Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[F:23][C:20]([F:21])([F:22])[C:19]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=[N:17][N:18]=1
Reactant: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 1-(4-benzyloxy-phenyl)-5-trifluoromethyl-1H-tetrazole (45.3 mmol) in ethanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-carbon catalyst (6 g). After 2 h, the mixture was filtered and the filtrate was evaporated to give the title compound (10.4 g) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([Cl:24])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
15.0 g (50 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid were dissolved in 127.5 ml dichloromethane in the presence of 0.75 ml DMF. 8.76 ml (2 eq.) Oxalyl chloride were added and after 4.5 hours, the solution was rotary evaporated to dryness. 9 ml Toluene were added and the resulting solution was again rotary evaporated, then dried under high vacuum yielding 16.25 g (quant.) of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride as a yellow oil of 86% purity according to HPLC analysis.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:33])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=3)=O)=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:36]/[N:35]=[C:16](/[C:18]1[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH3:25])[CH:19]=1)\[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][C:3]2([CH2:2][OH:1])[CH2:5][CH2:4]2)=[O:33])=[CH:9][CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC2(CO)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC2(CO)CC2)cc1

Procedure:
In analogy to example 151, step 3, N-(1-(hydroxymethyl)cyclopropyl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=460.4 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([OH:29])[CH:28]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]3[N:26]=[C:27]([O:29][CH2:2][C:3]4[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=4)[C:6]#[N:7])[CH:28]=[C:22]3[CH2:21]2)=[O:19])=[CH:14][CH:13]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(COc2cc3n(n2)CCN(C(=O)c2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.1 %

Procedure:
3-(bromomethyl)benzonitrile (0.086 g, 0.44 mmol) was added to a stirred suspension of 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.105 g, 0.4 mmol) and Cs2CO3 (0.261 g, 0.8 mmol) in ACN (2 mL). The mixture was stirred at room temperature for 16 hours, then diluted with water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 3-[({5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl}oxy)methyl]benzonitrile (0.089 g, 59% yield) as a white solid. C21H17FN4O2. 1H NMR (500 MHz, CDCl3) δ ppm 4.08 (br. s., 4 H), 4.74 (br. s., 2 H), 5.22 (s, 2 H), 5.51 (br. s., 1 H), 7.15 (t, J=8.5 Hz, 2 H), 7.44-7.51 (m, 3 H), 7.60 (d, J=7.8 Hz, 1 H), 7.65 (d, J=7.8 Hz, 1 H), 7.74 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[N:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH2:31]2>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH:31]2[C:12](=[O:14])[C:9]1[S:10][CH:11]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)[CH:8]=1
Reactant: Cc1nc(-c2csc(C(=O)O)c2)cs1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2csc(C(=O)C3C(=O)N(C(N)=O)c4ccc(Cl)cc43)c2)cs1

Procedure:
The title compound was prepared according to the procedure of Example 55. A 1.25 g (5.55 mmoles) sample of 4-(2-methyl-4-thiazolyl)-2-thiophenecarboxylic acid (prepared as described in Example 18) was converted to the acyl imidazole by reaction with 0.98 g (6.05 mmoles) of 1,1'-carbonyldiimidazole in 15 ml of N,N-dimethylformamide. After complete reaction this solution was transferred to an addition funnel and slowly added 1.06 g (5.04 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.66 g (13.59 mmoles) of 4-(N,N-dimethylamino)pyridine in 50 ml of N,N-dimethyl-formamide. Acidic workup followed by filtration and trituration with 2-butanone gave 0.50 g (1.20 mmoles) of title compound as a yellow solid, m.p. 238-241° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[N:43]([O-:45])=[O:44].[Na+]>>[N+:43]([C:14]1[N:13]([C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=2[C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:28]=1)([O-:45])=[O:44]
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c([N+](=O)[O-])n2[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 143.7 %

