Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:29]([CH:31]=[CH2:32])=[O:30].[NH4+].[Cl-]>C1COCC1>[OH:30][CH:29]([CH:31]=[CH2:32])[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:18])([F:19])[F:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=CC=O
Reactant: CCOC(=O)CNC(=O)c1ccc(F)cc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., 6.0 g (0.0205 mol) of ethyl (4-fluoro-2-trifluoromethylbenzoylamino)acetate dissolved in THF were added dropwise to 24.3 ml (0.049 mol) of a 2M lithium diisopropylamide solution in THF. After 1 h at −78° C., 1.4 g (0.025 mol) of acrolein dissolved in THF were added dropwise, and the mixture was stirred at −78° C. for 1 h. Saturated NH4Cl solution was then added, and the mixture was allowed to warm to RT. The mixture was extracted with CH2Cl2, and the combined organic phases were then washed and dried and the solvent was removed. The residue was purified chromatographically (SiO2; cyclohexane/ethyl acetate). This gave 4.7 g (66% of theory) of the title compound as a colorless solid (diastereomer mixture) which was reacted further without further purification.
Reaction SMILES: CC(C)[O-].[Al+3:5].CC(C)[O-].CC(C)[O-].[N+:14]([O-:17])([OH:16])=[O:15]>>[N+:14]([O-:17])([O-:16])=[O:15].[Al+3:5].[N+:14]([O-:17])([O-:16])=[O:15].[N+:14]([O-:17])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Agent: CC(C)[O-]
Agent: [Al+3]
Product: O=[N+]([O-])[O-]

Procedure:
Aluminum isopropoxide was used as the raw material. It is affordable and easy reacts with nitric acid to produce soluble aluminum nitrate. In 1 L beaker 500 ml of demineralized water was added. To this, 100 ml (142 g) of HNO3 was added and stirred for about 20 min. Next, 60 g of Al-isopropoxide (20 g at a time) was added to the nitric acid solution. Clear solution was formed in about 30 min. This solution was then used for further experiments.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:13][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2[nH]ccc12
Reaction time: 3 h
Yield: 94.7 %

Procedure:
1H-Indole-4-carbaldehyde (219 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to an orange solid and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.0 mg, 1.53 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (1H-indol-4-ylmethyl)-methyl-amine (229 mg, 94%) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1H), 7.29-7.24 (m, 2H), 7.03-6.93 (m, 2H), 6.51-6.50 (m, 1H), 3.88 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1]/[CH:2]=[C:3](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>CO>[ClH:1].[C:16]1(/[C:3](=[CH:2]\[Cl:1])/[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C/Cl)c1ccccc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NC/C(=C/Cl)c1ccccc1
Yield: 99.7 %

Procedure:
(E)-1-Chloro-2-phenyl-3-phthalimidopropene (445 mg) is treated as described for the Z-isomer with hydrazine hydrate (85 mg) in methanol (6 ml). Hydrolysis with 50% aqueous hydrochloric acid gives (E)-2-phenyl-3-chloroallylamine hydrochloride (152 mg): colorless needles; m.p. 185°-186°;
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]([CH3:20])[C:13]2=[N:14][CH:15]=[C:16](I)[CH:17]=[C:12]2[N:11]=1)[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:30].[Na+].[Na+].O.[Cl-].[NH4+]>[Cu](I)I.CN(C=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]([CH3:20])[C:13]2=[N:14][CH:15]=[C:16]([SH:30])[CH:17]=[C:12]2[N:11]=1)[CH3:2]
Reactant: [S-2]
Reactant: CCSc1ccccc1-c1nc2cc(I)cnc2n1C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccccc1-c1nc2cc(S)cnc2n1C
Temperature: 110 °C
Yield: 25.9 %

