Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1CCCC1.[CH3:20][C:21]([C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1O)=[O:22]>CO>[Br:29][C:27]1[CH:28]=[C:23]2[C:24](=[CH:25][CH:26]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[CH2:20][C:21]2=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mL of MeOH, 7.97 g of N-Boc-piperidin-4-one, and 3.34 mL of pyrrolidine were added to 8.60 g of 5-bromo-2-hydroxyacetophenone put in a 200-mL flask equipped with a condenser, and the mixture was overnight heated under reflux. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified through silica gel column chromatography (eluted with n-hexane/EtOAc=6/1) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH2:16][OH:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:5][CH2:1][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH2:16][OH:17])[CH:9]=1
Reactant: COc1cc(CO)cc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CO)cc(CBr)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
Carbon tetrabromide (3.47 g) was added to a stirred solution of 1,3-dihydroxymethyl-5-methoxy-benzene (800 mg) in anhydrous dichloromethane (16 mL) under argon. After cooling the resulting solution at 0° C., a solution of triphenylphosphine (2.68 g) in anhydrous dichloromethane (16 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioPrep 90 g column, Si60 15-40 μm, eluted with methanol/dichloromethane, 4:96) to give 1-bromomethyl-3-hydroxymethyl-5-methoxy-benzene (420 mg):
Reaction SMILES: Br[CH2:2][CH:3]([O:16][CH3:17])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C)C=O>[C:18]1(=[O:28])[N:22]([CH2:2][CH:3]([O:16][CH3:17])[CH2:4][O:5][C:6]2[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=2)[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: COC(CBr)COc1ncc(C(=O)N(C)C)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(COc1ncc(C(=O)N(C)C)s1)CN1C(=O)c2ccccc2C1=O

Procedure:
By a procedure analogous to Example 2, the product from Example 8 can be reacted with potassium phthalimide in N,N-dimethylformamide to give the solid title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].C([C:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23]Br)=[CH:20][CH:21]=2)[C:16](CC)=[C:15]([C:27](P(=O)([O-])[O-])([F:29])[F:28])[C:14]=1[Br:34])C>C1(C)C=CC=CC=1>[Br:34][C:14]1[CH:13]=[C:22]2[C:17](=[CH:16][C:15]=1[C:27]([P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])([F:28])[F:29])[CH:18]=[C:19]([CH2:23][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH:20]=[CH:21]2
Reactant: CCOP([O-])OCC
Reactant: CCc1c(Br)c(C(F)(F)P(=O)([O-])[O-])c(CC)c2cc(CBr)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reaction time: 1 h

Procedure:
To a solution of diethylphosphite (0.22 mL) in toluene (5 mL) at 0° C. was added NaH (60% in mineral oil, 20 mg). The reaction mixture was stirred for 1 hour and then a solution of diethyl[3-bromo-7-(bromomethy)-2-naphthyl](difluoro)methylphosphonate (220 mg) in toluene (2 mL) was added dropwise. The reaction was stirred for 1 h at 0° C., quenched with a solution of saturated NH4Cl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness and the residue was purified by flash chromatography eluting with 50% EtOAc/hexanes to afford the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].C(=O)([O-])[OH:11].[Na+]>O.[Pt]>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[C:4]([OH:11])=[O:5]
Reactant: O=C([O-])O
Reactant: OCC(CO)(CO)CO
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(CO)(CO)CO
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of pentaerythritol (10.0 g) in water (600 mL) was 5% platinum/carbon (hydrous article, 13.3 g). While maintaining pH of the reaction mixture to 6˜7 by means of 8% sodium hydrogen carbonate solution, it was stirred at 35° C. for 8 hours under an atmosphere of oxygen. After catalyst was filtered, and having removed, the reaction mixture was concentrated. After having put the obtained residue through ion exchange resin Amberlyst (Amberlyst: trade name) A-21 by means of 2N hydrochloric acid, it was purified by preparative medium pressure liquid chromatography W-prep 2XY (column: main column L, inject column M; automatic condition setting: dichloromethane:methanol=4:1, Rf=0.25, preparative isolation mode GR). Furthermore, the obtained residue was purified by preparative TLC (dichloromethane:methanol=4:1) to give the title compound (123 mg) having the following physical data.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:12][CH:11]2[NH:13][CH:8]([CH2:9][CH2:10]2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]([CH:25]=[O:26])[CH3:24]>>[CH3:8][C@H:9]([CH2:10][N:13]1[CH:11]2[CH2:10][CH2:9][C@H:8]1[CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:12]2)[CH2:22][N:23]1[C:24]2[C:3](=[CH:2][CH:1]=[CH:6][CH:7]=2)[CH2:4][CH2:5][C:25]1=[O:26]
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCC1CC2CC[C@@H](C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21

