Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH2:29](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4=[N:11][C:12]([NH:19][C@H:20]([C:22]5[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=5)[CH3:21])=[CH:13][CH:14]=[C:15]4[N:16]=[CH:29]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccc2ncn(-c3cc(C4CC4)[nH]n3)c2n1)c1ncc(F)cn1
Temperature: 25 °C

Procedure:
N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 16, 0.45 g) was dissolved into ethanol (20 mL) with Pd—C (60 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 95° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.08 g of the title compound. MS (electrospray): 365 (M+1) for C18H17FN8. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.30 (s, 1H) 7.70 (d, 1H) 6.70 (d, 1H) 6.50 (s, 1H) 5.30 (dd, 1H) 2.00 (m, 1H) 1.60 (d, 3H) 1.10 (m, 2H) 0.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[F:34]C1C=C(F)C=CC=1CBr>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][C:32]=2[F:34])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccc(F)cc2)n1
Reactant: Fc1ccc(CBr)c(F)c1
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccc(F)cc2F)n1

Procedure:
Prepared in a similar manner to ethyl 6-(5′-chloro-2′-{[(4-fluorophenyl)methyl]oxy}-2-biphenylyl)-2-pyridinecarboxylate but using 2,4-difluorobenzyl bromide in place of 4-fluorobenzyl bromide. LC/MS t=3.82, [MH+] 480.3
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23]Cl)[N:3]=1.[CH3:26][CH:27]1[O:32][CH:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.[I-].[Na+]>CC(C)=O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:25])[CH2:23][N:29]2[CH2:28][CH:27]([CH3:26])[O:32][CH:31]([CH3:33])[CH2:30]2)[N:3]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCl)nc2N)cc1I
Reactant: CC1CNCC(C)O1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CN3CC(C)OC(C)C3)nc2N)cc1I
Temperature: 55 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-[4-Amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-chloro-acetamide (477 mg, 1 mmol), 2,6-dimethyl morpholine (0.62 mL, 5 mmol) and sodium iodide (25 mg) were added to 20 mL acetone. The reaction mixture was stirred under nitrogen at 55° C. for 18 hours, then cooled and concentrated under reduced pressure. The residue was diluted with water and extracted with methylene chloride. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (0%-20% “Magic Base”/methylene chloride) to give 311 mg of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-(2,6-dimethyl-morpholin-4-yl)-acetamide as an amorphous solid, MS (M+H)=556.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[O:7].[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:6]2[O:16][CH2:15][CH2:14][CH2:13][O:7]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(OC)cc(C2OCCCO2)c1

Procedure:
3,5-dimethoxybenzaldehyde (5.00 g,30.12 mmole), 1,3-propanediol (9.15 g, 120.5 mmole), pyridinium para-toluenesulfonate (3.02 g, 12.05 mmole) and 80 ml dry benzene were refluxed with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The benzene was removed in vacuo and the remaining oil redissolved in dichloromethane and was washed with 10% NaHCO3 and H2O. The organic layer was washed over Na2SO4 and concentrated to an oil in vacuo which was purified by flash column chromatography using 2:1 hexane/ethyl acetate containing 0.5% triethylamine as eluent. (5.731 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:12]=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1.5 g of 4-fluorobenzamide was dissolved in 20 ml of dichloromethane and 2.3 ml of oxalyl chloride was slowly added thereto at room temperature, and then the mixutre was heated and refluxed for 16 hours. When the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was distilled under reduced pressure to produce the titled compound as a oil. Without purification processes, next process was proceeded.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 59 %

Procedure:
2-[2-(2-Methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is prepared by following the procedure described in example 1a (step 5a) using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 510 mg of 2-methyl-2,3-dihydro-1H-indole and 487 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.308 ml of pyridine and 8 ml of N,N-dimethylformamide. 400 mg of 2-[2-(2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: CO[C:3]1[C:4](=[O:17])[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH3:18]>CO>[NH2:18][C:3]1[C:4](=[O:17])[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc(Oc2ccccc2)c1=O
Reactant: N
Solvent: CO
Product: Nc1ccccc(Oc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
A solution of 2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one (2.0 g, described above) in methanol (30 ml) is cooled to -25° C. and saturated with gaseous ammonia. The mixture is heated in a pressure bottle at 80° C. for four hours and cooled to -70° C. The bottle is opened and the solvent is removed under reduced pressure. The residue is crystallized from ethyl acetate to give 2-amino-7-phenoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:17][C@@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20][NH2:21])[N:3]=1.O.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[O:17][C@@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@@H:12]2[OH:13])=[C:4]([S:20]([NH2:21])=[O:31])[N:3]=1
Reactant: NSc1nc(N)nc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: O
Product: Nc1nc(S(N)=O)c2ncn([C@H]3O[C@@H](CO)[C@H](O)[C@@H]3O)c2n1
Temperature: -10 °C
Yield: 86.5 %

