Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]([C:11]2[C:16](=[O:17])[C:15](Br)=[C:14]([CH3:19])[N:13]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH:12]=2)=[O:10])=[N:4][N:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]([C:11]2[C:16](=[O:17])[C:15]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)=[C:14]([CH3:19])[N:13]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH:12]=2)=[O:10])=[N:4][N:3]=1
Reactant: Cc1nnc(CNC(=O)c2cn(C3CCC3)c(C)c(Br)c2=O)o1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nnc(CNC(=O)c2cn(C3CCC3)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)o1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-1-cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide (preparation 24, 44 mg, 0.115 mmol), 3-(trifluoromethyl)phenyl-boronic acid (26 mg, 0.137 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol) in acetonitrile (0.5 mL) is added 2 M aqueous K2CO3 solution (0.10 mL, 0.20 mmol). After stirring for 18 h at 75° C., the reaction mixture is filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 40 mg (78% of theory); ESI mass spectrum: [M+H]+=447; Retention time HPLC: 1.09 min (Z003_001).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:35][CH3:36])=[C:10]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:24][CH:23]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:35][CH3:36])=[C:10]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:27]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C#CCCCO)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCO)cc1
Yield: 101.3 %

Procedure:
Pd(OH)2 (200 mg) was added to a solution of Intermediate 32 (200 mg, 0.40 mmol) in THF/MeOH (5 mL each). The solution was treated with H2 at ambient pressure for 3 h. The reaction mixture was then filtered through a plug of celite. The plug was washed with MeOH (50 mL) and the solvent was concentrated in vacuo to afford the title compound as a pale yellow solid (200 mg). ES/MS calcd. for C28H40N5O3+ 494.3. found m/z=494.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].Cl>CC#N>[CH:19]1([CH2:18][N:12]([C:9]2[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[S:13]([CH3:16])(=[O:15])=[O:14])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(N(CC2CC2)S(C)(=O)=O)ccc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.3 %

Procedure:
To a solution of methyl 2-hydroxy-5-(methylsulfonamido)benzoate (6.8 g, 27.72 mmol) in CH3CN (200 ml), (bromomethyl)cyclopropane (5.62 g, 41.58 mmol) and K2CO3 (7.66 g, 55.4 mmol) were added, and the reaction was stirred at RT for 4 days. The reaction mixture was poured into ice-water (400 ml), acidified with HCl 36% (pH=1) and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated to dryness. The resulting crude was purified by chromatography on silica gel column (petroleum ether:EtOAc=4:1) affording methyl 5-(N-(cyclopropylmethyl)methylsulfonamido)-2-hydroxybenzoate (6 g, 20.32 mmol, 73.3% yield).
Reaction SMILES: [NH2:1][C:2](=[O:27])[CH:3]([CH3:26])[C@H:4]([NH:18]C(=O)OC(C)(C)C)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[N:6]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:18][C@H:4]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:13][C:7]=2[N:6]=1)[C@@H:3]([CH3:26])[C:2]([NH2:1])=[O:27]
Reactant: CC(C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(N)=O)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
A solution of tert-butyl [(1S)-3-amino-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-methyl-3-oxopropyl]carbamate (Preparation 29, 3.07 g, 8.2 mmol) in DCM (50 mL) and TFA (10 mL) was stirred at room temperature for 3 hours before concentrating in vacuo. Saturated aqueous NaHCO3 solution (100 mL) was added and the product extracted with 2-MeTHF (4×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-40% acetonitrile in water. The resulting solid was dissolved in MeCN (40 mL) at 50° C. and methanol added before allowing the solution to cool. The resulting white precipitate was collected, dried, and further triturated with EtOAc (5 mL) twice to afford a white solid as the desired (2R,3S) diastereomer.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:15]([C:16]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2N2CCCC2)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1.C(O)(C)(C)C>C(N(CC)CC)C>[Cl:9][C:10]1[C:15]([C:16]([C:18]2[CH2:22][CH2:21][CH2:20][C:19]=2[NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOC(=O)CN
Reactant: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CCOC(=O)CNC1=C(C(=O)c2cccnc2Cl)CCC1

