Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([C:22]3[S:23][CH:24]=[C:25]4[C:29]=3[NH:28][C:27](=[O:30])[N:26]4C(OC(C)(C)C)=O)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:38]1[S:39][CH:40]=[C:41]3[C:45]=1[NH:44][C:43](=[O:46])[N:42]3C(OC(C)(C)C)=O)[CH:14]=2.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([C:22]3[S:23][CH:24]=[C:25]4[C:29]=3[NH:28][C:27](=[O:30])[NH:26]4)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:38]1[S:39][CH:40]=[C:41]3[C:45]=1[NH:44][C:43](=[O:46])[NH:42]3)[CH:14]=2
Reactant: Cn1c2ccc(-c3scc4c3[nH]c(=O)n4C(=O)OC(C)(C)C)cc2c2cc(-c3scc4c3[nH]c(=O)n4C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2ccc(-c3scc4[nH]c(=O)[nH]c34)cc2c2cc(-c3scc4[nH]c(=O)[nH]c34)ccc21
Reaction time: 3 h

Procedure:
Trifluoroacetic acid in an amount of 40 equivalents was added to the obtained tert-butyl 4-[9-methyl-6-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-9H-carbazol-3-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate and a reaction was carried out at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then an organic layer was taken and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[9-methyl-6-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-9H-carbazol-3-yl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on the charged tert-butyl 4-[9-methyl-6-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-9H-carbazol 3-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxy late was 90%.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Yield: 85.3 %

Procedure:
A mixture of (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (13.6 g, 0.048 mol) and Pd/C (1.4 g) in methanol (200 mL) was hydrogenated with a balloon overnight. The mixture was filtered through a pad of Celite and the solvent was removed to give (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (10.5 g, 86%), which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): 4.52 (d, J=8.4 Hz, 1H), 3.68 (m, 2H), 2.73 (dd, J=13.6&4.4 Hz, 1H), 2.58 (dd, J=13.6&6.0 Hz, 1H), 1.81 (m, 1H), 1.65 (m, 4H), 1.42 (s, 9H), 1.40-1.00 (m, 6H), 1.00-0.70 (m, 2H). MS (E/Z): 257 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:4]=2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[C:12]([CH2:18][CH3:19])[CH:11]=2)[N:8]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:4]2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[C:12]([CH2:18][CH3:19])[CH:11]=3)[N:8]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[C:3]=2[CH:25]=1
Reactant: CCc1ccc(CC2N=C(Cl)c3cc(Cl)ccc3N(C)C2=O)cc1CC
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1ccc(CC2N=C(c3ccc(F)cc3)c3cc(Cl)ccc3N(C)C2=O)cc1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
A 10 mL sealed tube was charged with (E)-5,7-dichloro-3-(3,4-diethylbenzyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.25 g, 0.505 mmol, 1 equivalent), 4-fluorophenylboronic acid (0.071 g, 0.505 mmol, 1 equivalent), Pd(OAc)2, (0.2 equivalents), PPh3 (0.2 equivalents), Cs2CO3 (2 equivalents) and DMF (3 mL). The tube was evacuated, flushed with nitrogen gas and placed in an oil bath at 100° C. for 1.5 hour. The mixture was cooled to ambient temperature, diluted with ethyl acetate (10 mL) and water (5 mL), and filtered through a pad of celite. The layers were separated and the organic phase was washed with brine (3×10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 70:30 hexanes:ethyl acetate) to provide an oil. This oil was dissolved in a mixture of acetonitrile (3 mL) and water (1 mL), and the solution was freeze-dried overnight to give (Z)-7-chloro-3-(3,4-diethylbenzyl)-5-(4-fluorophenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.12 g, 43%) as an off-white solid: mp 54-56° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.41-7.22 (m, 4H), 7.18-6.98 (m, 6H), 6.87 (d, J=8.6 Hz, 2H), 6.60 (d, J=4.6 Hz, 2H), 5.66 (d, J=15 Hz, 1H), 4.56 (d, J=15 Hz, 1H), 3.82-3.77 (m, 1H), 3.70 (s, 3H), 3.63-3.55 (m, 2H), 2.67-2.58 (m, 4H), 1.26-1.12 (m, 6H); APCI MS m/z 556 [M+H+].
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21]I>CN(C)C=O>[C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[N:8]2[CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 55.7 %

