Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[C:8]=1[S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(Cl)c1Sc1ncc[nH]1
Temperature: 0 °C
Yield: 94 %

Procedure:
Acetonitrile (20 ml) suspension of 2-mercaptoimidazole (1.0 g) and 2,3-dichloronitrobenzene (2.1 g), potassium carbonate (1.7 g) was stirred under refluxing for 6.5 hours. The reaction mixture was poured into ice-water. The deposited solids were collected by filtration, and washed with n-hexane. The thus obtained solids were dried, there was obtained 2-(2-chloro-6-nitrophenylthio)imidazole (2.4 g, yield: 94%) as yellow powdery product.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][CH:11]2[C:21]([NH:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[O:22])=[CH:3]1>O>[NH2:26][CH2:25][CH2:24][NH:23][C:21]([CH:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:22]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)NCCN)CC[C@@H]12
Reaction time: 2 h

Procedure:
To 16.5 mg of Tert-Butyl 2-{[(3-oxoandrost-4-en-17-yl)carbonyl]amino}-ethylcarbamate was added 0.5 ml of 95% trifluoroacacetic acid/water. On standing for 2 hours the volatile components were removed using a rotary evaporator. The resulting product (Formula XIV), which was an oil, was used without further purification. Mass spectrum: 359.23 (M+H)
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([C:13]([F:16])([F:15])[F:14])=[N:8][C:9]=1[O:10][CH2:11][CH3:12])=O>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([C:13]([F:16])([F:14])[F:15])=[N:8][C:9]=1[O:10][CH2:11][CH3:12])#[N:1]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(OCC)c(C(N)=O)c1OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C(F)(F)F)nc(OCC)c(C#N)c1OCC
Yield: 24.1 %

Procedure:
A mixture of 6.17 g (0.018 mol) of product of Example 23 and 100 ml of POCl3 was held at reflux for 7 hours and concentrated in vacuo. The residue was poured into water and extracted with ether. The ether extract was washed with 15% K2CO3, dried (MgSO4) and concentrated to give 1.44 g (24.6%) of product as an oil; nD25 1.4677.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[CH2:4][O:5][C@H:6]([CH2:8][CH:9]=[CH2:10])[CH3:7].C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl>[CH3:7][C@@H:6]1[O:5][CH2:4][C:3]2=[N:2][O:1][CH2:10][C@@H:9]2[CH2:8]1
Reactant: C=CC[C@H](C)OC/C=N/O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1C[C@H]2CON=C2CO1

Procedure:
To a solution of C5 (8.6 g, 0.06 mol) and triethylamine (0.455 g, 4.50 mmol) in dichloromethane (150 mL) at room temperature was slowly added a 6% aqueous solution of sodium hypochlorite (90 mL) while maintaining the internal temperature between 20° C. and 25° C. After the addition, the organic phase was separated, dried and concentrated in vacuo Silica gel chromatography (petroleum ether/ethyl acetate=10:1) provided the product as a yellow oil. Yield: 5.70 g, 40.4 mmol, 67%. LCMS m/z 142.1 [M+H+], 1H NMR (400 MHz, CDCl3), δ 4.68 (d, J=13.2 Hz, 1H), 4.59 (dd, J=10, 8 Hz, 1H), 4.18 (d, J=13.2 Hz, 1H), 3.76 (dd, J=12, 8 Hz, 1H), 3.59-3.66 (m, 1H), 3.39-3.50 (m, 1H), 2.14-2.19 (m, 1H). 1.42-1.51 (m, 1H), 1.25 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([O:16][C:17]([CH3:23])([CH3:22])[C:18](F)([F:20])[F:19])[CH2:14][OH:15].FC(F)C(C)(O)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([O:16][C:17]([CH3:23])([CH3:22])[CH:18]([F:19])[F:20])[CH2:14][OH:15]
Reactant: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Agent: CC(C)(O)C(F)F
Product: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)F