Procedure:
Add equimolar amounts of ethyl glycinate hydrochloride, triethylamine, and (2-chloro-3-pyridinyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone to t-butyl alcohol (170 ml per 0.020 mole of amine). Reflux the resulting mixture for 34 hrs, monitoring the reaction by thin-layer chromatography as needed. Cool the reaction mixture, and evaporate solvent. Wash a CHCl3 solution of the residue with water and with saturated aqueous NaCl solution. After drying the organic solution, evaporate the solvent to obtain the resulting enaminoketone, (2-chloro-3-pyridinyl)[2-(1-ethoxycarbonylmethanaminyl)-1-cyclopenten-1-yl]methanone, m.p. 114.5°-117.5° C., after recrystallization from isopropanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]/[C:12](=[C:19]1\[C:20](=[O:28])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].O1CCOCC1.[OH-].[Na+].Cl>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]/[C:12](=[C:19]1\[C:20](=[O:28])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1N/C(=C1\C(=O)Nc2ccccc21)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccccc1C(=O)O)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
176 mg (0.48 mmol) of (Z)-3-[1-(2-methoxycarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 15 ml of methanol and 2 ml of dioxane and after the addition of 1.4 ml of 1N sodium hydroxide solution stirred for two hours at 80° C. Then the mixture is neutralised 1.4 ml of 1N hydrochloric acid while being cooled, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]=1[O:11][CH3:12].[Cl:13][C:14]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:15]=1[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:8]=[C:18]([NH2:19])[C:17]([CH2:20][NH2:21])=[C:16]([C:15]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:14]=3[Cl:13])[N:7]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=N)N)ccc1N
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1cc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)ccc1N

Procedure:
The title compound, MS: m/e=389.9 (M+H+), was prepared from 4-amino-3-methoxy-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1.Cl.[N+](C1C=CC([C:27]2[CH:35]=[C:34]([NH:36][C:37]([NH2:39])=[NH:38])[CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])=CC=1)([O-])=O.C(N(CC)CC)C>CN(C)C=O>[ClH:1].[NH:36]([C:34]1[CH:35]=[CH:27][C:28]([C:29]([NH:2][CH2:3][CH2:4][C:5]2[CH:16]=[CH:15][C:8]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=2)=[O:30])=[CH:32][CH:33]=1)[C:37]([NH2:39])=[NH:38]
Reactant: N=C(N)Nc1ccc(C(=O)O)c(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: COC(=O)CCc1ccc(CCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(CCNC(=O)c2ccc(NC(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.4 %

