Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:40]([Cl:41])=[C:39]([O:42][CH3:43])[CH:38]=[C:37]([O:44][CH3:45])[C:36]=3[Cl:46])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)=O.[F:47][C:48]([F:52])([F:51])[CH2:49][NH2:50]>C(Cl)Cl>[F:47][C:48]([F:52])([F:51])[CH2:49][NH:50][CH2:15][C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:36]([Cl:46])=[C:37]([O:44][CH3:45])[CH:38]=[C:39]([O:42][CH3:43])[C:40]=3[Cl:41])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1
Reactant: NCC(F)(F)F
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CNCC(F)(F)F)c[nH]3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Sodium triacetoxyborohydride (101 mg, 0.476 mmol, 3 equiv) was added to a suspension of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (75 mg, 0.159 mmol) and trifluoroethylamine (15 μl, 0.188 mmol), 1.18 equiv) in DCM (3 mL) at rt, under an argon atmosphere. The reaction mixture was stirred for 18 h at rt, quenched by addition of H2O and extracted with DCM. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 98:1:1) followed by trituration in Et2O to afford 55 mg of the title compound as a yellow solid: ES-MS: 555 [M+H]+; tR=3.78 min (System 1); TLC: Rf=0.55 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][CH:2]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)[CH2:3][CH2:4][NH2:5].[Cl:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[S:16][C:15]([C:17]([NH:5][CH2:4][CH2:3][CH:2]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)[CH3:1])=[O:18])=[CH:14][CH:13]=1
Reactant: CC(CCN)n1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)s1
Product: CC(CCNC(=O)c1ccc(Cl)s1)n1ccnc1

Procedure:
When gamma-methyl-1H-imidazole-1-propanamine is treated with 5-chlorothiophene-2-carbonyl chloride by the procedure of Example 36, the above compound, m.p. 141°-143° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:56])[N:7]([C@H:19]([CH2:54][OH:55])[C@@H:20]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C@@H:21]([N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH2:8][C@@H:9](O)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:19]([C@@H:20]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:21]([N:31]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][C:23]2[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=2)[CH2:54][O:55][C@@H:9]([CH2:10][O:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:8]1)=[O:56])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C[C@@H](O)COC1CCCCC1)[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 16 h
Yield: 84.6 %

Procedure:
Dissolve [(1R,2S,3S)-2-benzyloxy-3-dibenzylamino-4-(3,5-difluorophenyl)-1-hydroxymethyl-butyl]-((R)-3-cyclohexyloxy-2-hydroxypropyl)-carbamic acid tert-butyl ester (0.940 g, 1.216 mmol) in benzene (6 mL) followed by the addition of tributylphosphine (0.369 g, 1.824 mmol) and N,N-tetramethyl azodicarboxamide (TMAD) (0.314 g, 1.824 mmol). Stir vigorously for 16 hours, filter the slurry, wash with hexanes and purify (silica gel chromatography, eluting with 5:95 to 15:85 ethyl acetate:hexanes) to give the desired compound as a white foam (0.777 g, 84.7%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:21]#[N:22].[Na+].CS(C)=O>O>[CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([C:21]#[N:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCC[C@H]1CCC(OS(=O)(=O)c2ccc(C)cc2)C1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC[C@H]1CCC(C#N)C1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A mixture of 190 mg of (1S,3RS)-1-butyl-3-(p-toluene-sulphonyloxy)cyclopentane (prepared in Reference Example 12), 150 mg of sodium cyanide and 1.5 ml of anhydrous dimethyl sulphoxide was stirred for 30 mins. at 50° C. After diluting with 3 ml of water, the mixture was extracted with 10 ml of a mixture of pentane and diethyl ether (1:1). The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulphate, and concentrated under ambient pressure at 50° C. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (1:3) as eluent to give 73 mg of the title compound having the following physical characteristics.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[CH3:18]I>O1CCCC1>[C:1]([NH:4][C:5]([CH3:18])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of diethyl 2-acetylaminomalonate (2.17 g) in dry tetrahydrofuran is added sodium hydride (0.26 g), and the mixture is stirred at room temperature for one hour. After stirring, methyl iodide (1.60 g) is added dropwise thereto, and the mixture is stirred overnight. The reaction mixture is concentrated, and to the residue is added ethyl acetate and water. The organic layer is separated, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of isopropyl ether and n-hexane to give diethyl 2-acetylamino-2-methylmalonate (1.80 g), m.p. 89°-90° C.
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[N:4][C:5]([I:8])=[N:6][CH:7]=1.[S-:10][C:11]#[N:12].[K+]>C(O)=O>[Br:1][C:2]1[C:3]([S:10][C:11]#[N:12])=[N:4][C:5]([I:8])=[N:6][CH:7]=1
Reactant: N#C[S-]
Reactant: Brc1cnc(I)nc1I
Agent: [K+]
Solvent: O=CO
Product: N#CSc1nc(I)ncc1Br
Yield: 82.4 %

