Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:30])[C:3]([NH:5][C@@H:6]([CH:27]([CH3:29])[CH3:28])[C:7]([N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH2:11][C@H:10]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:8])=[O:4].[O:31]1CC(O)O[CH2:33][CH:32]1O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:21]1([NH:20][C:18]([C@H:10]2[N:9]([C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:33][CH2:32][OH:31])[CH3:30])[CH:27]([CH3:29])[CH3:28])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC1COC(O)CO1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)[C@H](C)NCCO)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 146.2 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-aminopropanamido)-3-methylbutanoyl)-N-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (55 mg, 134 μmol, Eq: 1.00) was combined with MeOH (3 mL) to give a colorless solution. 1,4-Dioxane-2,5-diol (8.87 mg, 73.9 μmol, Eq: 0.55) was added followed by acetic acid (8 μL, 134 μmol, Eq: 1.00) and sodium cyanoborohydride (13 mg, 210 μmol, Eq: 1.5). The reaction was stirred at rt for 4 h and then quenched by dropwise addition of 1 M aqueous HCl. The reaction mixture was basified with 0.1 M aqueous NaOH, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to give (S)-1-{(S)-2-[(S)-2-(2-Hydroxy-ethylamino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (49 mg), m/z=454.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:9][CH:8]=1.O.[OH-].[Li+].Cl>C1COCC1.O.O>[C:13]12([C:10]3[CH:9]=[CH:8][C:7]([O:6]/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])=[CH:12][CH:11]=3)[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2
Reactant: COC(=O)C=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 12 h
Yield: 96.9 %

Procedure:
3-(4-Adamantan-1-yl-phenoxy)-acrylic acid methylester (569 mg, 1.82 mmol) was dissolved in THF/H2O mixed solution (3:1, 20 ml), to which lithium hydroxide monohydrate (153 mg, 3.65 mmol) dissolved in purified water (5 ml) was added, followed by stirring for 12 hours. The reaction solution was treated with 10% HCl solution and extracted with ethylacetate and NaCl solution. The organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc=3:1) to give the target compound as a white solid (526 mg, yield: 96.7%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>>[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[S:10][CH:9]=2)[CH:12]=1)(=[O:24])=[O:23]
Reactant: Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: O=S(=O)(CCCCl)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Yield: 78.5 %

Procedure:
3-Chloro-N-(3-(2-chloro thieno[3,2-d]pyrimidin-7-yl)phenyl)propane-1-sulfonamide (240 mg, 78% yield) was prepared in the same manner as Step 7 of Example 1 using 3-(2-chlorothieno[3,2-d]pyrimidin-7-yl)benzenamine (200 mg, 0.76 mmol) and 3-chloropropane-1-sulfonyl chloride (145 mg, 0.84 mmol).
Reaction SMILES: [CH2:1]([S:6]([OH:9])(=O)=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].P(Cl)(Cl)(Cl)(Cl)[Cl:11]>C1C=CC=CC=1>[CH2:1]([S:6]([Cl:11])(=[O:9])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCS(=O)(=O)O
Solvent: c1ccccc1
Product: CCCCCS(=O)(=O)Cl
Yield: 91 %

Procedure:
To a solution of (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]amino]pentylsulfonic acid (2.34 g, 4.80 mmol) in benzene (10 mL) was added phosphorus pentachloride (1.48 g, 7.21 mmol) at 22° C. The mixture was heated to reflux for 2 hours. This mixture was concentrated under reduced pressure and rediluted with CH2Cl2 (120 mL). This solution was washed with water (100 mL), dried over Na2SO4 and filtered. The organic solution was concentrated to afford 2.21 g of (4R)-4-[2, 5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride as pale yellow oil in 91% yield. LC/MS 504.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][O:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[CH2:20][CH2:19]4)=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>N1C=CC=CC=1>[O:37]1[CH2:36][CH2:35][N:34]([C:10]2[C:11]3[S:16][C:15]([CH2:17][N:18]4[CH2:19][CH2:20][N:21]([C:24](=[O:33])[CH2:25][O:26][CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][O:28]5)[CH2:22][CH2:23]4)=[CH:14][C:12]=3[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:42])[CH3:41])=[N:7][CH:6]=3)[N:9]=2)[CH2:39][CH2:38]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)COC5CCCCO5)CC4)cc3n2)cn1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)COC5CCCCO5)CC4)cc3n2)cn1