Procedure:
A mixture of 486 mg of methyl 4-(2-aminoethyl)hydrocinnamate hydrochloride, 672 mg of 4-nitrophenyl-4-guanidino-benzoate hydrochloride, 404 mg of triethylamine and 10 ml of dimethylformamide was stirred at room temperature under argon for 5 hours. The reaction mixture was then evaporated to dryness in vacuo, and the residue was chromatographed on 25 g of MCI gel. 520 mg of amorphous methyl p-[2-(p-guanidinobenzamido)ethyl]hydrocinnamate hydrochloride were obtained. IR bands (KBr) at 3339, 3187, 1727, 1678, 1644, 1579, 1500, 1289, 1107, 852 cm-1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C=O)C>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:18][C:5]1[C:4]([Br:3])=[CH:13][C:12]2[C:11]([CH3:14])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[C:7]=2[CH:6]=1
Reactant: COCCOCCl
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
720 mg (24 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 5.7 g (20 mmol) of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol dissolved in 75 ml of DMF are added dropwise and the mixture is stirred until the evolution of gas has ceased. 6.8 ml (59.3 mmol) of methoxyethoxymethyl chloride are then added at 0° C. and the mixture is stirred for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 16.6 g (91%) of the expected product are collected in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](S)=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>[Ni].C(O)C>[NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1nc(S)n(C)c1N
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ncn(C)c1N
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of ethyl 5-amino-2-mercapto-1-methylimidazole-4-carboxylate (1.0 g, 5.0 mmol), prepared by the method of Cook, Downer, and Heilbron, J. Chem. Soc. 2028.(1948), and W-2 Raney nickel (2 mL, 50% slurry in water)in ethanol (20 mL) were agitated in an ultrasonic cleaning bath at 50° C. for 1 hour. Sonication was continued for an additional 2 hours at 55° C. adding additional Raney nickel (ca 2 mL, 50% in water) every hour. Filtration followed by evaporation under reduced pressure afforded 0.81 g (96%) of the title compound as a tan crystalline solid which was used without further purification. m.p. 193°-194° C. TLC (10% methanol/90% ethyl acetate) Rf =0.19. 1H NMR (CDCl3, 300 MHz) d 1.39 (t, 3H), 3.46 (s, 3H), 4.34 (q, 2H), 4.75-4.95 (br, 2H), 7.01 (s, 1H). MS (DCl/NH3) m/e 170 (M+H)+. Anal calcd for C7H11N3O2.0.20 H2O: C, 48.66; H, 6.65; N, 24.32. Found: C, 48.98; H, 6.54; N, 24.12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C(OCC)(=O)C>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@H](Cc1ccc(N)cc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CO[C@H](Cc1ccc(NC(C)=O)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To (R)-(−)-3-(4-aminophenyl)-2-methoxypropionic acid (40 g) in a 0.5 L glass reactor was added ethyl acetate (80 g) and acetic anhydride (62.8 g). The mixture was stirred at 90° C. for 1 hour. Upon cooling, the solvent was removed by vacuum distillation, providing an oily residue. To this residue was added water (120 g) and ethyl acetate (120 g). After stirring for 10 min at 35° C., the layers were separated and the aqueous layer discarded. The organic layer solvent was removed by vacuum distillation. Acetone (120 g) was then added and the resulting mixture was warmed until dissolution was complete. The solution was cooled to 0° C., and the product precipitated which was collected by filtration. The solid was rinsed with acetone (20 g) and dried at 65° C. to afford 26 g of the title compound.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([O:9][NH2:10])[CH2:5][CH2:4]1.[CH3:11][C@:12]12[CH2:29][CH2:28][C@H:27]3[C@@H:17]([CH2:18][C:19](=[O:31])[CH:20]4[C@:25]3([CH3:26])[CH2:24][CH2:23][C:22](=O)[CH2:21]4)[C@@H:16]1[CH2:15][CH2:14][C:13]2=[O:32].[Na+].[Cl-]>O.C1COCC1>[ClH:1].[NH:3]1[CH2:8][CH2:7][CH:6]([O:9][N:10]=[C:22]2[CH2:23][CH2:24][C@@:25]3([CH3:26])[CH:20]([C:19](=[O:31])[CH2:18][C@@H:17]4[C@@H:27]3[CH2:28][CH2:29][C@@:12]3([CH3:11])[C@H:16]4[CH2:15][CH2:14][C:13]3=[O:32])[CH2:21]2)[CH2:5][CH2:4]1
Reactant: NOC1CCNCC1
Reactant: C[C@]12CCC(=O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=NOC3CCNCC3)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 4-piperidyloxyamine dihydrochloride (III-a, Prepn. 1, 100 mg) and Na2HPO4.12H2O (380 mg) in water (1.6 mL), a solution of androstane-3,6,17-trione (160 mg) in THF (3.2 mL) was added. After 2 hours at room temperature, NaCl (150 mg) was added and stirred for 15 min. The mixture was extracted with THF (2×2 mL) and the combined organic phases were washed with brine (3×3 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3 9:1:0.1). To the concentrated fractions 5M HCl in EtOAc was added. After dilution with Et2O, the solid was collected by filtration to give the title compound I-aa (140 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.68 (2H, bb), 4.17 (1H, m), 3.15-2.90 (5H, m), 2.60-1.10 (23H, m), 0.79 (3H, s), 0.78 (3H, s).
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[CH2:6][NH:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(OC)(C)(C)C.O>[Cl:12][CH:13]([Cl:17])[C:14]([N:5]1[CH2:6][C:7](=[O:9])[NH:8][CH:4]1[CH:1]([CH3:3])[CH3:2])=[O:15]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)C1NCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)C1NC(=O)CN1C(=O)C(Cl)Cl
Reaction time: 10 h
Yield: 49 %