Procedure:
To a mixture of 2-(2-ethylsulfanyl-phenyl)-6-iodo-3-methyl-3H-imidazo[4,5-b]pyridine (430 mg), copper iodide (229 mg), and DMF (3 ml), sodium sulfide nonahydrate (721 mg) was added at room temperature. The mixture was stirred with heating at 110° C. for 6 hours. Into the reaction mixture cooled to room temperature, saturated aqueous ammonium chloride water solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 85 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-thiol (hereinafter referred to as Present Compound 145):
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[S-:11][C:12]#[N:13].[K+].C(O)C>O>[S:11]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:12]#[N:13]
Reactant: N#C[S-]
Reactant: CC(=O)c1ccccc1Br
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
In accordance with the known process (Beilstein, 8, 94), 10.0 g (50 mmol) of o-bromoacetophenone and 4.9 g (50 mmol) of potassium thiocyanate were added to 80 ml of ethyl alcohol, and the resultant mixture was heated at 80° C. for 3 hours and then allowed to stand overnight. Added to the reaction mixture were 50 ml of water. Precipitated crystals were collected by filtration, washed with 50% aqueous ethyl alcohol and then dried, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:11]3[CH2:12][CH2:13][C:14]2=[C:15]([C:19]#[N:20])[C:16]([OH:18])=[O:17])[CH2:6]1)(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+].[H][H]>[Pd].C(O)C>[C:1]([O:4][C@H:5]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([C:19]#[N:20])[C:16]([OH:18])=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=C(C#N)C(=O)O)CC[C@@H]32)C1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C#N)C(=O)O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
37 g. of the ethyl ester of 3β-acetoxy-20-cyano-5,17(20)-pregnadiene-21-oic acid is mixed in 450 ml. of tetrahydrofuran and 150 ml. of ethanol with 2.5 g. of 10% palladium-charcoal catalyst and 2 ml. of N/10 sodium hydroxide solution and hydrogenated under normal pressure with hydrogen at room temperature. The reaction mixture is worked up as set forth in Example 1(b), thus obtaining the ethyl ester of 3β-acetoxy-20-cyano-5-pregnene-21-oic acid (34 g.), m.p. 170° C.
Reaction SMILES: COC([C@@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=S)CC(=O)C)=O.Cl.COC1C=C(NN)C=CC=1.[CH3:68][O:69][C:70]([C@H:72]1[CH2:76][C@@H:75]([S:77]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[C:86]([F:89])([F:88])[F:87])(=[O:79])=[O:78])[CH2:74][N:73]1[C:90]1[N:91]([C:96]2[CH:101]=[CH:100][CH:99]=[C:98]([O:102][CH3:103])[CH:97]=2)[N:92]=[C:93]([CH3:95])[CH:94]=1)=[O:71]>>[CH3:68][O:69][C:70]([C@@H:72]1[CH2:76][C@@H:75]([S:77]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[C:86]([F:89])([F:88])[F:87])(=[O:79])=[O:78])[CH2:74][N:73]1[C:90]1[N:91]([C:96]2[CH:101]=[CH:100][CH:99]=[C:98]([O:102][CH3:103])[CH:97]=2)[N:92]=[C:93]([CH3:95])[CH:94]=1)=[O:71]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(OC)c1
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: COc1cccc(NN)c1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(OC)c1

Procedure:
In analogy to the procedure described in example 192 h, a mixture of (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) and of (2R,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 3-methoxyphenylhydrazin hydrochloride (CAS Reg. No. 39232-91-2) to give a mixture of the title compound and (2R,4R)-1-[2-(3-methoxy-phenyl)-5-methyl-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as orange oil. MS (ESI): m/z=524.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][N:22]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:34][NH2:35]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:34][NH:35][C:28](=[O:30])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:25]([CH3:26])[N:24]=[CH:23][N:22]=2)=[CH:9][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ncnn2C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 48 %