Procedure:
(R)-tert-Butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (400 mg, 0.85 mmol) was treated with TFA (6 mL). The resulting mixture was stirred at rt for 30 min, then NaNO2 (41 mg, 0.59 mmol) was added. After the stifling was continued for 1 hr, the reaction was concentrated under vacuum. DCM (10 mL×2) was added and concentrated to remove the residue TFA to afford (R)-6-nitro-5-(4-phenoxyphenyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (160) (353 mg, quant. yield) as a yellow oil, which was used directly in next step without purification. LC-MS (ESI): m/z (M+1) 417.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([OH:22])[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][OH:22])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#CCO
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (2.15 g, 6.00 mmol) and triethylamine (6 mL, 0.04 mmol) in N,N-dimethylformamide (6 mL) was treated with propargyl alcohol (0.87 mL, 15.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (30 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) chloride (45 mg, 0.06 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (120 mL) and washed with a half-saturated aqueous sodium chloride solution (1×60 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×120 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (1.57 g, 91%) as an amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][NH2:21]>>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][NH:21][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCCc1cccs1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: O=C(NCCc1cccs1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-thiophen-2-ylethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a yellow solid. δH (CD3OD): 3.16 (2H, t), 3.65 (2H, t), 6.89–6.94 (2H, m), 7.03 (1H, s), 7.20 (1H, d), 7.66 (1H, s), 8.57 (1H, s); m/z (ES+)=306 [M+H]+.
Reaction SMILES: [C:1]1([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]1([N:11]2[C:15]([S:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1nnnn1-c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
A mixture of 1-(Naphthalen-1-yl)-1H-tetrazole-5-thiol (235 mg, 1.03 mmol), ethyl bromoacetate (189 mg, 1.13 mmol) and potassium carbonate (171 mg, 1.24 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture and the precipitate that formed collected to give ethyl 2-(1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio)acetate as a solid (306 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.C(OC(N1C[C@@H](S)C[C@H]1CN[C:32]([C:34]1[S:35][C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:38]=1)=[O:33])=O)C=C>C(#N)C>[CH2:42]([O:41][C:39]([C:36]1[S:35][C:34]([C:32](=[O:33])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:38][CH:37]=1)=[O:40])[CH3:43]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)OCC)s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole. see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature, under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid (90%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32]>>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Yield: 33 %

Procedure:
The starting indole (C) was prepared according to the procedure of Example 1, starting with 5-(N-cyclopentylmethylcarbamoyl)indole (A) and methyl 4-bromomethyl-3-methoxybenzoate (B) to yield methyl 4-[5-(N-cyclopentylmethylcarbamoyl)indol-3-ylmethyl]3-methoxybenzoate (C) (1.14 g, 33%) as a tan foam; partial NMR (80 MHz, CDCl3): 3.45(dd, 2H, CH2N), 3.93(s, 3H, OCH3), 3.95(s, 3H, OCH3), 4.17(s, 2H, ArCH2), 6.17(t, 1H, NHCO), 7.01(d, 1H, H2 -indole), 7.16(d, 1H), 8.04(br s, 1H, H4 -indole), 8.45(br s, 1H, NH).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[NH2:24][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=2)[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:35]
Reactant: O=C(NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2A (96 mg, 0.207 mmol) in THF (6 mL) and MeOH (6 mL) at RT was added palladium 5% wt on activated carbon (64 mg). The reaction mixture was stirred under a hydrogen balloon for 1 h. The reaction was filtered and the filtrate concentrated to give the title compound as a foam (68 mg, 100%). LC/MS (method A): retention time=2.65 min, (M+H)+=330.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:17][C:18](N)=[O:19].O>C(O)(=O)C>[F:15][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][C:12](=[O:14])[NH:17][C:18]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCNc1cccc(C(F)(F)F)c1
Reactant: NC(N)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 67.7 %

Procedure:
A solution of 3-(3-trifluoromethylphenylamino)propanoic acid (2.0 g) (prepared in Reference Example 95) and urea (1.0 g) in acetic acid (20.0 ml) was stirred with heating under reflux for seven hours. To the reaction mixture was water (50 ml) and the resulting mixture was extracted with ethyl acetate (30 ml×3). The organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(3-trifluoromethylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (1.5 g).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C1COCC1.[BH4-].[Na+].Cl>C(O)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C=O)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(CO)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 6.85 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 200 ml of an ethanol:THF=1:1 mixed solvent there was added 1.52 g of sodium borohydride while cooling on ice. After stirring at room temperature for 30 minutes, 1N hydrochloric acid was added to the reaction mixture while cooling on ice. The organic layer was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-fluoro-2-hydroxymethyl-6-methoxyphenol (6.1 g, crude product).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].CCCCCC>C1(C)C=CC=CC=1>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:31][CH2:30][C@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[O:32][C:6]=2[C:5]=1[CH3:9]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 93 %

