4c(C(=O)Cl)c(C)sc4c3)c2s1
Product: Cc1cc2nccc(Oc3ccc4c(C(=O)NCCN5CCOCC5)c(C)sc4c3)c2s1
Yield: 74.8 %

Procedure:
This material was prepared from 2-methyl-6-(2-methylthieno[3,2-b]pyridin-7-yloxy)benzo[b]thiophene-3-carbonyl chloride 139d (112 mg, 0.3 mmole) and 2-(morpholin-4-yl)ethylamine (157 mg, 1.2 mmole) in a similar manner as that described for example 108 to give a yellow solid (105 mg, 75%). 1H NMR (DMSO-d6) δ 8.44 (1H, d, J=5.5 Hz), 8.29 (1H, t, J=4.8 Hz), 7.94 (1H, d, J=8.7 Hz), 7.92 (1H, d, J=2.3 Hz), 7.31 (1H, s), 7.30 (1H, dd, J=2.3, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz), 3.60 (4H, t, J=4.2 Hz), 3.45 (2H, dt, J=4.8, 6.2 Hz), 2.64 (3H, s), 2.62 (3H, s), 2.55–2.41 (6H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3]OC1C2C(=O)C3C(=CC=CC=3)SC=2C=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1.C1(=O)OCCO1>C(N(CC)CC)C>[OH:1][CH2:2][CH2:3][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:37])[CH:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28]2)=[CH:23][CH:22]=1
Reactant: O=c1c2ccccc2sc2cccc(OCCO)c12
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Solvent: CCN(CC)CC
Solvent: O=C1OCCO1
Product: O=c1cc(-c2ccccc2)oc2cc(OCCO)ccc12
Yield: 83 %

Procedure:
In an analogous fashion to 2-hydroxyethoxythioxanthone in Example 29, 7-hydroxyflavone (Aldrich) was reacted with ethylene carbonate and triethylamine to obtain 7-hydroxyethoxyflavone (83% yield). This product was dissolved in THF. One equivalent of VDM and several drops of DBU were added. The reaction mixture was stirred overnight.
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]([CH2:27][CH2:28][CH2:29]Br)[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.[ClH:31].FC1(F)CCNC1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][Cl:31])[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
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: Cl
Agent: FC1(F)CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCCl)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 20.9 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (50 mg, 0.108 mmol), 3,3-difluoropyrrolidine hydrochloride (78 mg, 0.54 mmol, 5.0 eq), triethylamine (77 mg, 0.76 mmol, 7.0 eq), and sodium iodide (3.3 mg, 0.022 mmol, 0.2 eq) in anhydrous DMF (1.0 mL) was stirred at 50° C. for 6 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in MeOH (3 mL) and purified using HPLC (RT=10.16 min) to give a colorless oil. Crystallization from DCM/hexane afforded 9.4 mg (20.8%) of the byproduct as a white solid. 1H-NMR (CD3OD) 8.35 (s, 1H), 7.82 (s, 1H), 7.81 (d, 1H), 7.64 (s, 1H), 7.36 to 7.30 (m, 5H), 7.23 (d, 1H), 6.62 (s, 1H), 5.66 (s, 2H), 3.64 (t, 2H), 3.14 (t, 2H), 226 to 2.22 (m, 2H); LC-MS [M+H]+=417/419, RT=2.91 min.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][C:4]2=[CH:3][CH:2]=1.C1C(=O)N([I:31])C(=O)C1>CN(C=O)C>[I:31][C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][C:4]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2nccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(I)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
The (S)-tert-butyl 2-((pyrazolo[1,5-a]pyrimidin-5-ylamino)methyl)pyrrolidine-1-carboxylate (790 mg, 2.490 mmol) was dissolved in 10 mL of DMF, was added NIS (617 mg, 2.740 mmol). This mixture is stirred for 4 hr at rt, and then quenched with 10 mL of water. It was then diluted with 50 mL EtOAc and the organic layer was separated, washed twice with brine, and dried over MgSO4. It was concentrated and purified on the silica gel eluting with 20-100% EtOAc/hex to obtain 1.03 g (93%) an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([OH:32])=[O:31].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:37]1[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=1)[C:30]([OH:32])=[O:31])=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cccc(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone (0.1 g, 0.00025 mole) and 3-carboxyphenyl boronic acid (0.12 g, 0.00072 mole) in 2 ml dichloromethane was added copper acetate (0.091 g, 0.0005 mole) and triethylamine (0.1 ml, 0.00072 mole). This mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate evaporated to dryness. The crude product was purified by flash chromatography to give 0.027 g of 3-[3-(3-benzoyl-8-trifluoromethyl-quinolin-4-yl)-phenoxy]-benzoic acid: MS: MS (ESI) m/z 514; MS (ESI) m/z 512.
