Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[CH2:18][N:17]([C:19]4[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=4[CH3:28])[CH2:16][CH2:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1.C1COCC1>[Pd].CO>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:28])=[C:19]([N:17]2[CH2:16][CH2:15][C:13]3[N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:10]=[CH:11][C:12]=3[CH2:18]2)[CH:24]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(Cl)cc3)ncc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (4-Chloro-phenyl)-[6-(2-methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]amine (100 mg, 0.25 mmol) in the mixed solvent of THF (5 ml) and methanol (5 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-(4-chloro-phenyl)amine [12]as a off white solid [Yield: 81.5 mg, 88.2%]
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([S:25][CH2:26][CH2:27][CH2:28][OH:29])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[C:6]([S:25][CH2:26][CH2:27][CH2:28][O:29][S:1]([CH3:4])(=[O:3])=[O:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
Mesyl chloride (6 μl, 0.075 mmol) was added to a solution of 3-tritylsulfanyl-propan-1-ol (5 mg, 0.015 mmol) and triethyl amine (32 μl, 0.23 mmol) in THF (1 ml). After 30 minutes THF was evaporated under reduced pressure and the crude product dissolved in DCM, washed with a saturated solution of sodium hydrogencarbonate in water, a saturated solution of sodium chloride and dried with MgSO4. A yield of 10 mg was obtained after evaporation under reduced pressure (analytical HPLC: column Luna C18,00B-4251-E0: solvents: A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 10 min; flow 1.0 ml/minute; retention time 7.12 minutes detected at 214 and 254 nm). Structure verified by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[C:17]([CH2:18]Br)=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1)=[O:10].C[Si](C)(C)N[Si](C)(C)C.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11][C:9]1=[O:10]
Reactant: CSc1ncc(CBr)c(NC(=O)Nc2ccccc2Cl)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Temperature: 110 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a suspension of [(2-chlorophenyl)amino]-N-[5-(bromomethyl)-2-methylthiopyrimidin-4-yl]carboxamide (1360 g, 3.62 mole) of in 10 L 1-methyl-2-pyrrolidinone was added 136 mL hexamethyldisilazane. The mixture was heated to an internal temperature of 105-115° C. for 1.5 hours. The mixture was then cooled to 30° C. and treated with 20L water. The mixture was then stirred at 5-8° C. for 2 hours and filtered. The filters were collected and washed sequentially with water and hexanes. The product was placed in a drying oven and heated under vacuum for 16 hours to give 780 g (70.1%) of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d] pyrimidin-2(1H)-one (sulfide 10.1) as an off-white solid. (M+1 308)
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([O:8][CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:9][C:2]=1[C:1]([O:11][CH3:12])=[O:10]
Reactant: C[Si](C)(C)CCCCl
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCCC[Si](C)(C)C)ccc1O
Temperature: 90 °C

Procedure:
To a mixture of methyl gentisate (16.8 g, 0.1 mol) and potassium carbonate (15.2 g, 0.11 mol) in 80 ml of DMF, under a nitrogen atmosphere at 80° C., was added chloropropyltrimethylsilane (16.6 g, 0.11 mol) dropwise over 20 minutes. The mixture was heated at 90° C. for 8 hours. It was cooled and poured into 200 ml of water. The mixture was extracted with diisopropyl ether. The organic phase was washed with water, dried over sodium sulphate and then concentrated. After chromatography on silica of the yellow oil obtained (eluent: 90/10 heptane/CH2 Cl2), 3.3 g of a clean fraction of methyl 2-hydroxy-5-(3-trimethylsilanylpropyloxy)benzoate were recovered.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][C:45]=1[C:53]([F:56])([F:55])[F:54]>>[F:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](/[N:31]=[C:14]2/[N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]3)[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/2)=[O:50])=[CH:46][C:45]=1[C:53]([F:56])([F:55])[F:54]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)c(C(F)(F)F)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 43.8 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-fluoro-3-(trifluoromethyl)benzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-(trifluoromethyl)benzamide (43.8% yield). MS m/z=619.4 [M+H], calc 618.67 for C31H38F4N6O3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17].C(O)(=O)C>O>[CH3:22][O:21][C:19]1[CH:18]=[C:16]([N:17]=[CH:8][C:7]2[C:2]([NH2:1])=[N:3][C:4]([S:10][CH3:11])=[N:5][CH:6]=2)[CH:15]=[C:14]([O:13][CH3:12])[CH:20]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: COc1cc(N)cc(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N=Cc2cnc(SC)nc2N)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a suspension of 4.36 g (23.7 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (made as described in WO 98/33798) and 3.65 g (23.7 mmol) of 3,5-dimethoxyaniline in 165 mL of water was added 4.5 mL of glacial acetic acid. The reaction was stirred at 25° C. overnight and filtered. The filter pad was washed with water, and the filtrate was dried in vacuo to give 7.02 g (96%) of the title compound, which was used as is in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc(Cl)c4)cc23)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-l-piperazinyl)-naphthalene (0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride (0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was isolated using flash chromatography and trituration from hexane and recrystallization from ethyl acetate (with a seed crystal) to yield 0.076g (20%) of the title compound: mp 147°-148° C. HRMS m/e calculated for C22H22ClN3O; 379.1448. Observed m/e: 379.14473. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 68.95; H, 5.81; N, 10.96.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C1C(=O)N([I:35])C(=O)C1>C1COCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][Si:10]([CH:11]([CH3:13])[CH3:12])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[CH:4][C:3]=1[I:35]
Reactant: CC(C)[Si](OCCc1ccc(Br)s1)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCCc1cc(I)c(Br)s1)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of (2-(5-bromothiophen-2-yl)ethoxy)triisopropylsilane (7.24 g, 20 mmol) in dry THF (80 mL) at −5° C. was added LDA (20 mL in THF, 30 mmol) dropwise. After stirred for 1 h, NIS (6.75 g, 30 mmol) in dry THF (20 mL) was added dropwise and the resulting mixture was stirred for another 2 h. The reaction was quenched with water (30 mL) and the resulting mixture was extracted with EtOAc (3×150 mL), washed with brine, dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.9 g, 61%).