Procedure:
45 g (0.35 mole) of 2-isopropyl-4-oxo-imidazolidine (Example 3) were dissolved in 250 ml of methyl tert.-butyl ether, 17.2 g (0.43 mole) of sodium hydroxide in 20 ml of water were added, and 57 g (0.39 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred for 10 hours and the solid precipitate was filtered off with suction, washed with water and dried under reduced pressure to give 41 g (49% of theory) of 1-dichloroacetyl-2-isopropyl-4-oxo-imidazolidine of melting point 172°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].Cl[C:9]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=[CH:11][N:10]=1>>[CH3:1][O:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH:5][C:9]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Reactant: COC(C)(C)CN
Product: COC(C)(C)CNc1nccc2cnc(SC)nc12

Procedure:
The title compound was prepared according to the method described for Preparation 175 using 2-methoxy-2-methylpropan-1-amine and 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33). The residue was purified by elution through an SCX-2 column using 50% methanol in chloroform followed by 50% chloroform in 7N NH3/MeOH followed by silica gel column chromatography eluting with EtOAc.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15](O)[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:16]=1
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol (Int-5e, 11.7 mmol) was charged to 250 mL round-bottom flask. To this flask was added 4 mL N, N-dimethylaniline, followed by 40 mL POCl3. This suspension was sonicated to break up the starting material and stirred at room temperature for 18 hours. After 18 hours, all starting material had dissolved. The solution was reduced in vacuo and cooled to 0° C. in an ice bath. The reaction was then quenched with sat. NaHCO3(aq) and extracted with DCM (x3). The combined organics were dried over Na2SO4 and the solvent was removed in vacuo. The resulting oil was purified via silica gel column with a 20% to 100% ethyl acetate in hexanes gradient to yield 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine (Int-5f) (2.65 grams, 77% across 2 steps) as a white solid.
Reaction SMILES: [ClH:1].C([NH:4][NH:5][C:6]1[S:7][C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1)=O>C(O)C.Cl>[ClH:1].[NH:5]([C:6]1[S:7][C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[NH2:4]
Reactant: O=CNNc1nc2c(s1)CCCC2
Agent: Cl
Solvent: CCO
Product: NNc1nc2c(s1)CCCC2
Yield: 117.3 %

Procedure:
A solution of 40.2 g of 1-formyl-2-(4,5,6,7-tetrahydro-benzothiazolyl)-hydrazine hydrochloride in 400 ml of ethanol and 100 ml of concentrated hydrochloric acid is boiled under reflux for 4 hours. Concentration of the mixture and drying of the residue gives 41.5 g of 2-hydrazino-4,5,6,7-tetrahydro-benzothiazole hydrochloride of melting point 177°-179° C. as a hygroscopic substance of sufficient purity for further reactions.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19](=O)(OCC)[O:20]CC.[O-]CC.[Na+]>C(O)C>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:2]3[NH:1][C:19](=[O:20])[NH:18][C:16](=[O:17])[C:3]=3[N:4]=[N:5]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(Cn2nnc(C(N)=O)c2N)cc1
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2nnc3c(=O)[nH]c(=O)[nH]c32)cc1
Yield: 50.9 %