Procedure:
Compound 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1-difluoro-2-methylpropan-2-yloxy)ethanol was prepared following the procedure used to prepare 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol of Example 31, except that 1,1-difluoro-2-methylpropan-2-ol (10 eq) was used instead of 2-trifluoromethyl-2-propanol (25 eq). 1H-NMR: 400 MHz, (CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57-7.49 (m, 3H), 5.85 (dd, J=9.2, 3.6 Hz, 1H), 5.61 (t, J=56.4 Hz, 1H), 3.94 (dd, J=11.6, 9.6 Hz, 1H), 3.65 (dd, J=11.6, 4.4 Hz, 1H), 2.69 (s, 3H), 2.18 (br s, 1H), 1.32 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[BH3-]C#N.[Na+].Cl.O>C1COCC1>[CH3:10][C:9]1[C:2]([OH:1])=[C:3]([CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(O)c(C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 8 (0.90 g, 5.9 mmol) and NaBH3CN (1.1 g, 17.7 mmol) in THF (36 mL) was slowly added 1 M HCl (17.7 mL) to keep pH of the mixture at 3. The mixture was stirred at room temperature for 3 h. Water (50 mL) was added, and then the mixture was extracted with diethyl ether (50 mL×3). The combined organic layers were dried over Na2SO4 and then evaporated. The obtained white powder (0.58 g, 70%) was used to next step without further purification. 1H-NMR (CDCl3, 400 MHz): δ6.85 (1H, d, J=8.1 Hz), 6.37 (1H, d, J=8.1 Hz), 2.22 (3H, s), 2.19 (3H, s). 13C-NMR (CDCl3, 100 MHz) δ152.8, 127.6, 115.1, 109.9, 107.0, 15.5, 8.2.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][P:16]([CH2:19][CH:20]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21](O)=[O:22])([OH:18])=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:44]1([NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[C:44]1([NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:56])[CH3:57])[NH:53][C:21](=[O:22])[CH:20]([CH2:19][P:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])([OH:18])=[O:17])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Reactant: O=C(O)C(CCc1ccccc1)CP(=O)(O)CCCCN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(=O)(O)CCCCN1C(=O)c2ccccc2C1=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
The crude product from Step G was dissolved in tetrahydrofuran (80 mL) and the solution was cooled in an ice bath. A slurry of 1,1'-carbonyldiimidazole (4.09 g, 25.2 mmol) in tetrahydrofuran (10 mL) was added over 10 min with additional tetrahydrofuran (3×5 mL) to complete the transfer. After 30 min, a solution of L-leucine N-phenylamide (5.60 g, 27.1 mmol) in tetrahydrofuran (10 mL) was added over 10 min with additional tetrahydrofuran (5 mL) to complete the transfer. The homogeneous solution was allowed to slowly warm to room temperature and stirred for 16 h. The mixture was concentrated on a rotary evaporator to remove most of the tetrahydrofuran and the residue was partitioned between ethyl acetate (150 mL) and 2N aqueous hydrochloric acid (75 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (2×25 mL). The crystals which spontaneously formed in the organic layer were separated by filtration and partioned between chloroform (300 mL) and 2N aqueous hydrochloric acid, and the chlorform layer was washed with saturated aqueous sodium chloride (50 mL). The sodium chloride layer was extracted with chloroform (2×25 mL). The combined chlorform extracts were dried (magnesium sulfate), filtered, and evaporated. The residue was dissolved in boiling tetrahydrofuran (100 mL), allowed to cool to 25° C., evaporated to a mass of 40 g, and dissolved in ethyl acetate (150 mL). After 2 h at 25° C., the crystals were separated by filtration,washed with ethyl acetate (2×20 mL) and ether (20 mL), and dried under vacuum to give 6.17 g of almost colorless crystals. Evaporation of the mother liquor and recrystallization produced a second crop of 1.62 g (total yield 54% for steps F-H) of (2-(((4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl)hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17](=[CH:21][N:22](C)[CH3:23])[C:18](=O)[CH3:19])=[CH:11][N:10]=3)[N:7]=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:35].CC[O-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:8]([C:9]3[N:10]=[CH:11][C:12]([NH:15][C:16]([C:17]4[C:18]([CH3:19])=[N:35][CH:23]=[N:22][CH:21]=4)=[O:25])=[CH:13][N:14]=3)[N:7]=[C:6]([C:26]([F:27])([F:28])[F:29])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)C(=CN(C)C)C(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ncncc1C(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Yield: 4 %

Procedure:
N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-2-[(dimethylamino)methylene]-3-oxobutanamide (0.3 g, 0.78 mmol) and formamidine acetate (98 mg, 0.94 mmol) were dissolved in ethanol and added NaOEt (60 mg, 0.94 mmol). The above mixture was refluxed for 3 h. Ethanol was removed on rotavapour and worked up (H2O/AcOEt) to obtain the crude. Crude was purified by column on 60-120 mesh silica gel using AcOEt and Petether (1:1) as eluent to obtain the title compound (12 mg) as a brown solid. M.P.: 201-203° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.29 (s, 1H), 9.26 (s, 2H), 9.19 (s, 1H), 8.99 (s, 1H), 6.68 (s, 1H), 2.64 (s, 3H), 2.55-2.49 (m, 1H), 1.02-0.94 (m, 2H), 0.83-0.75 (m, 2H). MS (m/z): 389.93 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22]C(OC(C)(C)C)=O)[CH2:18][C@H:17]2[CH2:30][CH2:31][CH3:32])[C:12]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]2[CH2:14][CH2:15][C@H:11]([NH:10][C:9](=[O:34])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[O:33])[C@H:17]([CH2:30][CH2:31][CH3:32])[CH2:18]1
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 5 h