Procedure:
A mixture of (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 4.77 g, 17.8 mmol) and methyl iodide (2.2 mL, 35.3 mmol) in N,N-dimethylformamide (30 mL) was purged with argon and then heated in a sealed tube at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with sodium bicarbonate and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, evaporated and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales 120 g column, eluting with 25-75% ethyl acetate/hexanes followed by recrystallization from ethyl acetate to give (4S,7R)-2-phenyl-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.8 g) of white crystals. The filtrate was evaporated and recrystallized from ethyl acetate to give a further 0.53 g, and the resulting filtrate was evaporated, dissolved in dichloromethane, treated with decolorizing charcoal and crystallized from dichloromethane to give a further 0.77 g of product. The total yield was 4.1 g (82%). EI(+)-MS (M+H) 283.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]([O:10][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(OS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2.0 g (10.8 mmol) of ethyl 4,4,4-trifluoroacetoacetate in 10 ml of DMF was added 2.28 g of p-toluenesulfonyl chloride and 4.24 g of cesium carbonate and stirred at room temperature overnight. The reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.27 g of ethyl 4,4,4-trifluoro-3-p-toluenesulfonyloxy-2-butenoate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:4]=2[C:5]2[C:9]([CH3:10])=[N:8][O:7][C:6]=2[C:11]2([N:14]=1)[CH2:13][CH2:12]2.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:19][C:17]1[CH:16]=[CH:15][C:4]2[C:5]3[C:9]([CH3:10])=[N:8][O:7][C:6]=3[C:11]3([CH2:13][CH2:12]3)[N:14]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[C:3]=2[CH:18]=1
Reactant: Cc1noc2c1-c1ccc(Cl)cc1C(Cl)=NC21CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1noc2c1-c1ccc(Cl)cc1C(c1ccc(F)cc1)=NC21CC1
Temperature: 82 °C

Procedure:
To a solution of 6,8-dichloro-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane] (61.9 mg, 0.211 mmol) in toluene (22 mL) was added 4-fluorophenylboronic acid (37 mg, 0.264 mmol) and Pd(Ph3P)4 (11.22 mg, 9.71 μmol). The reaction was evacuated and purged with N2 (g) (3×), followed by addition of aqueous Na2CO3 (211 μl, 0.422 mmol, 2 M). The reaction was heated to 82° C. for 15 min at which time LC-MS analysis indicated complete conversion to desired product. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude product was purified on Biotage system (5% EtOAc:95% Hexanes to 10% EtOAc:90% Hexanes). The product 8-chloro-6-(4-fluorophenyl)-1-methylspiro[benzo[e]isoxazolo[5,4-c]azepine-4,1′-cyclopropane] (62 mg, 0.176 mmol, 83% yield) was obtained as a white crystals. LC/MS m/z 353 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.77 (m, 1H), 7.75-7.71 (m, 1H), 7.45-7.38 (m, 2H), 7.19-7.26 (m, 3H), 2.52 (s, 3H), 1.29 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C#N)[CH:5]=[CH:4][N:3]=1.C[Mg]I.CC[O:15][CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:16](=[O:15])[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: CCOCC
Reactant: N#Cc1ccnc(Cl)c1
Agent: C[Mg]I
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4-cyanopyridine (41.6 g) in dry ether under a nitrogen-atmosphere was added methylmagnesium iodide (200 mL, 3M in ether) dropwise. The resulting mixture was stirred at room temperature overnight. The solids which were formed were collected and poured immediately on a mixture of 1000 g ice, 500 mL water and 250 mL 6N HCl. The aqueous solution was allowed to reach room temperature and then extracted with ether (800 mL) and the combined organic layers were dried (sodium sulfate) and evaporated to give a red oil which crystallised on standing. This material was taken up in a mixture of ether (ca 300 mL) and heptane (˜50 mL). The solution was cooled in an acetone/dry-ice bath which resulted in formation of yellow solids that were filtered and air-dried for 30 minutes to give the title compound (21.7 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[C:3]1=[O:16].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:30])([F:31])[F:17])[CH2:6][CH2:5]2)[C:3]1=[O:16]
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of 1-methylspiro[indoline-3,4′-piperidin]-2-one (100 mg, 0.46 mmol) in CH2Cl2 (5 mL) was added 3-(2-trifluoromethyl-phenyl)-acrylic acid (120 mg, 0.56 mmol), HOBt (124 mg, 0.92 mmol), EDCI (181 mg, 0.92 mmol) and DIEA (297 mg, 2.30 mmol). The reaction mixture was stirred at rt overnight. The above mixture was concentrated and the residue was purified by preparative HPLC to give (E)-1-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one (50 mg, 26%). 1H NMR (CDCl3): 1.85-2.00 (m, 4H), 3.72 (s, 3H), 3.90-4.00 (m, 2H), 4.15-4.30 (m, 1H), 4.40-4.50 (m, 1H), 6.80-6.90 (m, 2H), 7.10-7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.45-7.60 (m, 2H), 7.68-7.72 (m, 2H), 7.91-8.00 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([C:7]1[S:11][C:10]([N:12](C)[C:13](=O)OC(C)(C)C)=[N:9][C:8]=1[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)=[O:6])[CH3:2]>FC(F)(F)C(O)=O>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:8]1[N:9]=[C:10]([NH:12][CH3:13])[S:11][C:7]=1[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[O:6]
Reactant: CCOCC(=O)c1sc(N(C)C(=O)OC(C)(C)C)nc1-c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: CCOCC(=O)c1sc(NC)nc1-c1ccco1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Compound 623 (550 mg, 1.50 mmol) was dissolved in trifluoroacetic acid (2 mL), followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated sodium hydrogencarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 624 (344 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[S:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:12]1[S:13][C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[CH:6][C:5]=2[N:11]=1
Reactant: COc1cc(NC(=S)c2c(F)cccc2F)cc(OC)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Product: COc1cc(OC)c2sc(-c3c(F)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.5 %