Procedure:
To a solution of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (506 mg, 1.17 mmol) in methanol (3 mL) was added hydrazine monohydrate (1 mL), and the mixture was stirred at 25° C. for 10 hrs. The mixture was filtered to obtain a white solid (225 mg, yield 48%). LC-MS (ESI) m/z: 402 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.10 (s, 6H), 3.33 (s, 2H), 3.58 (s, 3H), 4.88-4.92 (m, 2H), 7.20-7.22 (m, 3H), 7.34-7.40 (m, 4H), 7.54-7.62 (t, J=8.4 Hz, 1H), 7.79 (s, 1H), 12.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9](Cl)=[O:10].[F:13][C:14]1[C:19]([F:20])=[C:18]([CH3:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[CH2:24][OH:25].N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9]([O:25][CH2:24][C:15]1[C:16]([F:23])=[C:17]([F:22])[C:18]([CH3:21])=[C:19]([F:20])[C:14]=1[F:13])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2.06 Grams of (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid chloride was added to a mixture of 1.78 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methanol, 0.87 g of pyridine and 20 ml of tetrahydrofuran under ice-cooling. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into about 100 ml of ice water and extracted twice with 100 ml of ethyl acetate. The combined ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to obtain 2.75 g (yield: 87%) of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate.
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14](O)=[O:15])[CH:9]=[CH:10][C:11]=1[F:12].CO>C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of borane dimethyl sulfide (2M in THF, 18.30 mL) was added cautiously to a solution of 2-(3,4-difluorophenyl)acetic acid (2.1 g) in THF (20 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred for 1 h. The reaction was cooled in an ice bath and methanol (5 mL) was added dropwise. The reaction was stirred until bubbling ceased and the solvent evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane to 4:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 1.92 g.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:45][C:46]1[CH:47]=[CH:48][C:49]([CH2:52][C:53]([NH:55][C:56](=[S:57])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]5[CH2:27][CH2:26][CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:28][CH:29]=2)=[O:54])=[CH:50][CH:51]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reaction time: 0.08 h
Yield: 36.2 %

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (63 mg) was dissolved in ethanol (1.5 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (111 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.954 ml) was added thereto, followed by stirring for 13.5 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, to which diethyl ether (2 ml) and hexane (2 ml) were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (34.1 mg, 36.2%) as white powder.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]([C:23]1[C:24]([O:31]C(C)(C)C)=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[CH2:8]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]([C:23]1[C:24]([OH:31])=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]([NH2:27])=[O:4])[CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)Oc1c(C#N)cccc1C1=CC2CCC(C1)N2Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: NC(=O)c1cccc(C2=CC3CCC(C2)N3Cc2ccccc2)c1O
Temperature: 65 °C

Procedure:
Trifluoroacetic Acid (50 mL) and sulfuric acid (20 mL) were added to crude 3-(8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-2-tert-butoxy-benzonitrile (37.53 g, 0.101 mol) and the reaction mixture was heated at 65° C. overnight, poured into ice water and neutralized to pH 7. The aqueous layer was extracted EtOAc (3×) and the solvent was evaporated. The reaction mixture was purified by silica gel chromatography (10 min 7% MeOH:DCM, 10 min 10% MeOH: DCM, ramping to 20% MeOH:DCM over 30 min) to provide the title compound (22.15 g). (m/z): [M+H]+ calcd for C21H22N2O2 335.17. found 335.4
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].ClCl.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: ClCl
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 80 °C
Reaction time: 5 h
Yield: 14.5 %

Procedure:
2.00 g (20 mmol) of hydantoin was dissolved in 30 ml of acetic acid. The solution was then heated to a temperature of 80° C. under stirring with chlorine being introduced thereinto for 5 hours. The reaction system was then allowed to cool to room temperature. The dissolved chlorine was then removed by introducing nitrogen into the reaction system. To the reaction solution was then added 3.76 g (40 mmol) of phenol. The reaction mixture was then heated to a temperature of 70° C. for 8 hours. The reaction solution was then allowed to cool to room temperature. The reaction solution was then concentrated under reduced pressure to distill off acetic acid and phenol. To the resulting residue was then added 50 ml of water. The mixture was then heated to effect dissolution. The solution was then allowed to stand. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 0.55 g (2.89 mmol; yield: 28.9%) of 5-(p-hydroxyphenyl)hydantoin in the form of white flake crystal.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13]O)=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: Cc1nn(-c2ccccc2)nc1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccc2)nc1CBr
Temperature: 120 °C
Yield: 91.5 %