Procedure:
To a solution of {(3S)-1-[(1S,2R,4R)-4-tert-butoxycarbonylamino-2-propyl-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (3.88 g, 8.2 mmol) in CH2Cl2 (90 mL) was added TFA (45 mL) at RT. The reaction was stirred for 5 h and concentrated in vacuo. The residue was partitioned between 1N NaOH (100 mL) and EtOAc (150 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 (S)-1-[(1S,2R,4R)-4-amino-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate. MS found: (M+H)+=374.3.
Reaction SMILES: C1(C[N:8]2[CH2:14][CH:13]([OH:15])[C:10]3([CH2:12][CH2:11]3)[CH2:9]2)C=CC=CC=1.[ClH:16]>CO>[ClH:16].[CH2:11]1[C:10]2([CH:13]([OH:15])[CH2:14][NH:8][CH2:9]2)[CH2:12]1
Reactant: OC1CN(Cc2ccccc2)CC12CC2
Agent: Cl
Solvent: CO
Product: OC1CNCC12CC2
Yield: 99 %

Procedure:
5-(Phenylmethyl)-5-azaspiro[2.4]heptan-7-ol (assumed 941.9 mg, 4.63 mmol) was dissolved in a solution of 4.6 mL of 1N aq HCl in 40 mL of MeOH, degassed and placed under argon. 10% Pd/C (280 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon overnight. The contents were then degassed and filtered through Celite, and the Celite pad was washed with MeOH. The resulting filtrate was concentrated in vacuo and azeotroped with MeOH (3×40 mL) to provide the pure 5-azaspiro[2.4]heptan-7-ol hydrochloride (685 mg, 99%). LCMS: (M+H)+: not detected.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[C:30]#[N:31].CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.CC1CCCO1.C(=O)([O-])[O-].[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.[Pd].O>[NH2:21][C:19]1[C:18]([CH3:22])=[N:17][C:16]2([C:23]3[C:5](=[CH:4][CH:3]=[C:2]([C:33]4[CH:32]=[C:29]([CH:28]=[C:27]([O:26][CH3:25])[CH:34]=4)[C:30]#[N:31])[CH:24]=3)[CH2:6][CH2:7][C:8]32[CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[N:20]=1
Reactant: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(N)=N3)CC1
Reactant: COc1cc(C#N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Solvent: CC1CCCO1
Solvent: O
Product: COc1cc(C#N)cc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CC3)CCC(OC)CC2)c1
Temperature: 130 °C

Procedure:
7′-Bromo-4-methoxy-5″-methyl-3′,4′-dihydrodispiro[cyclohexane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 5, 0.184 g, 0.47 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.122 g, 0.47 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (0.013 g, 0.05 mmol), sodium tetrachloropalladate(II) (6.95 mg, 0.02 mmol), 2-methyltetrahydrofuran (3 mL) and potassium carbonate (2.0 M, 0.708 mL, 1.42 mmol) were added to a microwave vial. The vial was sealed and heated with MW for 30 min at 130° C. The same amount of ligand and Pd-catalyst were added again and the reaction was heated in the MW for 15 min at 130° C. Water and 2-Me THF was added and the water phase was eliminated. The organic phase was washed once with brine and once with water. The organic phase was concentrated in vacuo. The product was purified using prep HPLC. Fractions containing the isomeric products were collected separately and the MeOH was evaporated. DCM was added and the mixture was poured into a phase separator. The organic phase was concentrated in vacuo to give:
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(Cl)c3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (3-chlorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1N solution of sodium carbonate in water (0.5 mL, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexanes) to give the desired product. LCMS calculated for C15H13ClN5OS (M+H)+: m/z=346.1. Found: 346.0.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([CH3:22])[CH:16]=1)=O)(C)(C)C>ClCCl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][NH2:12])=[O:23])=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NN)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
500 mL trifluor acetic acid was added to 70 g N′-(4-bromo-3-methyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester in 1 L dichlormethane. The reaction was stirred 1 h at RT and evaporated. The residue was basicfied with 1N sodiumhydroxide and extracted with saturated sodiumchloride solution and tetrahyrofuran. The organic layer was evaporated and the residue crystallized with ethyl acetate to give 25 g desired product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O:16][CH2:17]C)=[O:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C1C(=O)N([Br:26])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:26][C:3]#[C:2][CH2:1][O:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C#CCOc1cccc2c1OC(C(=O)OCC)C2
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C1Cc2cccc(OCC#CBr)c2O1