Reaction SMILES: ClC1C=[C:4](C=CC=1)[C:5]([O:7]O)=O.ClCC[N:15]([CH2:41][CH2:42][Cl:43])[C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([CH2:22][C@@H:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:21]=1.[Cl:44]CCl>>[C:36]([O:35][C:33]([NH:32][C@H:23]([CH2:22][C:20]1[CH:21]=[C:16]([N:15]([O:7][CH2:5][CH2:4][Cl:44])[CH2:41][CH2:42][Cl:43])[CH:17]=[CH:18][C:19]=1[CH3:40])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[O:34])([CH3:38])([CH3:39])[CH3:37]
Reactant: ClCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(N(CCCl)CCCl)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Product: Cc1ccc(N(CCCl)OCCCl)cc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
Adapting literature known protocols (Tercel, et al., J. Med. Chem. 1995, 38, 1247-1252; Kirkpatrick, U.S. Pat. No. 5,602,278; Kirkpatrick, et al., Anti-Cancer Drugs, 1994, 5, 467-472; and Kirkpatrick, et al., U.S. Pat. No. 7,399,785), tert-butyl(3R)-3-(tert-butoxycarbonylamino)-4-[5-(2-chloroethoxy(2-chloroethyl)amino)-2-methyl-phenyl]butanoate (21a) is prepared by adding 3-chloroperoxybenzoic acid (1.42 g, 80 wt-%, 6.6 mmol) to a solution of tert-butyl(3R)-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-3-(tert-butoxycarbonylamino)butanoate (6e) (2.43 g, 5.0 mmol) in dichloromethane (DCM) (30 mL) at about room temperature for about 2 h. The reaction is followed by TLC and/or LC/MS to completion. After quenching with a saturated aqueous solution of sodium hydrogencarbonate (NaHCO3), the reaction mixture is extracted with DCM (3×). Further aqueous work-up and purification by silica gel column chromatography yield the title compound (21a).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/P(OCC)(OCC)=O)=[CH:7]\[CH3:8])=[O:5].[K].C([O-])(C)(C)C.[Br:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:30]/[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:23])[N:29]=1)[CH3:1]
Reactant: C/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)/C=C/C=C/c1cccc(Br)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 5.88 g of 4-phosphonocrotonic acid triethyl ester in 60 ml of tetrahydrofuran is mixed in portions with 2.5 g of potassium-tert-butanolate with stirring and under argon atmosphere at -20° C. After 30 minutes, a solution of 2.6 g of 6-bromopyridine-2-aldehyde is instilled at -20° C. and the mixture is stirred at this temperature for another hour. The reaction mixture is poured on ice, shaken out with diethyl ether, the organic phase is washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate=95/5. 2.66 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienoic acid ethyl ester is obtained as crude product.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH:25]1([C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:31]2[CH:32]=[CH:33][C:34]([C:35]([N:9]3[CH2:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[NH:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=4)=[O:36])=[CH:38][CH:39]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccccc2Nc2ccccc21
Reaction time: 8 h

Procedure:
5,11-Dihydro-10H-dibenzo[b,e][1,4]diazepine (1.96 g) in dichloromethane (50 mL) containing N,N-diisopropylethyl amine (1.3 g) was reacted with the crude 4-cyclohexylbenzoyl chloride prepared as described above (2.22 g). The reaction mixture was kept at room temperature overnight, then washed with water and saturated aqueous sodium bicarbonate. The solution was dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was refluxed with the gradual addition of hexane until crystallization was noted. Cooling and filtration afforded the title compound as colorless crystals (1.28 g), m.p. 175–176° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CS(C)=O.C[CH2:54][O:55][C:56](C)=[O:57].CCCCCC>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:54][O:55][C:56]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:16]2)=[O:57]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (200 