Procedure:
170 ml (103 mmol; 3 equivalents) of a freshly prepared 20% aqueous solution of potassium ferricyanide is added to 10.3 g (33.3 mmol) of N-(3,5-dimethoxyphenyl)-2,6-difluorobenzenecarbothioamide dissolved in 150 ml of a 1.5M soda solution. The reaction medium is maintained under stirring at ambient temperature for 24 hours, then the beige precipitate formed is filtered, washed with water and dried (6.8 g; yield=66%). The mother liquors can be extracted by 3 times 75 ml of dichloromethane, then the organic phases are washed with a saturated solution of sodium chloride. After concentration under reduced pressure, the residue obtained can be purified on a silica column (eluent: ethyl acetate/heptane: 1/3) in order to provide another 2 g of expected product (overall yield=86%). Melting point: 136-138° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C1CCN2C(=NCCC2)CC1>C(O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2nc3ccccc3[nH]2)cc1
Yield: 15.3 %

Procedure:
2-Chlorobenzimidazole (0.033 moles, 5.0 g), 4-nitrothiophenol (0.033 moles, 4.14 g), and DBU (0.033 moles, 5.0 g) in 200 ml ethanol were heated at 55° C. for 3 hr. The reaction was concentrated, ethyl acetate added, washed with water, dried over sodium sulfate and the solvent removed. The solid was slurred in hexane to yield 2-(4-nitrophenylthio)benzimidazole 1.37 g, 15%. Mass Spec (FD) 271. Calculated for C13H8N3O2S: C, 57.55; H, 3.34; N, 15.49. Found: C, 57.50; H, 5.54; N, 15.23.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][CH:12]=[N:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: O
Product: O=c1nc[nH]c2ccc(I)cc12
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-amino-5-iodo-benzoic acid (5.00 g, 19.0 mmol) and formamide (3.43 g, 76.0 mmol) were heated to 150° C. for 4 hours and then cooled to room temperature. Water was added and the solution was filtered and washed with water several times to give 3.6 g (70%) of 6-iodo-1H-quinazolin-4-one. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 8.09 (dd, 1H, J=2.0, 8.8 Hz), 7.45 (d, 1H, J=8.8 Hz).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:32]1[CH:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:11]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[K+]>[Pd].C(O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C@@H:12]2[CH2:13][CH2:14][C@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[N:11]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc([N+](=O)[O-])cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reaction time: 8 h
Yield: 5.7 %

