Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Br)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c(Br)nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: C1CCNCC1
Product: O=c1c2[nH]c(N3CCCCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
The title compound was prepared from 1,3-di-cyclopropylmethyl-8-bromo xanthine (1.2 g, 0.0037 mol) and piperidine (0.79 g, 0.009 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:36]C)[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:23]#[C:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=3)[CH:6]=[CH:5][C:4]1=2)C.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:3]1([CH3:36])[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:23]#[C:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:34][CH:35]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(CC)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(C(F)(F)F)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-diethyl-8-(4-trifluoromethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 9) 70.0 mg (0.148 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: [C:1]([O:5]C)(=O)[CH2:2][OH:3].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1>>[OH:3][CH2:2][C:1]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)=[O:5]
Reactant: COC(=O)CO
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)CO)n1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from methyl glycolate and 2-amino-4-methylthiazole, 1H NMR (300 MHz, CDCl3) δ 10.11 (br s, 1H), 6.55 (s, 1H), 5.58 (br s, 1H), 4.36 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C(O[C:15](OCC)(OCC)[CH2:16][CH3:17])C>>[CH2:16]([C:17]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1)[CH3:15]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNC(=O)c1ccc(O)cc1
Product: CCc1nnc(-c2ccc(O)cc2)o1
Yield: 96.7 %

Procedure:
A mixture of 19 parts of 4-hydroxybenzoic acid hydrazide and 89.8 parts of 1,1,1-triethoxypropane was refluxed overnight. After cooling the precipitate was filtered off, washed with petroleumether and dried, yielding 23 parts (96.7%) of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenol (interm. 8).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:14])([C:6](=[O:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH3:5].Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:5][C:4]([CH3:14])([C:6](=[O:13])[CH:7]([N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:3]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)C(=O)C(CCOc1ccccc1)n1cncn1

Procedure:
2.6 g of sodium hydride, 16.7 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one and 20.1 g of 1-bromo-2-phenoxyethane are reacted by a method similar to that of Example 1b.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:37])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C:9]1([CH3:37])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1
Reactant: COc1c(N2CC3(CC3)C(C)(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Product: COc1c(N2CC(C)(N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
The 7-[7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid produced in Reference Example 29 (870 mg, 1.676 mmol) was dissolved in concentrated hydrochloric acid (10 mL) in an ice bath, and the mixture was stirred at room temperature for 20 minutes and washed chloroform (20 mL×5). Saturated aqueous solution of sodium hydroxide was added to the aqueous layer in an ice bath to adjust the pH to 12.0, and the pH was further adjusted to 7.4 by adding hydrochloric acid. The solution was extracted with a mixed solution (chloroform : methanol, 10:1) (200 mL×2), and then, with lower layer of a mixed solution (200 mL) (chloroform : methanol : water, 7:3:1). The organic layers were combined and dried with anhydrous sodium sulfate, and the solvent was removed by distillation. The residue was purified by recrystallization from ethanol, and the crystals were dried under reduced pressure to obtain 644 mg (1.535 mmol, 92%) of the title compound as a pale pink powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1-c1ccncc1
Temperature: 90 °C
Yield: 49.3 %

Procedure:
A mixture of 2,4-dichloro-5-methoxy-pyrimidine (3.0 g, 1.0 eq.), 4-pyridinylboronic acid (2.26 g, 1.1 eq.), Pd(PPh3)2Cl2 (0.58 g, 0.05 eq.), K3PO4—H2O (10.67 g, 3.0 eq.), H2O (3 ml) and 1,4-Dioxane (20.0 ml) was heated at 90° C. and refluxed overnight. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers was wash with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a yellow thick liquid (1.83 g, 49.26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(O)(C)C>[OH:12][C@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:24])[CH3:23])[CH2:13][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN2CCCCC2)C(C)C)ccc1OC

Procedure:
A solution of 0.25 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate in 4 ml of isopropanol and 0.99 ml of piperidine is stirred at 70° C. over 1 hour. The reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.24 (9:1 dichloromethane-methanol); Rt=17.40 (gradient II).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:11])=[C:5](C)[CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:21]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)=[CH:8][CH:7]=1)=[O:11])[CH2:22][CH3:23]
Reactant: CCCN(CCC)CCCCNC(=O)Nc1ccc(CN)cc1C
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNC(=O)Nc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 43.1 %

Procedure:
The compound (195.6 mg) obtained in Example 12-2 was dissolved in anhydrous methanol (7.8 ml) and added with 2-imidazole carboxaldehyde (88.4 mg) and trimethyl orthoformate (0.200 ml) and the whole was stirred at room temperature for 14 hours. Then, the solution was added with sodium borohydride (69.2 mg) and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The resultant was added with water and subjected to extraction with chloroform. The extract was washed with a saturated saline solution and dried with magnesium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (101 mg) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:6]2[C:2]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)=[CH:3][C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccc(F)cc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
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+]
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2ccc(F)cc2)c1)C(=O)OC(C)(C)C
Yield: 69.5 %