Procedure:
67.98 g (0.293 mol) of the compound from Example 46 and 61 g (0.340 mol) of NBS are stirred at 20° C. for 30 minutes in the presence of 5 g of AgNO3 in 2.5 l of acetone. The mixture is concentrated to about 500 ml, poured onto 2 l of ice/water and shaken twice with 500 ml of ethyl acetate each time. The mixture is filtered, and the ethyl acetate phases are dried over Na2SO4 and evaporated. The residue is flash chromatographed on silica gel (eluent: petroleum ether/acetone 3:1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)=[O:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][NH:27][N:26]=1>>[CH3:24][C:25]1[C:29]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12]([C:14]4[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=4)=[O:13])=[N:10][C:5]3=[CH:4][CH:3]=2)=[CH:28][NH:27][N:26]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1ccc(C(=O)Nc2nc3ccc(-c4c[nH]nc4C)nc3s2)cc1
Yield: 17 %

Procedure:
The titled compound (yield=17%, yellow solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1C (Example 3) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (s, 3H) 3.91 (s, 3H) 6.56 (br. s., 1H) 7.76 (d, J=8.59 Hz, 1H) 8.12 (d, J=8.59 Hz, 4H) 8.25 (d, J=8.59 Hz, 2H) 13.15 (br. s., 1H); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:17][S:18][C:19](SC)=[CH:20][N+:21]([O-:23])=[O:22]>C(#N)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:19]([S:18][CH3:17])=[CH:20][N+:21]([O-:23])=[O:22])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NC1CCCC(c2csc(NC(=N)N)n2)C1
Yield: 67.1 %

Procedure:
A solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.5 g.) in boiling acetonitrile (25 ml.) was treated with 1,1-di(methylthio)-2-nitroethylene (0.35 g.) and the mixture heated under reflux for 7 hours. The reaction mixture was evaporated to dryness and the residue crystallised from methanol to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-1-methylthio-2-nitroethylene (0.5 g.) as a yellow solid. The n.m.r. spectrum in d6 dimethylsulphoxide included signals at 1.2-2.2(m) 3.3(s), 3.7(m), 6.27(s), 6.65(s) and 6.69(br s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5]2.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])[CH:11]=[CH:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCOc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCCCCCCOc1ccc2cc(/C=C/C(=O)OC)ccc2c1

Procedure:
A mixture of 5.2 g of 6-bromo-2-heptyloxynaphthalene, 25 ml of triethylamine, 4.3 ml of methyl acrylate, 0.072 g of palladium acetate and 0.392 g of tri-o-tolylphosphine is refluxed for 16 hours. The reaction mixture is then cooled and is partitioned between ethyl acetate and water and the organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated down. The residue is chromatographed over 250 g of silica gel using toluene/ethyl acetate (3:1) and then crystallized from toluene. This gives methyl (E)-3-(heptyloxynaphth-2-yl)acrylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([C@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[N:9]=2)=[CH:4][CH:3]=1.[C@H]1(O)C2C(=CC=CC=2)CC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(F)cc3)nn2[C@@H]2CCc3ccccc32)C1
Agent: O[C@@H]1CCc2ccccc21
Product: CC(=O)N1CCc2c(c(-c3ccc(F)cc3)nn2[C@H]2CCc3ccccc32)C1

Procedure:
According to Scheme 7: In analogy to the synthesis of (12a), but taking (R)-1-indanol instead, 1-[(S)-3-(4-fluoro-phenyl)-1-indan-1-yl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (12b) was obtained. Rt=2.46 min (LC method 6). Detected mass: 376.17 [M+H+].
Reaction SMILES: [OH-].[Na+].C(O)C.[C:6]([NH:14][C:15]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[C:6]([NH:14][C:15]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=[CH:21][C:16]=1[C:17]([OH:19])=[O:18])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(-c2nccs2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(-c2nccs2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
0.35 mL of 10% aqueous sodium hydroxide was added to 5 mL of ethanol suspension containing 0.25 g of methyl 2-(benzamido)-4-(thiazol-2-yl)benzoate at room temperature, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.23 g of 2-(benzamido)-4-(thiazol-2-yl)benzoic acid as white solid.