Procedure:
To 0.70 g (0.66 mmol) of 10% palladium on carbon was added a solution of 6.4 g (11 mmol) of tert-butyl(2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]-5-(4-nitrobenzyl)pyrrolidine-1-carboxylate from Step A in 75 mL of anhydrous ethanol followed by 1.2 g (12 mmol) of potassium acetate. The resulting suspension was agitated under an atmosphere of hydrogen at 50 psi for 8 h. then filtered through a plug of Celite®. The plug was washed with ethanol (100 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.31 g, 76%). LC-MS: m/z (ES) 498.4 (MH)+.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH2:27])[N:21]=[CH:20]3)O1.[CH3:29][O:30][C:31]1[CH:46]=[CH:45][C:34]([CH2:35][O:36][C:37]2[C:42](Br)=[C:41]([CH3:44])[CH:40]=[CH:39][N:38]=2)=[CH:33][CH:32]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C(O)(C)C.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][C:37]2[C:42]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[C:22]([NH2:27])[N:21]=[CH:20]4)=[C:41]([CH3:44])[CH:40]=[CH:39][N:38]=2)=[CH:45][CH:46]=1
Reactant: COc1ccc(COc2nccc(C)c2Br)cc1
Reactant: CC1(C)OB(c2ccc3nc(N)ncc3c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COc2nccc(C)c2-c2ccc3nc(N)ncc3c2)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a mixture of potassium phosphate (2.07 g, 9.73 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (1.06 g, 3.89 mmol), 2-(4-methoxybenzyloxy)-3-bromo-4-methylpyridine (1.000 g, 3.24 mmol), and S-PHOS (0.162 mmol) in isopropyl alcohol (21 mL) and water (7 mL) was added palladium acetate (0.0364 g, 0.162 mmol). The mixture was stirred at 75° C. After 4 hrs, the reaction mixture was diluted with EtOAc (ca. 100 mL) and washed with water and brine. After drying with sodium sulfate, the organic fraction was stripped onto silica and purified by silica gel chromatography using 1-8% MeOH in CH2Cl2 w/NH4OH to provide 6-(2-(4-methoxybenzyloxy)-4-methylpyridin-3-yl)quinazolin-2-amine as a tan solid. M+H+=373.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[CH3:14])[CH:6]=[N:5]2.[C:22]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1>[C:25]([O:24][C:22]([N:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH3:14])[CH:6]=[N:5]3)[CH:31]=[N:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Product: C[C@@H](Nc1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1)c1cccc(Cl)c1
Temperature: 110 °C

Procedure:
A mixture of (6-Bromo-quinoxalin-2-yl)-[(R)-1-(3-chloro-phenyl)-ethyl]-amine (0.38 g, 1.0 mmol), N-Boc-4-pyrazole boronic acid pinacol ester (0.37 g, 1.2 mmol), caesium carbonate (1.36 g, 4.1 mmol) and potassium iodide (0.017 g, 0.1) in 1,4-dioxane (20 mL) was degassed at RT under vacuum and placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(0)) (0.053 g, 0.1 mmol) was added at RT. The reaction mixture was heated at 110° C. in a microwave reactor for 180 minutes. The organic mixture was diluted with ethyl acetate (150 mL) and washed with water (20 mL×2) and brine (20 mL). The organic solvent was evaporated in vacuo to afford the crude product.
Reaction SMILES: C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[C:45]([CH3:50])[CH:44]=2)[C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.B>>[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[C:45]([CH3:50])[CH:44]=2)[CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(CC2OCCN(Cc3ccccc3)C2=O)ccc1F
Agent: B
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: Cc1cc(CC2CN(Cc3ccccc3)CCO2)ccc1F

Procedure:
N-Benzyl-2-(4-fluoro-3-methylbenzyl)-morpholine was prepared as described for example 70, intermediate (a), but using N-benzyl-2-(4-fluoro-3-methylbenzyl)-morpholin-3-one and borane and was isolated as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10](=[O:15])[NH:11][CH2:12][CH2:13][OH:14])[CH3:9])(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C@H:8]([CH3:9])[C:10]([NH:11][CH2:12][CH2:13][OH:14])=[O:15]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)NCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, [(R)-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.78 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (1.8 ml, 23.4 mmol) was slowly added. The pale yellow reaction mixture was stirred at room temperature for 2 h then concentrated to afford (R)-2-amino-N-(2-hydroxy-ethyl)-propionamide trifluoroacetate as a light yellow oil which was used without further purification.