Procedure:
In 30 ml of formic acid, a reaction of 4.11 g of 5-bromo-2,4-diiodopyrimidine and 1.17 g of potassium thiocyanate was conducted at room temperature (20° C.) for 5 hours in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 82.4% yield of 5-bromo-2-iodo-4 thiocyanopyrimidine, m.p. 199°-202° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:15]C)=[O:14])[CH:8]=[CH:9][CH:10]=1)#[N:4]>CO>[C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)C(Nc1cccc(C#N)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cccc(NC(C(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
50 ml of 1 N sodium hydroxide solution are added to a solution of 9.5 g (35.6 mmol) of methyl (3-cyanophenylamino)-2-phenylacetate in 150 ml of methanol, and the mixture is stirred at room temperature for 21 hours. The reaction mixture is evaporated, the residue is acidified to pH 1 using 25% HCl, and the resultant precipitate is filtered off, giving (3-cyanophenylamino)-2-phenylacetic acid as colourless crystals of m.p. 159-162°.
Reaction SMILES: [Na].Cl.Cl.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][CH:6]=1.C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])C>C(O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[N:11]=[C:17]([OH:16])[C:18]([C:19]([OH:21])=[O:20])=[CH:24][N:10]=2)=[CH:7][CH:6]=1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reaction time: 0.08 h
Yield: 102671.1 %

Procedure:
A solution of 14.8 g (0.642 mmol) of sodium in 750 ml of dry ethanol is stirred at 0° and 44.6 g (0.214 mmol) of 4-aminobenzamidine 2HCl [Shaw and Cooley, J. Am. Chem. Soc., 79, 3561 (1957)] is added. The mixture is stirred 5 minutes under nitrogen and 46.2 g (0.214 mmol) of diethyl ethoxymethylenemalonate is added. After stirring for 30 min, the mixture is refluxed for 4 hr and allowed to stand overnight at room temperature. The salt is filtered and washed with isopropanol. The salt is suspended in 214 ml of 2 N potassium hydroxide and stirred at 70° C. for 4 hr. After treating with a small amount of charcoal, the filtrate is added to 325 ml of 2 N HCl with stirring. The acid is filtered, washed with water, ethanol, and ether, and dried to give 50.8 g of the title compound, mp 312°-314° C. dec. The product is recrystallized from dimethylacetamide-water to give 44.5 g mp 313°-314° C. dec. ##EQU42##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1O.C(=O)([O-])[O-].[K+].[K+].C(S)CC.BrC(F)(F)C(F)(F)Br.[OH-].[Na+]>CN(C)C=O>[N+:8]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: CCCS
Agent: FC(F)(Br)C(F)(F)Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Into a pressure bottle was placed 2-chloro-4nitrophenol (15.0 g, 0.086 mole), potassium carbonate (11.9 g, 0.86 mole), propanethiol (1.5 g, 0.02 mole), 1,2-dibromotetrafluoroethane (33.7 g, 0.13 mole), and N,N-dimethylformamide (115 ml). The pressure bottle was sealed, and the mixture was stirred at 50° C. for 48 hours. The pressure bottle was cooled to room temperature, opened, and the contents poured into a separatory funnel. Approximately 200 ml of a 2N aqueous sodium hydroxide solution was added to the separatory funnel. The resultant mixture was extracted with four 300 ml portions of diethyl ether. The extracts were combined and washed with two 100 ml portions of a 2N aqueous sodium hydroxide solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving an oil. The reaction described above was repeated three additional times. The residual oils form the four experiments were combined and purified by column chromatography on silica gel, eluting with n-heptane:toluene (95:5), yielding 57.6 g of 3-chloro-4-bromo-1,1,2,2-tetrafluoroethoxy)nitrobenzene as an oil.
Reaction SMILES: C(OC([NH:11][C:12]1([PH:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: NN1CCCC(NC(=O)OCc2ccccc2)([PH](=O)Nc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: NN1CCCC(N)([PH](=O)Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Palladium black (10 mg) was added to a solution of (3S, P (R or S))-3-benzyloxycarbonylamino-1-amino(phenylamino)phosphinyl-2-piperidone (71.0 mg, 0.1764 mmol) in methanol (7 mL), and the resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40](C)[CH3:41])=[CH:35][CH:34]=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[CH:49](OC1C=CC(B(O)O)=CC=1)(C)C>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH3:49])=[CH:35][CH:34]=3)=[CH:29][C:28]=2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1
Product: CCCOc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substituting 4-propoxyphenyl boronic acid for 4-isopropoxyphenyl boronic acid in Step 2.
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[CH2:19]1[O:21][CH2:20]1.C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>O.C(O)C>[CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:19][CH2:20][OH:21])[C:11]([CH3:17])([CH3:18])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: C1CO1
Reactant: CCCCN(C(C)=O)C1CC(C)(C)NC(C)(C)C1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCN(C(C)=O)C1CC(C)(C)N(CCO)C(C)(C)C1