mg, 0.67 mmol), Pd(OAc)2 (30 mg, 0.2 equiv), DPPP (55 mg, 0.2 equiv), TEA (0.93 mL, 10 equiv) and MeOH:DMSO (1:1, 4 mL) was stirred for 16 h under CO (balloon) at 80° C. LC-MS and TLC (20% EtOAc-Hexane) showed completion of the reaction. The Reaction mixture was concentrated to remove MeOH and diluted with EtOAc (10 mL), and washed with water (2×25 mL). The organic layer was dried (Na2SO4), concentrated and purified by silica gel column chromatography (eluent=20% EtOAc-Hexane), giving pure 1,3-dihydro-isoindole-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester (150 mg, 81%). MS (APCI+): m/z 178.1 (MH+−Boc).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH3:43][C:44]1[S:48][C:47]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:46][C:45]=1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:74](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:41][O:40][C:18]1[CH:17]=[C:16]([CH2:15][O:14][C:4]2[C:3](/[CH:1]=[CH:74]/[C:45]3[N:46]=[C:47]([N:49]4[CH2:50][CH2:51][O:52][CH2:53][CH2:54]4)[S:48][C:44]=3[CH3:43])=[CH:7][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:39]=[CH:38][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=1[CH3:27]
Reactant: Cc1sc(N2CCOCC2)nc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCOCC5)sc4C)cc3OC)c(C)o2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.5 %

Procedure:
A mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (1.05 g), (5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)triphenylphosphonium chloride (1.40 g), potassium carbonate (0.39 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give methyl 3-[4-({2-methoxy-4-[({4-[(E)-2-(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as pale-yellow crystals (0.55 g, yield 40%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 183-184° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:38][CH:37]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C(=O)c4ccccc4)cc3)(CC1)CC2
Yield: 14.8 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobenzophenone (67.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-benzoylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (11.5 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].O>CN1C(=O)CCC1>[C:21]([NH:25][C:6]1[C:5]([C:9]([NH2:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc(Cl)ncc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carboxamide (10.0 g), DIPEA (11 mL) in NMP (30 mL) were stirred at 25° C. tert-Butylamine (6.6 mL) was charged to the mixture, and the mixture was stirred at 25° C. for 16 h. Water (100 mL) was added to the mixture at 25° C. The mixture was stirred for 1 h. The suspension was filtered, washed with water (50 mL) and dried in a vacuum oven at 40° C. with a nitrogen bleed for 24 h to give 4-(tert-butylamino)-2-chloropyrimidine-5-carboxamide as a white solid (8.7 g, 84%). 1H NMR (DMSO-d6) δ 9.41 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 1.42 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[C:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CCO.C(OCC)(=O)C.[Pt]=O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COc1ccc2nccc(C#CC3CCC4(CC3)OCCO4)c2c1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(CCC3CCC4(CC3)OCCO4)c2c1

Procedure:
Platinum oxide ((0.462 g) was added to a solution of 4-(1,4-dioxa-spiro[4.5]dec-8-yl-ethynyl)-6-methoxy-quinoline (0.83 g, 2.53 mmol) in EtOH (30 ml) and ethyl acetate (10 ml) and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The catalyst was filtered off and the filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc/-methanol 9/1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[C:9]2=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37]Cl.CN(C=[O:43])C>>[O:17]=[C:16]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:18])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:43])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)=[CH:3][C:4]=1[O:19][CH3:20]