Procedure:
Suspended in 1 ml of toluene were 200 mg (1.316 mmol) of trimethylhydroquinone (TMH) and 100 mg of Sc-Bent, followed by heating under reflux for 10 minutes under an argon gas stream. After a solution of 430 mg (1.45 mmol) of isophytol in 1 ml of toluene was added dropwise over 5 minutes under heating and reflux, TMH and isophytol were further reacted each other for 1 hour. The reaction liquid was cooled, to which 20 ml of n-hexane were added. The resulting mixture was filtered and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: n-hexane-ether system), whereby 527 mg of the title compound were obtained in the form of a brown oil. (Yield: 93%, GLC purity: 99%)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:13][N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:23]=[O:24]>>[Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[C:13]([CH2:23][OH:24])[N:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ncc(Sc2cccc(Cl)c2)[nH]1
Reactant: C=O
Product: CC(C)(C)[Si](C)(C)OCc1nc(CO)c(Sc2cccc(Cl)c2)[nH]1
Yield: 33 %

Procedure:
An aqueous solution of 2.0 g (5.6 mmol) of 2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazole (45') in 37% formaline (10 ml) was heated at 120° C. for 10 hours in a sealed tube. The reaction mixture was washed out with methanol from the tube, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1), the crude product was washed with n-hexane, and filtered to give 716 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methanol (46) (yield 33%). mp 136-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:22]([CH3:24])[CH3:23].O>CN(C)C=O>[CH:22]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])([CH3:24])[CH3:23]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC(C)C)c1
Temperature: 62.5 °C

Procedure:
A solution of methyl 3-hydroxy-4-nitrobenzoate (5.9 g) in dimethylformamide (40 mL) is treated with potassium carbonate (6.2 g) and 2-bromopropane (3.7 g), and the stirred solution is heated at 60-65° C. for 4 hours. After cooling, water (100 mL) is added and the solution is extracted with toluene (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated in vacuo, to give methyl 3-isopropoxy-4-nitrobenzoate, in the form of a pale yellow solid (5.9 g), m.p. 46-48° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:22]=[C:21]4[C:17]([NH:18][C:19](=[O:31])[N:20]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:16]([C:32]([O:34]CC)=O)[N:15]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37]C1C(C(OCC)=O)=NC(NC2C=CC(CO)=CC=2)=NC=1NC1C=CC=CC=1OC>ClCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:22]=[C:21]4[C:17]([NH:18][C:19](=[O:31])[N:20]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[C:16]([C:32]([NH2:37])=[O:34])[N:15]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1nc(Nc2ccc(Cn3ccnc3)cc2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(Nc2ccc(CO)cc2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccc(Cn4ccnc4)cc3)nc21
Yield: 100 %

Procedure:
Ethyl 2-(4-((1H-imidazol-1-yl)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(4-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.180 g, 0.440 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.713 g, 4.44 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using Biotage silica gel chromatography (10% methanol in ethyl acetate) to afford the title compound (0.700 g, >100%). MS (ESI) m/z 486.5 [M+1]+.
Reaction SMILES: [C:1]1(C)C=CC=C(C#N)C=1.NO.[OH:12][N:13]=[C:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO>[OH:12][N:13]=[C:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:1])[CH:16]=1
Reactant: Cc1cccc(C#N)c1
Reactant: NC(=NO)c1ccccc1
Agent: NO
Solvent: CCO
Product: Cc1cccc(C(N)=NO)c1
Yield: 97.7 %

Procedure:
The reaction of m-tolunitrile (1 g, 8.54 mmol) and hydroxylamine (0.78 cm3, 12.8 mmol, 1.5 eq) in EtOH (8.5 cm3) was performed in the same manner as in the preparation of N′-hydroxybenzimidamide, to give the product N′-hydroxy-3-methylbenzimidamide (1.25 g, 97.7%) as a white solid, mp 92° C. (lit 88-90° C.).