Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.[CH2:5]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19](C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)[CH:6]=[CH2:7]>CO>[CH2:5]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=1)[CH2:11][CH2:12]2)[CH:6]=[CH2:7]
Reactant: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)Cl
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC

Procedure:
Acetyl chloride (5 ml) was cautiously added to methanol (25 ml) and (1R*,2R*,5S*,6R*)-8-allyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 94; 1.23 g, 2.16 mmol) dissolved in the resulting solution. After standing for 4 weeks, the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (25 ml) and saturated aqueous sodium carbonate (2×15 ml), the organic layers dried (MgSO4) and evaporated to leave the title compound as a gum. (1.07 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])O.[Na+].[CH2:17]([O:25][C:26](Cl)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>O>[CH2:17]([O:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCOC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
To an aqueous solution dissolved 153 g of 4-aminosalicylic acid and 170 g of sodium hydrogen carbonate in 2200 ml of water, 193 g of n-octylchloroformate was dropwise added over 2 hours at room temperature. After finishing dropwise addition, the mixture was further stirred for 5 hours at room temperature. An aqueous solution containing 30 g of concentrated hydrochloric acid and 1200 ml of water was added to the reaction mixture. Precipitated crystals were filtered and dried to obtain 148 g of desired 4-(n-octyloxycarbonylamino)salicylic acid as colorless crystals. Yield was 48%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CN(C)C=O>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: CN(C)C=O
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and N,N-dimethylformamide (125 ml) is stirred at about 80° C. for 24 hours. Unreacted 2-chloro-acrylonitrile and 2,6-difluorobenzyl azide as well as N,N-dimethylformamide are distilled off (distillate 100 ml) by raising the external temperature to about 130° C. and gradually evacuating to about 100 mbar. After cooling to 100° C., water (100 ml) is allowed to run in. The crystallization of the product is initiated by seeding the brown emulsion. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 30 minutes. The product is isolated by filtration and washed with water (100 ml). The product is dried in vacuo at about 60° C. Yield: 34.40 g=78.1% (beige crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.CCN(C(C)C)C(C)C>C1COCC1>[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-n5ccnc5)cc4)CC3)c2cc1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (16.5 mg, 0.05 mmol), prepared as described in Example 3a, was dissolved in anhydrous THF (2 mL) and to it was added 4-imidazol-1-yl-phenylamine (12 mg, 0.075 mmol) followed by DIEA (14 μL, 0.075 mmol) and the mixture was stirred at 65° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 2 mg (5%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-imidazol-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 2H), 7.63 (m, 3H), 7.55-7.40 (m, 5H), 7.33 (s, 1H), 4.37 (m, 2H), 4.07 (s, 6H), 3.76-3.58 (m, 2H), 3.14 (m, 2H), 2.18-1.90 (m, 3H). LC/MS (ESI): calcd mass 458.2, found 459.5 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:30]#[N:31])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:30]([C:13]1[CH:14]=[C:9]([CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:10]=[CH:11][N:12]=1)#[N:31]
Reactant: C[Si](C)(C)C#N
Reactant: CCOC(=O)C(C)Cc1ccncc1
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Cc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.6 %

Procedure:
Ethyl 2-methyl-3-(4-pyridyl)propionate (5.9 g, 30.5 mmol) was dissolved in ethyl acetate (25 ml) and 3-Chloroperbenzoic acid (ca. 77%, 7.5 g, 33.4 mmol) was added thereto. The reaction mixture was stirred at room temperature for 14 hrs and subjected to a silica gel (120 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (3:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (18 ml), and trimethylsilyl cyanide (4.5 g, 45.0 mmol) and N,N-dimethylcarbamoyl chloride (3.5 g, 32.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (3.7 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29]O.CS([Cl:35])(=O)=O.O>CN(C)C=O>[Cl:35][CH2:29][C:3]1[C:4]([CH3:28])=[CH:5][CH:6]=[C:7]([N:8]([C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)[CH3:27])[C:2]=1[CH3:1]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2,6-dimethyl-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl) cinnamoylglycyl]amino]benzene (2.00 g) in N,N-dimethylformamide (100 ml) was added methanesulfonyl chloride (784 mg) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature and overnight at ambient temperature. To the mixture was added water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was pulverized with diethyl ether to give 1-chloromethyl-2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzene (2.00 g) as white powder.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]1([CH3:16])[CH3:15])(=[O:3])C.[O:17]1CCOCC1>>[C:11]([O:10][C:8]([C@H:6]1[CH2:7][C@@H:4]([C:1]([OH:3])=[O:17])[C:5]1([CH3:16])[CH3:15])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)C1(C)C
Reactant: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Reaction time: 3 h
Yield: 78 %