Reaction SMILES: [Cl-].C([NH+](CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[NH:22][N:11]=[N:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(Cc2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A mixture of triethylammonium chloride (4.14 g, 30 mmol) and sodium azide (1.95 g, 30 mmol) was treated with a solution of (4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) in toluene (14 ml) and the mixture was stirred and heated at 100° C. for 5 h. The cooled mixture was treated with water (10 ml) and the mixture separated. The aqueous phase was stirred and treated dropwise with concentrated hydrochloric acid until the product had precipitated from solution. The precipitated product was filtered off, washed with water and dried to yield the title compound as a white solid (1.27 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:43])[CH2:10][N:11]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=1)[C:12]([C:14]1[CH:15]=[N:16][N:17]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:13].N1C=CC=CC=1.[CH3:50][C:51](Cl)=[O:52]>C(Cl)Cl>[C:51]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](=[O:43])[CH2:10][N:11]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=1)[C:12]([C:14]1[CH:15]=[N:16][N:17]([C@H:23]2[CH2:28][CH2:27][C@H:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:13])(=[O:52])[CH3:50]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(N)cccc3Cl)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cccc3NC(C)=O)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of compound 11-3 (45 mg, 0.07 mmol) in 1:1 mixture of pyridine and DCM (5 mL) was added CH3COCl (6 μL, 0.08 mmol) at 0° C. and stirred for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% EtOAc/hexane as eluent) to provide compound 13-1 (50 mg, quant.) as a yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][CH2:35][C:36]#[C:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]#[C:36][CH2:35][CH2:34][CH2:33][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:39][CH:40]=1
Reactant: OCCCC#Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCC#Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
33.4 g (0.205 mol) of N-hydroxyphthalimide and 53.8 g (0.205 mol) of triphenylphosphine were added to a solution of 33.1 g (0.186 mol) of 5-hydroxy-1-(4-fluorophenyl)-1-pentyne in 430 ml of dry tetrahydrofuran. 35.7 g (0.205 mol) of diethyl azodicarboxylate were then added dropwise in the course of 2.5 hours with temperature control (max. 40° C.). Stirring was carried out overnight at room temperature, the mixture was evaporated down under reduced pressure and the residue was taken up with 300 ml of dichloromethane. The solution was washed twice with sodium carbonate solution and once with saturated sodium chloride solution. After drying and evaporating down, the crude product was purified by chromatography over silica gel. The eluents used were initially dichloromethane/n-hexane and subsequently pure dichloromethane. Yield: 82%; mp.: 85°-88° C. 250-MHz-1H-NMR (in DMSO-d6): δ[ppm]=1.9-2.1 (m, 2H); 2.68 (t, 2H); 4.342 (t, 2H); 7.18 (t, 2H); 7.4-7.6 (m, 2H); 7.85 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].[N:12]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:12])=[O:6]
Reactant: c1ccncc1
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Product: NC(=O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-5-chlorobenzoic acid (2.88 g; 12.2 mmol; Note 1) and pyridine (1.04 mL; 12.8 mmol) in MeCN (100 mL) at room temperature was added (Boc)2O (3.47 g; 15.9 mmol) in one portion. The mixture was aged 30 min, (NH4)2CO3 was added in one portion. After stirring approximately 16 h at room temperature, volatiles were removed in vacuo. The residue was partitioned between EtOAc/water and the layers were separated. The aqueous layer was extracted with EtOAc (×2), combined organics were washed (10% HCl, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid. LC/MS (method A) tR 1.65 min; m/z 234, 236 (M+H, Br isotopes).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]1.[Cl:10][C:11]1[C:16]([CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>C(O)CCC>[Cl:10][C:11]1[N:12]=[CH:13][N:14]=[C:15]([NH:1][C@H:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([CH2:8][OH:9])[CH2:3]2)[C:16]=1[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)C1
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)C1)OCC
Yield: 85.2 %

Procedure:
A solution of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (0.485 g, 3.69 mmol) (Ho, J. Z.; Mohareb, R. M.; Anh, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109-114), 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (0.392 g, 1.48 mmol) (Montgomery, J. A.; Hewson, K. J. Med. Chem. 1967, 10, 665-667) and triethylamine (0.30 mL, 2.22 mmol) in butanol (4 mL) was microwave irradiated at 150° C. for 450 seconds. The solution was concentrated and purified by flash chromatography (100% EtOAc) to give the title compound (0.454 g, 85%).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:22]C(C)C)[N:5]([P@@:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:27][O:28][K].Cl>>[OH:28][NH:27][C:3](=[O:2])[C@H:4]([N:5]([P@@:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:22]