Procedure:
1-(4-((2-(6-Aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone (110 mg) was reacted with 80 μL acetic anhydride in 500 μL pyridine overnight at 40° C. to give N-(5-(4-morpholino-6-((4-(2-(tetrahydro-2H-pyran-2-yloxy)acetyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyridin-2-yl)acetamide. This intermediate was subjected to Procedure D to remove the THP protecting group and give 6.3 mg of 184 after purification. MS (Q1) 512.3 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=1[C:20]([F:23])([F:22])[F:21].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:15]1[C:14]([C:20]([F:23])([F:22])[F:21])=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][CH2:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cccc(F)c2C(F)(F)F)c(=O)[nH]1
Reactant: NCc1ccccc1
Product: Cc1cc(C)c(CNC(=O)c2cccc(NCc3ccccc3)c2C(F)(F)F)c(=O)[nH]1
Temperature: 210 °C
Yield: 31.1 %

Procedure:
A suspension of N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-fluoro-2-(trifluoro methyl)benzamide (0.80 g, 2.34 mmol) in benzylamine (2.6 ml, 23.4 mmol) was heated in a microwave reactor at 210° C. for 4 h. After cooling distilled water (20 ml) was added to the slurry and 2M HCl was added until the suspension was at pH5. and the mixture was extracted using EtOAc (3×50 ml). The combined organics were washed with pH5 HCl solution (2×50 ml), brine (30 ml), dried using Na2SO4 filtered and evaporated. The resultant oil was purified using a 50 g Isolute silica column eluting with a gradient of 0% to 5% MeOH in DCM to afford the title compound as an off-white solid (313 mg, 29%). LC-MS 94%, m/z=430.2, 1H NMR (500 MHz, Acetone-d6) δ 7.41-7.16 (m, 8H), 6.69 (d, J=8.5 Hz, 1H), 6.50 (d, J=7.4 Hz, 1H), 5.87 (s, 1H), 5.84 (s, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.35 (d, J=5.6 Hz, 2H), 2.28, (d, J=4.0 Hz, 3H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Yield: 94.8 %

Procedure:
A solution of trans-N-Boc-2-methyl-6-(ethenyl propionyl)piperidine (2.0 g, 6.70 mmol) in 3 mL of ethanol was shaken under 58 psi of H2 pressure over 0.65 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 1.8 g (90%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 4.16-4.08 (q, 2H), 3.93-3.83 (m, 2H), 2.36-2.28 (t, 2H), 2.04-1.08 (m, 20H); 13C NMR (62.7 MHz) 155.4 (s), 79.1 (s), 60.3 (s), δ 1.0 (s), 47.2 (s), 31.9 (s), 29.6 (s), 28.5 (s), 26.9 (s), 25.8 (s), 24.2 (s), 20.5 (s), 14.2 (s) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=3[F:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3F)cccc2c1N
Yield: 69.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2,5-difluoro-phenylboronic acid (160 mg, 1.00 mmol) were reacted to afford the title compound (116 mg, 70% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.97-7.91 (m, 1H), 7.83-7.69 (m, 2H), 7.27-7.05 (m, 3H), 3.46 (apparent quartet, J=7.0 Hz, 2H), 1.74-1.59 (m, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=343 (M+H). HPLC 2.01 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]2[NH:11][C:12](=[S:13])[NH:14][C:15]2=[O:16])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1ccc(O)c(Br)c1
Yield: 75.8 %

Procedure:
Prepared according to the procedure described in Example 1 using 3-bromo-4-hydroxybenzaldehyde (3.1 g, 15 mmoles), 2-thiohydantoin (1.7 g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid (35 ml), to afford the pure product (3.4 g), mp 262° C. (dec).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][O:13][C:12]2=[O:17])=[CH:5][CH:4]=1.[CH3:20][NH2:21]>CO.O1CCCC1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:17])[O:13][CH2:14][C:15]([NH:21][CH3:20])=[O:16])=[CH:5][CH:4]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCc1ccc(C(F)(F)F)cc1
Reaction time: 12 h