Procedure:
A stirred solution of (1S,3R)-tert-butyl 3-acetyl-2,2-dimethylcyclobutanecarboxylate (2.4 g, 10.62 mmol) in dioxane (270 ml) aqueous NaOBr solution (about 180 ml) was added slowly at about 0° C. and stirred at the same temperature for about 3 hours then allowed to stirred at room temperature for about 4 hours (the yellow colored solution turned to white color). After completion of the reaction (monitored by TLC), the reaction mixture was washed with methyl t-butyl ether (3×150 ml), the aqueous layer was adjusted pH (2-3) with 1N HCl and the aqueous layer was extracted with EtOAc and dried over Na2SO4 and the solvent was evaporated to afford title compound as an off white liquid. Wt: 1.9 g; Yield: 78%; 1H NMR (300 MHZ, CDCl3): δ 2.82-2.67 (m, 2H), 2.57-2.50 (m, 1H), 2.04-1.98 (m, 1H), 1.42 (s, 9H), 1.34 (s, 3H), 1.05 (s, 3H); IR (KBr, cm−1): 3205, 1731, 1694, 1460, 1371, 1236, 1157, 1108, 846, 721; Mass: [M+Na]+ 251 (40%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][C:43]([NH:42][CH2:41][CH2:40][O:39][CH3:38])=[O:51])[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCNC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCOC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N6O4 [(M+H)+] 723.3187, observed 723.3191.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.[Si](I)(C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][NH:13][CH2:12]3)=[C:8]([C:28]([NH2:29])=[O:30])[CH:7]=[N:6][N:5]2[CH:31]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CNC[C@@H]1CF
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 128.1 %

Procedure:
A solution of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (1.15 g, 2.345 mmol) in Acetonitrile (15 mL) at 0° C. was added TMS-I (1.277 mL, 9.38 mmol) dropwise and the resulting mixture was stirred for 10 min. and then allowed to warm to RT and stir for 1 hr. The reaction was quenched with 1.5 mL of MeOH and stirred for 10 minutes. The solid was collected as a hydroiodide salt of the title compound (1.07 g, 94% yield). MS (ES+) m/z: 356.1, 358.0 (M+H); HPLC: 96.7%, retention time: 1.525 min (analytical HPLC Method H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7]>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7]
Reactant: N#CCOc1ccccc1Br
Solvent: C1CCOC1
Product: NCCOc1ccccc1Br
Temperature: 0 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-bromophenoxy)acetonitrile (5.63 g, 26.68 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of BH3 in tetrahydrofuran (143 mL, 5.30 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 20° C. in an oil bath and quenched by the addition of water (10 ml). The resulting mixture was concentrated under vacuum and diluted with water. The pH value of the aqueous solution was adjusted to 10 with 1N sodium hydroxide and extracted with 6×50 mL of dichloromethane. The organic layers was combined and concentrated under vacuum. This resulted in 5.67 g (crude) of 2-(2-bromophenoxy)ethanamine as pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([N:22]=[C:23]=S)[CH:21]=1>CO>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([NH:22][C:23]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:21]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: Cc1ccc(F)cc1N=C=S
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
In methanol (30 ml) was dissolved methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol). To the resulting solution was added 5-fluoro-2-methylphenyl isothiocyanate (1.0 g, 5.98 mmol). After the resulting mixture was stirred at room temperature for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The mixture was stirred at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1, v/v) eluate fractions, methyl (2-(5-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (810 mg, 56% (2 steps)) was obtained as a pink solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[CH:17]=[CH2:16]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-hydroxybenzenesulfonyl azide synthesized in Synthetic example 2 (1.72 g, 8.63 mmol, and 1.00 Eq) was dissolved in DMF (17 mL), and then sodium hydroxide (354 mg, 8.85 mmol, and 1.03 Eq) and allylbromide (14.0 g, 116 mmol, and 13.4 Eq) were added thereto. The solution was stirred at room temperature for 16 hours and water (50 mL) was added thereto, followed by extraction with diethylether (3×20 mL). The obtained organic layer was dried with sodium sulfate and the organic solvent was removed by the evaporator (30° C.). The product was purified by column chromatography (hexane/ethyl acetate 10:1) to obtain 4-allyloxybenzenesulphonyl azide as pale yellow oil (0.89 g, and 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:40][O:41][C:42]1[CH:61]=[CH:60][C:45]([C:46](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CO>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37][C:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]3[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:61][CH:60]=3)[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](CO)O2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Yield: 71.9 %