Reactant: COc1cc(N)ccc1N1C(=O)C2CCCCN2C1=O
Reactant: CN(C)C=O
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)c2ccccn2)ccc1N1C(=O)C2CCCCN2C1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-amino-2-methoxyphenyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione (250 mg; 0.908 mmol) in DMF (5 mL) was added DIEA (316 μL; 1.82 mmol) followed by picolinyl chloride HCl (194 mg; 1.09 mmol). The reaction mixture was stirred at 50° C. overnight and then cooled to rt and washed with CH2Cl2 and H2O. The organic layer was concentrated and purified by flash column chromatography (EtOAc) yielding N-(4-(1,3-dioxotetrahydroimidazo[1,5-a]pyridin-2(1H,3H,5H)-yl)-3-methoxyphenyl)picolinamide, 1.3.1.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[F:27][C:26]([F:29])([F:28])[CH2:25][O:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1ccc(Sc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Sc2ccccc2)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
A solution was obtained by combining 20.2 g of 4-hydroxyphenyl phenyl sulfide which had been synthesized according to the well-known formulation, 15.3 g of 2,2,2-trifluoroethyl p-toluenesulfonate, 12.4 g of potassium carbonate, and 80 g of DMF. The solution was aged at 100° C. for 16 hours. The aged solution was cooled to room temperature, to which 50 g of water was added to quench the reaction. To the solution, 200 g of toluene was added for extraction. The organic layer was separated, and washed with 100 g of 5 wt % sodium hydroxide aqueous solution and water in sequence. On subsequent concentration in vacuum, 16.4 g of the target compound, phenyl 4-(2,2,2-trifluoroethoxy)phenyl sulfide was obtained as oily matter. Yield 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[N:14]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[N:14]=[C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:40]#[C:39][C:37]([CH3:38])([OH:41])[CH3:36])[N:12]=1
Reactant: C#CC(C)(C)O
Reactant: COc1ccc(Nc2nc(NC(C)C)nc(Oc3ccc(I)cc3)n2)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Nc2nc(NC(C)C)nc(Oc3ccccc3C#CC(C)(C)O)n2)cc1Cl
Reaction time: 6 h
Yield: 70.1 %

Procedure:
A mixture of compound N-(3-Chloro-4-methoxy-phenyl)-6-(4-iodo-phenoxy)-N′-isopropyl-[1,3,5]triazine-2,4-diamine (0.4 g, 0.78 mmol), triethylamine (0.27 ml, 1.95 mmol) in dimethylformamide (3 mL) was added bis(triphenylphosphine)palladium(II)chloride (27 mg, 0.04 mmol), CuI (15 mg, 0.08 mmol) and 2-methyl-3-butyn-2-ol (0.11 ml, 1.17 mmol). It is stirred under nitrogen atmosphere for 6 hrs. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as a pale yellow solid (0.256 g, 70%). mp 138-140° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 254 nm, Rt 16.80 min, 97.77% purity; MS (CI): m/z 468 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[N:22]1[N:23]([C:27]2([C:30](=N)OCC)[CH2:29][CH2:28]2)[N:24]=[CH:25][CH:26]=1.C(N(CC)CC)C.C(O)(=O)C>C(O)C>[N:22]1[N:23]([C:27]2([C:30]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH2:29][CH2:28]2)[N:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2nccn2)CC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5nccn5)CC4)[nH]c3n2)C1)N1CCCC1
Yield: 2.9 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (0.4 g, 1.36 mmol) in ethanol was added ethyl 1-(2H-1,2,3-triazol-2-yl)cyclopropanecarbimidate (600 mg, crude), triethylamine (5 mL) and acetic acid (6 mL). The reaction mixture was heated to reflux for 12 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was dried over sodium sulfate and concentrated. The crude material was purified via preparative TLC to afford the title compound (16 mg). MS (ES+) (M+H) 407.3; LCMS retention time 1.793 min (Method N1).