Procedure:
A mixture of 5-Amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide (example 1, step a) (7.59 g, 30.7 mmol), diethyl carbonate (4.72 g, 39.9 mmol) and sodium ethoxide (3.76 g, 55.3 mmol) in ethanol (97.1 mL) was heated to reflux overnight. The solid was filtered, washed with EtOH and dried to give 3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (8.542 g, 15.6 mmol, 50.9% yield) which was used in the consecutive step without further purification. MS (m/e): 272.0 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:12][C:11]([CH3:14])([CH3:13])[N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]2[CH2:22][F:23])=[CH:4][CH:3]=1.[CH3:24][S:25]SC.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:18]([O:17][C:15]([N:10]1[C@H:9]([CH2:22][F:23])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=2)[O:12][C:11]1([CH3:14])[CH3:13])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(Br)cc2)OC1(C)C
Reactant: CSSC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-butyl lithium (n-BuLi), (1.78 g, 28 mmol, 1.2 eq) was added to a solution of tert-butyl (4S,5R)-5-(4-bromophenyl)-4-(fluoromethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (9.0 g, 23 mmol) in 30 ml of anhydrous tetrahydrofuran (THF) at −78° C. in 30 min, and the reaction mixture was stirred for 30 minutes under N2. 3.1 ml of dimethyldisulfide (1.5 eq) was added, and stirred for 30 min. The reaction mixture was warmed up to room temperature and stirred for 1 hour. A saturated solution of ammonium chloride (50 ml) and ethyl acetate (50 ml) was added and stirred for 30 min. The organic layer was washed with brine (50 ml) and dried over sodium sulfate. After purification, via a column, 8.15 g of white solid of the desired product was obtained.
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]=[O:24]>>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]1[CH2:23][OH:24])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cncn1C(c1ccccc1)c1ccccc1
Reactant: C=O
Product: COC(=O)c1cnc(CO)n1C(c1ccccc1)c1ccccc1

Procedure:
2.9 g (0.01 mol) of 1-benzhydryl-5-methoxycarbonyl-imidazole (Example 8) and 25 cc of 50% methanolic formaldehyde solution were heated for 36 hours to 135° C. 3.15 g of 1-benzhydryl-2-hydroxymethyl-5-methoxycarbonyl-imidazole, m.p. 160° C., were obtained from the reaction mixture in an almost quantitative yield.
Reaction SMILES: C([O:8][C:9]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)C1C=CC=CC=1.C([SiH](CC)CC)C>[Pd].C(O)C>[F:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:10]([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)[C:9]=1[OH:8]
Reactant: Fc1cccc(OCC2CO2)c1OCc1ccccc1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CCO
Product: Oc1c(F)cccc1OCC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
To a mixture of 2-{[2-(benzyloxy)-3-fluorophenoxy]methyl}oxirane (8 g, 29.2 mmol), ethanol (65 ml) and Pd/C (0.5 g) under N2, triethylsilane (9.3 ml, 58.2 mmol) was added dropwise. The solution was stirred for 16 h at room temperature and filtered through Celite. The solvent was evaporated, Na2CO3 (10%) was added and the solution was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to dryness. Flash column chromatography (isooctane/EtOAc) yielded the title compound (3.5 g). MS m/z (rel. intensity, 70 eV) 184 (M+, bp), 153 (44), 139 (31), 128 (99), 57 (23).
Reaction SMILES: C([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:7]=1[C:8]([OH:10])=O)(O)=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[I:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH:4]=[C:8]([O:10][C:16](=[O:18])[CH3:17])[C:7]=2[CH:11]=1
Reactant: O=C(O)COc1ccc(I)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1coc2ccc(I)cc12
Temperature: 140 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Place 2-carboxymethoxy-5-iodo-benzoic acid (Preparation 21a; 7 g, 21 mmol) acetic anhydride (35 ml), sodium acetate (4 g), and acetic acid (5 mL) into a 50 mL round bottom flask. Heat the resulting mixture at 140° C. under stirring for 5 h and cool to room temperature. Add water (12 mL) into the mixture gradually maintaining the temperature below 60° C. and continue to stir for 18 h. Dilute with water (200 mL) and collect the resulting precipitate via vacuum filtration. Wash the solid with water and dry to give the final product (6 g, 95%). MS (electrospray, m/z) 303 (M+1).