Procedure:
Using tert-butyl {{5-bromo-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate (0.60 g), 3-thienylboronic acid (0.35 g), tetrakis(triphenylphosphine)palladium (0.24 g) and sodium carbonate (0.43 g), a procedure as in Reference Example 56 was performed to give the title compound as a colorless solid (yield 0.42 g, 69%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H]2CC[C@H](C=O)CC2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C[C:21](C)=[O:22].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]1([C:21]([OH:22])=[O:26])[CH2:9][CH2:8][CH2:7][C@@H:6]([F:18])[C@@H:5]1[F:19])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1(C(=O)O)CCC[C@@H](F)[C@@H]1F
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
The compound (16) (10.0 g) and acetone (50 ml) were mixed and the mixture was stirred at 35° C. for 30 minutes. Jones reagent (8N) (4.7 ml) was added to the mixture in the temperature range of 30 to 40° C. and the mixture was stirred at 35° C. for 2 hours. After the reaction mixture had been cooled to 30° C., toluene (200 ml) and water (200 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, an aqueous solution of sodium thiosulfate and water, and then dried over anhydrous magnesium sulfate, giving 4-ethoxy-2,3-difluoro-(trans-4-cyclohexyl)-carboxylic acid (31) (8.8 g). The yield based on the compound (16) was 83.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:30]([O:37][C:38]([N:40]([CH2:42][CH2:43]Cl)[CH3:41])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:43][CH2:42][N:40]([C:38]([O:37][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:39])[CH3:41])[C:12]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Yield: 51 %

Procedure:
A mixture of 5 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.8 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride, 1.1 g of potassium hydroxide and 70 ml of dimethylsulfoxide is treated in the same manner as described in Example 1-(1). 3.75 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5](Br)=[CH:4][N:3]=1.[C:24]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)(OC(C)(C)C)=O>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([C:34]2[CH:33]=[N:32][N:31]([CH3:24])[CH:35]=2)=[CH:4][N:3]=1
Reactant: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2cnc(N)nc2-n2ncc3ccc(C#CC(C)(C)O)cc32)cn1

Procedure:
4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.075 g) was reacted 1-Boc-4-pyrazoleboronic acid pinacol ester via Suzuki Coupling to afford 9.5 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 360. 1H NMR (400 MHz, DMSO) delta 12.71 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.02 (s, 2H), 5.45 (s, 1H), 1.47 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[CH:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](OC2C=CC=CC=2)=[N:44][C:45]#[N:46])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH:20]/[C:43](=[N:44]/[C:45]#[N:46])/[O:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN/C(=N/C#N)Oc1ccccc1)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (190 mg, 0.35 mmol) and diphenyl cyanocarbonimidate (83 mg, 0.35 mmol) in DCM (10.0 mL) was added DIEA (0.12 mL, 0.70 mmol). The reaction mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to give (S,Z)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-((cyanoimino)(phenoxy)methylamino)pentyl 6-fluoroisoquinolin-3-ylcarbamate, which was used without further purification. LRMS (M+H+) m/z 650.2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([Cl:31])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1Cl
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C(F)(F)F)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28]>CN(C=O)C.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>[CH3:30][Si:29]([C:27]#[C:28][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(C#C[Si](C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.5 %

Procedure:
Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.65 g, 4.40 mmol) and Cu(I)I (168 mg, 0.880 mmol) in triethylamine (3.07 mL, 22.0 mmol) and DMF (40 mL) for 20 min. Then, ethynyltrimethylsilane (2.16 g, 22.0 mmol) and Pd(PPh3)4 (254 mg, 0.220 mmol) were added, the reaction was flushed with nitrogen, sealed and stirred at rt for 24 h. The reaction was concentrated to a brown oil, and purified by BIOTAGE® Horizon (160 g SiO2, 20-40% EtOAc/hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-((trimethylsilyl)ethynyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (980 mg) as a yellow solid. LC-MS retention time 3.230 min; m/z 346.17 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 7.18 (s, 1H), 4.77 (dd, J=9.2, 5.1 Hz, 1H), 3.20 (br. s., 1H), 3.14-3.39 (m, 1H), 2.33 (dd, J=13.2, 9.4 Hz, 1H), 1.69-1.78 (m, 1H), 1.34-1.56 (m, 1H), 1.49 (s, 9H), 0.85 (dt, J=8.5, 5.7 Hz, 1H), 0.41-0.47 (m, 1H), 0.22-0.24 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([S:48]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)(=[O:49])=[O:50])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(S(=O)(=O)N4CCOCC4)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (44 mg) and 4-(4-bromo-benzenesulfonyl)-morpholine (prepared from 4-bromobenzenesulfonyl chloride, morpholine and pyridine in acetonitrile, 51 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[4-(morpholine-4-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-87) as a yellow powder (53 mg, 68%).