Procedure:
Compound 6 (0.62 g, 1.24 mmol) in dry pyridine (25 mL) was treated with 4-monomethoxytrityl chloride (0.46 g, 1.49 mmol) at room temperature for 16 h. After addition of methanol (5 mL), the mixture was concentrated to dryness. The residue was dissolved in dichloromethane (60 mL) and washed successively with water (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and water (3×40 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give 7 (0.71 g, 72%) as a foam: 1H NMR (DMSO-d6): δ2.21 (d, 1H, H-2′ J2′,2″=14.3 Hz), 2.6-2.7 (m, 1H, H-2″), 3.1-3.3 (2m, 2H, H-5′ and H-5″), 3.64 and 3.65 (2s, 6H, 2×OCH3), 4.1-4.2 (m, 1H, H-4′), 4.2-4.3 (m, 1H, H-3′), 5.68 (d, 1H, OH-3′, JH,OH =5.2 Hz), 6.24 (d, 1H, H-1′, J1′,2″=7.0 Hz), 6.7-6.8 and 7.1-7.3 (2m, 29H, 2 MMTr and NH-6), 7.83 and 8.21 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 796 [M+H]+, 408 [BH2]+, (FAB−) m/z 794 [M−H]−, 406 [B]−; UV (95% ethanol): λmax 275 nm (ε 30900), λmin 246 nm (ε 12800); [α]D20 =+14 (c 1.03, DMSO).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:13]([O:21][CH3:22])(=[O:20])[C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17]>[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)Cl.CO>[C@@H:2]12[N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C@@H:5]([CH:4]=[CH:3]1)[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:13]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(C)(C)OC(=O)n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=C(C(=O)OC)[C@@H]2C=C[C@H]1N2C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
A mixture of tert-butyl 1H-pyrrole-1-carboxylate (XLV) (3.50 g 20.93 mmol), dimethyl but-2-ynedioate (XLVI) (2.57 mL, 20.93 mmol) and AlCl3 (28 mg, 0.21 mmol) were stirred for 3 days at 70° C. The crude product was purified by silica gel chromatography using 100% DCM then DCM/MeOH 1000/1→500/1 to give (1R,4S)-7-tert-butyl 2,3-dimethyl 7-azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylate (XLVII) as a yellow oil (3.41 g, 11.04 mmol, 53% yield). 1H NMR (CDCl3) δ ppm 1.40 (s, 9H), 3.80 (s, 6H), 5.44 (s, 2H), 7.13 (d, J=13 Hz, 2H); ESIMS found for C15H19NO6 m/z 332 (M+Na).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1.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.[Cu]I>[CH3:23][Si:22]([C:26]#[C:27][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 3-iodobenzoate (I15) (4.02 g, 13.2 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol) and copper(I) iodide (0.13 g, 0.68 mmol) was dissolved in anhydrous THF (50 mL) under a nitrogen atmosphere and the resulting solution degassed by bubbling nitrogen through it. Triethylamine (9.2 mL, 66 mmol) was added and the mixture was then stirred for 10 minutes before addition of TMS-acetylene (3.8 mL, 27 mmol). The resulting mixture was then stirred for 18 hours. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I16) (3.57 g, 99%) as a cream crystalline solid; 1H NMR (400 MHz, CDCl3) δ 8.06 (ddd, J=1.7, 1.7, 0.5 Hz, 1H), 7.92 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.60 (ddd, J=7.7, 1.4, 1.4 Hz, 1H), 7.35 (ddd, J=7.8, 7.8, 0.5 Hz, 1H), 1.59 (s, 9H), 0.26 (s, 9H). LCMS Method C: rt 7.46 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33].O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][C:10]2[C:11](=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:32]1=[O:33]
Reactant: CSc1ncc(CNc2ccccc2Cl)c(Nc2ccccc2)n1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N(c1ccccc1)C(=O)N(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A cooled solution of 5-(2-chlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine (6 g) and 5.2 mL of triethylamine in 75 mL of tetrahydrofuran was added dropwise 8.5 mL of phosgene (20% in toluene) in 35 mL of tetrahydrofuran. The mixture was stirred at room temperature overnight. Additional 3 mL phosgene (20% in toluene) was added to the mixture. After stirring for 15 minutes the mixture was treated with water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography using 10:45 ethyl acetate/hexanes as eluant to give 2.1 g of 3-(2-chlorophenyl)-7-methylthio-1-phenyl-3,4-dihydropyrimido[4,5-d]-pyrimidin-2(1H)-one as a white solid, m.p. 79.5-82.4° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-c1ncccn1
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1-c1ncccn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A298 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.