Procedure:
A mixture of 2-amino-9-(β-L-ribofiiranosyl)purine-6-sulfenamide 17 (200 mg, 0.637 mmol), ethanol (90 mL) and water (6.4 mL) was vigorously stirred at −10° C. in a salt-ice bath. A solution of MCPBA (80%, 137.0 mg, 0.637 mmol) in ethanol 5.5 mL was added dropwise over a period of 15 minutes. The mixture was allowed to stir and warm as the ice melt (8 h), and stirred at ambient temperature for addition 14 h. A small amount of precipitate was filtered out and the filtrate evaporated at 23° C. to dryness. The residue was triturated with ethyl ether (30 mL) and the solid was collected by filtration, washed with ethyl ether (10 mL). The solid was again suspended in ethyl ether (25 mL), filtered, and dried to give 182 mg (87%) of 2-amino-9-(β-L-ribofuranosyl)purine-6-sulfinamide 18 as a colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1.[OH-].[Na+]>ClCCl>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.1 g (36.2 mMol) benzoyl chloride are dissolved in 150 ml abs. dichlormethane and cooled to ca 0° C. under moisture exclusion. 10.4 g (36.2 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide (substance 14) are dissolved in 50 ml abs. dichlormethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. Subsequently, the suspension is added to 60 ml 2 M sodium hydroxide and extracted twice, each with 80 ml dichlormethane. The combined organic phases are washed twice, each with 60 ml water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3 to 95/5) and recrystalized from 75 ml acetonitrile. Colorless crystals with a MP of 100–102° C. are recovered; yield: 9.8 g (69%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([C:16]2[N:17]=[N:18][N:19]([C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@@H:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([C@@H:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH3:22])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@@H](O)c1cn([C@H](C)c2ccccc2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@@H](O)c4cn([C@H](C)c5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (R)-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-((R)-1-phenyl-ethyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[CH3:22].C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+].O>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>[C:1]([O:5][C:6]([C:7]1[C:8]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([F:15])[CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
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: CC(C)O
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
Compound A (80.0 g, 311 mmol) and 3-fluoro-4-methylphenylboronic acid (52.7 g, 342 mmol) were suspended in isopropyl alcohol (260 mL, 3.5 mol). A solution of sodium carbonate (56.1 g, 529 mmol) in water (260 mL, 15 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (3.6 g, 3.1 mmol) was then added and the mixture was stirred at 90° C. for 17 hours. The mixture was concentrated under reduced pressure and suspended in water (200 mL). The aqueous phase was extracted with EtOAc (600 mL) and separated. The organic phase was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (4-6% 5×120 g column) to yield compound B as a clear oil (68.2 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[C:23]([F:39])[CH:22]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[C:36]([O:37][CH3:38])=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:26])=[C:23]([F:39])[CH:22]=3)[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 18 h
Yield: 35.3 %

Procedure:
2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.344 mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg, 0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20 mmol) was added. The reaction mixture was stirred in a closed vial at 100° C. for 18 h, cooled, diluted with water (5 mL) and brought to pH=7 using solid sodium carbonate. The resulting mixture was diluted with ethanol (0.5 mL) and stirred for 5 min. The precipitate was filtered, washed with water (5 mL) and dried in air for 20-30 min. It was then suspended in ethanol (˜10 mL), treated with solid sodium bicarbonate (130 mg) and stirred vigorously for 45 min. The insoluble salts were filtered off and filtrate was concentrated in vacuo. The residue was crystallized from ethanol-water (1:7; 8 mL) and dried in vacuum to afford the title compound as a white solid (65 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=6.82 Hz, 6H) 1.49-1.62 (m, 2H) 1.77 (br. d., 2H) 1.95 (app. t, J=11.2 Hz, 2H) 2.15 (s, 3H) 2.73 (br. d., J=11.12 Hz, 2H) 3.33 (s, 3H) 3.71 (m, J=7.83 Hz, 1H) 3.91 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.90 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 7.88 (dd, J=7.33, 3.03 Hz, 1H) 7.97 (s, 1H) 8.20-8.32 (m, 2H); [M+H] calc'd for C25H32F3N7O3, 536. found 536.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([Li])CCC.[CH3:14][O:15][CH2:16][C:17](=[O:19])[CH3:18]>>[OH:19][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:18])[CH2:16][O:15][CH3:14]
Reactant: Oc1ccccc1Br
Reactant: COCC(C)=O
Agent: [Li]CCCC
Product: COCC(C)(O)c1ccccc1O