Procedure:
In general accordance with the procedure of Example 2Ag2, 27.2 g of crude product are obtained starting from 25.4 g (0.10 mol) of N-n-butyl-N-(2,2,6,6-tetramethyl-4-piperidinyl)acetamide [Example 2Ah1] and 17.6 g (0.40 mol) of ethylene oxide in 100 ml of water and 100 ml of ethanol. Chromatography over silica gel using the solvent system ethyl acetate/ethanol/triethylamine =30: 1:1 gives 17.2 (58%) of the desired N-n-butyl-N-[1-(2-hydroxyethyl)-2,2,6,6-tetramethylpiperidin-4-yl]acetamide in the form of a viscous oil which solidifies during storage; m.p. 72°-82° C.
Reaction SMILES: C([O-])C.[Na+].[CH3:5][CH2:6][C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11].[CH2:14]([N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C(N1C=CN=C1CCl)C1C=CC=CC=1.[I-].[K+]>C(O)C>[CH2:14]([N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][CH:8]([C:7](=[O:13])[CH2:6][CH3:5])[C:9](=[O:12])[CH2:10][CH3:11])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: CCC(=O)CC(=O)CC
Agent: CC[O-]
Agent: Cl
Agent: [I-]
Solvent: CCO
Product: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a solution of 1.74 ml (4.7 mmol; ˜21% solution in ethanol) sodium ethanolate in 18 ml dry ethanol were added 600 mg (4.7 mmol) 3,5-heptanedione and stirred at ambient temperature for 30 min. Then a solution of 1-benzyl-2-chloromethyl-1H-imidazole (prepared from 1.081 g (4.5 mmol) 1-benzyl-2-chloromethyl-1H-imidazole hydrochloride in 7 ml ethanol and 1.74 ml (5 mmol; ˜21% solution in ethanol) sodium ethanolate) was added together with 30 mg potassium iodide. The mixture was heated to 50° C. for 10 min and then immediately cooled to ambient temperature and concentrated under reduced pressure at max. 30° C. Purification by flash-chromatography on silica gel with heptane/ethyl acetate 1:1 as eluent provided 423 mg 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione as light brown oil: MS (ISP): 299.2 ((M+H)+.).
Reaction SMILES: [CH:1]1([N:4]([CH3:24])[C:5]2[C:6]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([O:14]CC)=O)[N:10]=2)[CH2:3][CH2:2]1.[CH3:25][NH2:26]>C(O)C>[CH:1]1([N:4]([CH3:24])[C:5]2[C:6]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([NH:26][CH3:25])=[O:14])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Reactant: CN
Solvent: CCO
Product: CNC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ethyl 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (0.6 gm, 0.00173 mol) was dissolved in ethanol (2 ml) in sealed tube. To this 40% aqueous methyl amine (10 ml) was added. The resulting reaction mass was stirred for 18 h at room temperature. After completion of reaction, the solid was collected by filtration. It was washed with ethanol (2 ml) followed by hexane (5 ml) to get crude product. It was purified by column chromatography by using 100-200 mesh silica gel and 1-2% MeOH: DCM as eluent to get 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-N-methylacetamide as a white solid. Yield—150 mg, (32.82%); 1H-NMR: (400 MHz, CDCl3); δ=8.17 (bs, 1H), 3.84 (s, 2H), 3.06 (s, 3H), 2.88-2.82 (m, 8H), 1.94-1.88 (m, 2H), 1.78-1.72 (m, 2H), 0.80-0.75 (m, 2H), 0.53-0.49 (m, 2H); LC-MS [M+H]=331.0; HPLC purity=99.60%.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]2)=[C:13]([Cl:26])[CH:12]=1.O>C(O)C>[Cl:26][C:13]1[CH2:12][C:11](=[N:10][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:16]=[CH:15][C:14]=1[CH2:17][N:18]1[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]1
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Reactant: O=Cc1ccccc1O
Solvent: O
Solvent: CCO
Product: CC1(C)CON(CC2=C(Cl)CC(=NCc3ccccc3O)C=C2)C1=O