Procedure:
A solution of 0.75 g (2.74 mmol) of 3-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-oxazolidine-2,4-dione obtained in step 2.1., in 10 ml of methanol is admixed with 8 ml (16.47 mmol) of a solution (2M) of methylamine in tetrahydrofuran. Stirring is continued at ambient temperature for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:11])[CH2:9][O:10][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: OC[C@H](O)c1ccc(Cl)nc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(Cl)nc2)cc1
Reaction time: 0.33 h

Procedure:
To a cooled 5° C., stirred solution of (R)-1-(6-chloro-pyridin-3-yl)-ethane-1,2-diol (17.8 grams) in anhydrous pyridine (100 mL) was added p-toluenesulfonyl chloride (19.5 grams) in one portion. After 20 minutes, the cooling bath was removed and stirring was continued an additional 12 hours. The reaction solution was concentrated in vacuo, azeotroped with toluene (2 times), diluted ethyl acetate, washed with half-saturated aqueous brine, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo. The resulting solids were recrystallized from ethyl acetate/hexanes to afford the title compound as colorless crystals, 23.3 grams 1H NMR (400 MHz, CDCl3)=8.29 (s, 1H); 7.72 (d, 2H); 7.64 (d, 1H); 7.32 (d, 2H); 7.28 (d, 1H); 5.00 (dd, 1H); 4.09 (AB pattern, 2H); 2.44 (s, 3H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH2:16].C(O)(=O)C>CCO>[CH3:15][NH:16][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(NC)c1ccccc1
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a solution of ethyl benzoylacetate (30 g, 156 mmol) and methylamine (2 M in THF, 390 mL, 780 mmol) in EtOH (150 mL), was added acetic acid (44.7 mL, 780 mmol). The reaction mixture was heated to reflux with stirring for 15 hours. The reaction mixture was cooled, concentrated and partitioned between DCM and 1M HCl. The phases were separated and the organic layer dried over Na2SO4, filtered and concentrated to give the title compound (32 g), used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[OH:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl.C(OCC)C>N1C=CC=CC=1>[C:8]1([CH:6]([OH:7])[CH2:5][O:4][CH2:3][CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(O)c1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
8.3 g of 2(2-hydroxyethoxy)-1-(1-naphthyl)ethanol was dissolved in 50 ml of pyridine. The solution was cooled to -25° C. Thereto was added 6.8 g of p-toluenesulfonyl chloride. The resulting mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 6.3 g of colorless, oily 1(1naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:34]=[CH:33][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([F:32])=[C:15]([NH:17][C:18](=[O:31])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[C:20]=3[Cl:30])[CH:16]=2)=[C:8]([N+:35]([O-:37])=[O:36])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:35]([O-:37])=[O:36])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:32])=[C:15]([NH:17][C:18](=[O:31])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[C:20]=4[Cl:30])[CH:16]=3)[CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc(N)cc3[N+](=O)[O-])ccc2F)c1Cl
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
Potassium thiocyanate (1.63 g, 16.8 mmol) was suspended in acetic acid (40 mL), and the suspension was stirred at room temperature for 10 min. N-[5-(4-Amino-2-nitrophenoxy)-2-fluorophenyl]-2-chloro-3-(1-cyano-1-methylethyl)benzamide (1.57 g, 3.36 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (966 mg, 6.05 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 2 hr. A solution of bromine (400 mg, 2.50 mmol) in acetic acid (5 mL) was added, and the mixture was further stirred at room temperature for 6 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (400 mL)/tetrahydrofuran (200 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (500 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure to give the title compound (458 mg, 26%) as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][C@H:13]1[C:26]1[O:30][N:29]=[C:28]([CH3:31])[N:27]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C@@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:13]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[N:27]=2)[CH2:14]1
Reactant: Cc1noc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc([C@@H]2C[C@H](N)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Reaction time: 5 h

Procedure:
To absolution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate (250 mg) in CH2Cl2 (10 mL) was added TFA (3 mL) at RT. The reaction was stirred for 5 h and concentrated in vacuo. The residue was partitioned between 1N NaOH (30 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the organic phases were combined, washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (1S,2R,4R)-4-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate. MS found: (M+H)+=331.
Reaction SMILES: CN.[CH3:3]NC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]([S:19](=[O:22])(=[O:21])[NH2:20])=[C:16](C)[N:17]=2)=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][CH:16]=[C:15]([S:19](=[O:22])(=[O:21])[NH:20][CH3:3])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CNC
Reactant: Cc1nc(-c2ccc(Cl)cc2)[nH]c1S(N)(=O)=O
Agent: CN
Product: CNS(=O)(=O)c1c[nH]c(-c2ccc(Cl)cc2)n1
Yield: 4.4 %