Procedure:
2-(2-hydroxy-1-methoxypropan-2-yl)phenol was prepared according to the procedure described for 417a using 2-bromophenol (400 μL, 3.4 mmol), n-butyllithium in hexanes (1.6 M, 5.0 mL, 7.9 mmol) and methoxyacetone (412 uL, 4.48 mmol). 1H NMR (400 MHz, CDCl3) δppm 1.64 (s, 3H), 3.45 (d, J=9.3 Hz, 1H), 3.47 (s, 3H), 3.77 (d, J=9.3 Hz, 1H), 6.85 (m, 1H), 6.90 (m, 1H), 7.04 (m, 1H), 7.20 (m, 1H), 9.22 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N(Br)[C:13](=[O:14])C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][O:14][CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(Br)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCc1cc(C)c(Br)c(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
2-bromomesitylene (5.00 g) was dissolved in carbon tetrachloride (50 mL). NBS (4.45 g) and benzoyl peroxide (182 mg) were added to the solution, and the mixture was stirred at 80° C. for three hours. The reaction mixture was returned to room temperature and filtered. The solid collected by filtration was washed with n-heptane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane). The resulting fraction was concentrated under reduced pressure. The residue was dissolved in THF (120 mL). Sodium methoxide (28% solution in methanol, 9.35 mL) was added to the solution, and the mixture was stirred at 80° C. for four hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. Water was added to the residue, followed by extraction with DCM. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 5%). The resulting fraction was concentrated under reduced pressure, and the residue was purified again by NH silica gel column chromatography (n-heptane) to give the title compound (880 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl[C:23]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:23]2[C:32]3[C:27](=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[CH:16][CH:15]=1)[C:3]([O:2][CH3:1])=[O:21])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1nccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 78.9 %

Procedure:
To N-(t-butyloxycarbonyl)tyrosine methyl ester (1.42 g, 4.82 mmol) in dry DMF (10 ml) was added 1-chloro-2,6 naphthyridine (0.79 g, 4.82 mmol) and cesium carbonate (1.65 g, 5.06 mmol) and the reaction stirred at 45° under N2 for 2 days. The DMF was evaporated, EtOAc added and washed (3×) with water, dried (MgSO4), and evaporated in vacuo. The residue was chromatographed (SiO2; 40 to 100% EtOAc/isohexane) to afford the title compound as white foam (1.61 g, 82%). δH (CDCl3) 9.29 (1H, s), 8.76 (1H, d, J 5.74 HZ), 8.17 (1H, d, J 5.74 Hz), 8.11 (1H, d, J 5.8 Hz), 7.43 (1H, d, J 5.8 Hz), 7.22-7.18 (3H, m), 5.03 (1H, br s), 4.61 (1H, br s), 3.75 (3H, s), 3.15-3.05 (2H, m), 1.44 (9H, s); m/z (ES+, 70V) MH+424.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([CH3:26])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].N1C=CC=CC=1.[CH:42]([O:45][C:46](Cl)=[O:47])([CH3:44])[CH3:43]>ClCCl>[CH:42]([O:45][C:46]([N:14]1[CH2:15][CH2:16][CH2:17][CH:11]([N:7]([C:8](=[O:10])[CH3:9])[CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=2)[C:12]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([CH3:26])[C:13]1=2)=[O:47])([CH3:44])[CH3:43]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0210 g, 0.0410 mmol) and pyridine (0.0100 ml, 0.123 mmol) in dichloromethane (1.00 ml) was added 1M isopropylchloroformate (solution in toluene) (0.120 ml), 0.123 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvents were evaporated on a rotavapor (rotary evaporator). Purification by silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hexane) provided the titled compound (0.0180 g, 72%) as white crystalline. MS (ES+): 599 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
Dissolve 3,4-difluoronitrobenzene (2.0 g, 12.6 mmol) in acetonitrile (35 mL) and add piperazine-1-carboxylic acid tert-butyl ester (4.7 g, 25.2 mmol). Heat the mixture at reflux for 16 h. Cool the mixture to room temperature and concentrate in vacuo. Partition the residue between dichloromethane (75 mL) and water (75 mL), separate the organic portion and extract the aqueous portion with dichloromethane (2×25 mL). Combine the organics and dry (Na2SO4), filter, and concentrate in vacuo to give 2.83 g (72%) of the title compound. MS/ES m/z 270.2 [M-tertBu+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[CH:14]=[C:13]([NH:15][C:16](=[O:59])[NH:17][C@@H:18]2[CH2:22][CH2:21][N:20]([C:23]3[N:31]=[C:30]4[C:26]([N:27]=[CH:28][N:29]4[C@@H:32]4[CH2:36][C@H:35]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C@@H:34]([OH:42])[C@H:33]4[OH:43])=[C:25]([NH:44][CH2:45][CH:46]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:24]=3)[CH2:19]2)C=C(Cl)N=1.[S:61]1C=CC=[C:62]1N=C=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:47]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:45][NH:44][C:25]2[N:24]=[C:23]([N:20]3[CH2:21][CH2:22][C@@H:18]([NH:17][C:16]([NH:15][C:13]4[S:61][CH:62]=[CH:9][CH:14]=4)=[O:59])[CH2:19]3)[N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][N:29]3[C@@H:32]2[CH2:36][C@H:35]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[C@@H:34]([OH:42])[C@H:33]2[OH:43])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C=Nc1cccs1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cc(Cl)nc(Cl)c5)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccs5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-{(R)-3-[3-(2,6-dichloro-pyridin-4-yl)-ureido]-pyrrolidin-1-yl}-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate (Example 73) by replacing 2,6-dichloro-4-isocyanato-pyridine with 2-thienyl isocyanate.