Reactant: COC(=O)[C@@H](CC(C)C)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Reactant: NO[K]
Agent: Cl
Product: C[C@H](C(=O)NO)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
N-((R)-Methylphenylphosphinyl)-N-benzyl-D-leucine methyl ester (181 mg, 0.55 mmol) is treated with a solution of NH2OK (2.2 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478). The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The desired product is purified over flash silica eluting with THF. The resulting residue is crystallized by dissolving in ethyl acetate and adding hexane until the solution becomes cloudy. N-Hydroxy-2(R)-[[(R)-methylphenylphosphinyl]-benzylamino]-propionamide is obtained as hard, dense colorless crystals: MS-IS m/z 333 [M+H]+, 355 [M+Na]+. (R1 =benzyl, R2 =methyl, R3 =phenyl, R4 =phenyl).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[NH3:19]>>[NH2:1][C@H:2]([C:15]([NH2:19])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: N
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of Tyr(3-tBu)-OMe (12.4 g, 49 mmol) and concentrated aqueous ammonia (240 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the thus obtained residue was subjected to silica gel column chromatography (CHCl3:MeOH=10:1), giving Tyr(3-tBu)-NH2 (T1) (10 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1O.[NH3:26]>S(Cl)(Cl)=O.C(#N)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([NH2:1])=[C:3]([NH2:26])[N:4]=2)=[N:9]1
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.602 g (10.677 mmol) of 6-amino-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol in 45 ml of thionyl chloride were added and heated under reflux for 3 h. The reaction mixture was diluted with 200 ml of dry acetonitrile and, with ice-cooling, added dropwise to 500 ml of concentrated aqueous ammonia solution (35% strength). The mixture was stirred at RT overnight. The acetonitrile was removed on a rotary evaporator and the precipitate was filtered off with suction. This gave 3.541 g (purity 67%, 66% of theory) of the target compound. A small amount was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([O:28][C:29](C)(C)[CH3:30])=[O:27])[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:33])[CH:3]=1.Cl.CCOC(C)=O>CCO>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:19][CH2:20][CH:21]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:23]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)COC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 157.1 %

Procedure:
A mixture of 1.07 g of tert-butyl ({1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}oxy)acetate, 20 ml of 4M HCl-EtOAc solution and 20 ml of EtOH was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the obtained residue was recrystallized from EtOH-ether to give 855 mg of ethyl ({1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}oxy)acetate hydrochloride.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:17][N:8]2[C:7]1=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:25]N1C(=O)CCC1=O.C1(O)C=CC=CC=1>C1COCC1>[Br:25][C:12]1[NH:11][C:10]2[C:9]3=[N:15][C:16]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:17][N:8]3[C:7](=[O:24])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]cnc21
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCCCCn1c(=O)n2nc(-c3ccccc3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 4-pentyl-8-phenyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (25 mg, 0.078 mmol) in THF (5 mL) was added N-Bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by preparative LCMS (method B) to provide the desired product as white powder. 1HNMR (400 MHz, CD3OD): δ 8.25 (m, 2H), 7.50 (m, 3H), 4.31 (t, J=7.3 Hz, 2H), 1.88 (m, 2H), 1.43 (m, 4H), 0.95 (m, 3H). LCMS calculated for C17H18BrN6O (M+H): 401.1; found: 401.0, 403.0.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:13][OH:14]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[N:13][OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NO
Reactant: CCCCCC(=O)CCCCC
Product: CCCCCC(CCCCC)=NO
Yield: 80 %

Procedure:
Using the general procedure described in Sedgwick, Organic Chemistry of Nitrogen, pages 169-175 (1937 Edition), 1.2 moles of 6-undecanone is reacted with an alcohol solution of 1 mole of hydroxylamine at room temperature to produce 0.8 moles of 6-undecanone oxime, ##EQU1## contaminated with 3.5% 6-undecanone.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.F[C:24]1[C:25]([O:34][C:35]2[CH:36]=[N:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=2)=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([NH2:30])[CH:29]=1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][C:24]1[C:25]([O:34][C:35]2[CH:36]=[N:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([NH2:30])[CH:29]=1)#[N:5]
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2Oc2ccccc2C#N)cn1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
60 mg of 2-hydroxy-benzonitrile and 70 mg of potassium carbonate were added to an N-methylpyrrolidinone (2 ml) solution of 150 mg of 5-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenylamine obtained in (step 3), and the reaction liquid was stirred at 90° C. for 5 hours. Water was added to the reaction liquid, and the deposit was taken out through filtration to obtain the entitled compound.