Procedure:
Substituting aqueous methylamine for the dimethylamine in Example 3 2-(4-chlorophenyl)-4-methyl-sulfamoylimidazole, melting at 246°-248°, was obtained (4.4% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([OH:9])=[N:6][C:7]=1[OH:8].[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>[OH-].[Na+]>[OH:9][C:5]1[N:6]=[C:7]([OH:8])[C:2]([NH:1][C:18]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:19])=[C:3]([OH:10])[N:4]=1
Reactant: Nc1c(O)nc(O)nc1O
Reactant: S=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1nc(O)c(NC(=S)Nc2ccccc2)c(O)n1
Temperature: 60 °C

Procedure:
75 g of 5-amino-2,4,6-trihydroxypyrimidine was dissolved in 1.5 to 5% sodium hydroxide with vigorous overhead stirring producing a violet solution. The reaction was heated to 60° C. and 63 ml phenyl isothiocyanate was added dropwise over 1.5 hours. The reaction turned pale yellow. The reaction was stirred an additional 2 hours at 60° C., cooled and acidified with glacial acetic acid producing a light yellow precipitate. This was filtered to yield about 75 g of N-(2,4,6-trihydroxy-5-pyrimidyl)-N'-phenylthiourea.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:24])[CH2:20][C:21]([OH:23])=O)[N:18]=2)[CH:11]=[CH:12][CH:13]=1.[CH3:25][NH2:26].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:24])[CH2:20][C:21]([NH:26][CH3:25])=[O:23])[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CN
Reactant: CC(CC(=O)O)n1nnc(-c2cccc(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)CC(C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Oxalylchloride (2 mL, 3.9 mmol) was added during 5 minutes to 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butanoic acid in DCM (40 mL) and DMF (5 drops) under argon. The mixture was stirred at r.t. for 3 h and then was MeNH2 (2M in THF, 3.6 mL, 7.2 mmol) added and the resulting mixture was stirred o.n. Saturated NaHCO3 (75 mL) was added and the mixture was extracted with CHCl3 (3×100 mL). The combined organic phases were dried (MgSO4) and concentrated. The crude was purified by flash column chromatography (SiO2, Heptane-EtOAc 1:2) to give 0.74 g (74%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH3:15]I>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:14][CH:13]2[CH2:12][N:11]([CH3:15])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(C23CNCC2C3)c1
Reactant: CI
Agent: Cl
Product: CN1CC2CC2(c2cccc(Cl)c2)C1

Procedure:
By the method of Example 10, 1-(m-chlorophenyl)-N-methyl-1,2-cyclopropanedicarboximide, m.p. 72°-73° C., prepared from 1-(m-chlorophenyl)-1,2-cyclopropanedicarboximide (Example 6) and methyl iodide gives 1-(m-chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 180°-182° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:37]([N:36]([CH3:40])[CH3:35])=[O:38])[CH2:25][CH2:26]2)[CH2:15][CH2:14]1
Reactant: COc1ccc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(Cl)c1Cl
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2CCN(CC[C@H]3CC[C@H](NC(=O)N(C)C)CC3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.92 g (2 mmol) trans-4-{2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dichloromethane (60 ml), triethylamine (1.26 ml, 9 mmol) was added followed by 0.21 ml (2.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature. The solution was washed with water (2×10 ml), dried and evaporated in vacuo. Purification with flash chromatography gave 0.66 g trans-1-{4-[2-[4-(2,3-dichloro-4-methoxy-phenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea, melting at 196-8° C. This product was dissolved in dichloromethane (60 ml), then 6.4 ml (6.4 mmol) borontribromid solution (1M in CH2Cl2) was dropped in at 5° C. and the mixture stirred at room temperature for 24 hours. The reaction was monitored by TLC. 4 ml methanol was added, followed by 25 ml saturated NaHCO3 solution. After separation the organic layer was dried and evaporated in vacuo. Purification with flash chromatography gave 0.4 g of the title compound, melting at 278-80° C.