Procedure:
To a solution of (5-Methyl-2-phenyl-2H-[1,2,3]triazol-4-yl)-methanol (0.25 g, 1.30 mmol) in 10 ml of toluene was added PBr3 (0.53 g, 1.90 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.30 g, 90%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:27]([CH3:30])([CH3:29])[OH:28])[CH:5]=[C:6]([O:25][CH3:26])[C:7]=1[O:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[N:12]=[C:11]([CH3:24])[N:10]=1.[N:31]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:27]([CH3:30])([CH3:29])[OH:28])[CH:5]=[C:6]([O:25][CH3:26])[C:7]=1[O:8][C:9]1[C:14]2[N:15]=[N:31][N:16]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:13]=2[N:12]=[C:11]([CH3:24])[N:10]=1
Reactant: O=N[O-]
Reactant: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCC(CCC)n1nnc2c(Oc3c(Br)cc(C(C)(C)O)cc3OC)nc(C)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[[5-amino-2-methyl-6-[(1-propylbutyl)amino]-4-pyrimidinyl]oxy]benzene-methanol (0.70 g) in 35 mL of glacial acetic acid, 0.10 g of sodium nitrite in 1 mL of water was added dropwise. The mixture was stirred at room temperature for 20 minutes and then diluted with water, basified with 1 N NaOH and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4 and stripped of the solvent under reduced pressure to yield the title compound as viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[N:14]=[CH:13][N:12]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COCc1cc(Cl)ncn1
Solvent: C1COCCO1
Product: COCc1cc(Nc2ccc(Cl)c(Cl)c2)ncn1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
A mixture of 3,4-dichloroaniline (1.328 g, 8.20 mmol) and 4-chloro-6-(methoxymethyl)pyrimidine (0.65 g, 4.10 mmol) in dioxane (20.5 ml) was heated at 100° C. for 54 h, cooled to room temperature and concentrated onto Na2SO4. The residue was purified on silica gel using 50-100% ethyl acetate in hexanes, then 10-15% methanol in ethyl acetate. The desired fractions were concentrated to give a dark brown solid which was triturated with DCM to yield N-(3,4-dichlorophenyl)-6-(methoxymethyl)pyrimidin-4-amine as a brown solid (0.66 g, 57%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.67 (1H, d, J=1.00 Hz), 7.69 (1H, d, J=2.51 Hz), 7.44 (1H, d, J=8.53 Hz), 7.29 (1H, dd, J=8.53, 2.51 Hz), 6.95 (1H, br. s.), 6.81 (1H, d, J=1.00 Hz), 4.45 (1H, d, J=0.50 Hz), 3.50 (2H, s). LCMS: R.T.=0.77; [M+H]+=283.98.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:9]([O:10][CH2:11][CH:12]([OH:19])[CH2:13][NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:21](OC)=[O:22].C[O-].[Na+]>C(O)(C)C.O.CO>[C:15]([NH:14][CH2:13][CH:12]([OH:19])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH2:2][NH:1][C:21](=[O:22])[NH:5]2)([CH3:16])([CH3:18])[CH3:17]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)NCC(O)COc1cccc(N)c1CN
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C)NCC(O)COc1cccc2c1CNC(=O)N2

Procedure:
Analogously to Example 4(f), 8.0 g of 2-aminomethyl-3-(3-tert.-butylamino-2-hydroxy-propoxy)-aniline are reacted first with 3.3 g of methyl chloroformate in a mixture of 28 ml of isopropanol and 28 ml of water and then with 3.2 g of sodium methylate in 30 ml of methanol. After working up, 5-(3-tert.-butylamino-2-hydroxy-propoxy)-3,4-dihydro-1H-quinazolin-2-one with a melting point of 204°-205° is obtained.