Procedure:
A warmed solution of 0.48 gram (0.004 mole) of salicylaldehyde in 35 mL of ethanol was stirred, and 1.0 gram (0.004 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone was added in one portion. The reaction mixture was heated an additional 30 minutes and then 15 mL of water was added. The mixture was filtered, and the filtrate was cooled. The resultant oily suspension solidified when abraded. The solid was collected by filtration to yield, when dried, 0.87 gram of 2-[[2-chloro-4-[(2-hydroxyphenyl)methylimino]phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 105°-107° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][NH:11][N:10]=2)[CH:8]=1)#[N:2].Cl[CH2:29][C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:12][N:11]([CH2:29][C:30]3[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=3)[N:10]=2)[CH:8]=1)#[N:2]
Reactant: Cn1ccnc1CCl
Reactant: COc1ccc(C#N)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C#N)cc1-c1nn(Cc2nccn2C)cc1NC(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
To a solution of N-(3-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.56 mmol) in 3 mL of DMF was added 2-(chloromethyl)-1-methyl-1H-imidazole (109 mg, 0.84 mmol) and cesium carbonate (547 mg, 1.68 mmol). The reaction mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 82.2 mg (32%) of N-(3-(5-cyano-2-methoxyphenyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=454.1; 1H NMR (400 MHz, CDCl3) δ: 9.53 (s, 1H), 8.73 (dd, 1H), 8.64 (s, 1H), 8.48 (dd, 1H), 8.26 (s, 1H), 7.80 (d, 1H), 7.68 (dd, 1H), 7.06 (d, 1H), 6.97 (m, 2H), 6.83 (s, 1H), 5.42 (s, 2H), 3.85 (s, 3H), 3.63 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH3:35])[C:32](Cl)=[O:33])=[CH:27][CH:26]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:32](=[O:33])[CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH3:35])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)C(=O)Cl)cc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cnc(NC(=O)C(C)c3ccc(OC)cc3)c(Cc3ccccc3)n2)cc1
Temperature: 55 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, to a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (8 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 2-(4-methoxyphenyl)propanoyl chloride (16) prepared above at room temperature, and the mixture was heated with stirring at 55° C. for 14 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was purified twice by column chromatography (silica gel 50 g, dichloromethane/ethyl acetate=9/1, and silica gel 50 g, n-hexane/ethyl acetate=9/1→6/1) to give Compound 11w (942 mg, <quant.) as a colorless foamy solid containing some impurities.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:14]O>>[CH3:14][O:4][C:3](=[O:5])[C@H:2]([NH2:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: N[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H](N)c1ccc(F)cc1

Procedure:
(R)-Amino-(4-fluoro-phenyl)-acetic acid was treated with HCl gas (8 g) dissolved in methanol at room temperature for 24 hours. The reaction mixture was concentrated and aqueous sodium bicarbonate was added until the pH of the mixture remained basic. The aqueous layer was extracted three times with dichloromethane. The combined extracts were dried (Na2SO4) and concentrated afford the title compound as an oil. 1HNMR (400 MHz, CDCl3)δ 1.90 (br s, 2H), 3.67 (s, 3H), 4.58 (s, 1H), 7.00 (m, 2H), 7.30 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](=[O:28])[NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=2)[CH:14]=1)=[O:21])[CH3:18]
Reactant: Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Yield: 71 %

Procedure:
A mixture of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (225 mg, 1.03 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (224 mg, 1.13 mmol), propylphosphonic anhydride in ethyl acetate 50% (1.63 g, 1.51 ml, 2.57 mmol) and N,N-diisopropylethylamine (398 mg, 524 μl, 3.08 mmol) in tetrahydrofuran (7 ml) was refluxed for 18 hours. The solvent was evaporated, the residue was triturated with saturated aqueous sodium hydrogen carbonate. The precipitated solid was filtered off, washed with water and dried in vacuo, affording 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (292 mg, 71%) as light brown solid. Mp.: 233.5° C. MS: m/z=400.1 (M+H+).