Procedure:
Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (107LH63)(0.094 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15 mmol), NaI (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c5)(0.025 g). HPLC-MS (ammonium acetate) [M+H]+=383.34
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:21])[CH2:9][CH2:8][N:7]([CH2:10][CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[O:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH:11]1[CH2:10][N:7]1[CH2:8][CH2:9][C:5]([CH2:3][OH:2])([CH3:21])[CH2:6]1
Reactant: COC(=O)C1(C)CCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(CO)CCN(CC2COc3ccccc3O2)C1

Procedure:
The reduction of 84 mg (0.28 mmol) of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidine-3-carboxylic acid methyl ester with 20 mg (0.53 mmol) of LiAlH4 was performed using the procedure described above. Purification by column chromatography (silica gel, methanol/triethylamine/dichloromethane, 1:1:99) yielded the desired pure alcohol.
Reaction SMILES: C(O[CH:5]([O:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.C[Si](C)(C)[O:20][C:21]1[N:26]=[C:25]([O:27][Si](C)(C)C)[C:24]([F:32])=[CH:23][N:22]=1.C(=O)([O-])O.[Na+].O>C(#N)C>[C:15]([O:14][CH2:13][O:12][CH:5]([N:22]1[CH:23]=[C:24]([F:32])[C:25](=[O:27])[NH:26][C:21]1=[O:20])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:17])[CH3:16]
Reactant: C[Si](C)(C)Oc1ncc(F)c(O[Si](C)(C)C)n1
Reactant: CC(=O)OCOC(OC(C)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCOC(c1ccccc1)n1cc(F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
A solution of α-acetoxymethoxybenzyl alcohol acetate (1.43 g; 6 mmoles) prepared in Example I - 1 and 2,4-di-(trimethylsilyloxy)-5-fluoropyrimidine (1.37 g; 5 mmoles) in dry acetonitrile (25 ml) is cooled at 0° C. Stannic chloride (d=2.26; 0.58 ml; 5 mmoles) is added thereto, and the mixture is stirred at 0° C. for 30 minutes, then mixed with sodium hydrogencarbonate (2.52 g; 30 mmoles) and water (2.5 ml), and vigorously stirred at 0° C. The insoluble materials are filtered off and washed with acetonitrile and methylene chloride. The organic layer is washed with an aqueous saturated solution of sodium hydrogencarbonate and then with saturated brine, dried over magnesium sulfate, and evaporated. The residue is chromatographed on a column of silica gel and eluted with benzene-ethyl acetate (2:1). The eluate is recrystallized from ether to give the title compound (0.88 g; yield 57%). mp. 108°-109° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:7]1[C:8]([NH2:11])=[N:9][CH:10]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=1
Reactant: COCCc1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCCc1cnc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2-methoxyethyl)pyrazin-2-amine (80 mg, 0.522 mmol) in DCM (1.7 mL) was added NBS (93 mg, 0.522 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After quenched with NaHCO3, the reaction mixture was extracted with DCM 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. The crude material was used in next step reaction without purification. LCMS (m/z): 232.1/234.1 (MH+), 0.49 min.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:35]
Reactant: Cc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 153 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-methylphenyl)ethanone, the mixture was stirred for 5 hours at room temperature. Aqueous 1N sodium hydroxide was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was Washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (66 mg, 51% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][N:5]2[CH:12]=1.Br.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]2[CH:12]=1
Reactant: COc1ccc2nc(C)cn2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cn2cc(O)ccc2n1
Yield: 30 %

Procedure:
A mixture composed of 1.92 g (11 mM) of 2-methyl-6-methoxyimidazo[1,2-α]pyridine and of 7.26 g (45 mM) of pyridinium hydrobromide is heated to melting point for 8 hours. The mixture is then cooled and water is added thereto. The aqueous phase is brought to a basic pH with sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The desired product is thus obtained in the form of a beige solid with a yield of 30%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:21])=[CH:15]/[C:16](OCC)=[O:17])=[CH:10][CH:9]=2)[CH:7]=1.CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:21])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)ccc2OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1ccc(Cl)cc1-c1ccc(/C(C)=C/CO)cc1

Procedure:
(E)-Ethyl 3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enoate (0.90 g, 2.72 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52 b to give (E)-3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourless oil; 0.785 g (100%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>>[CH:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH:20]([C:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH:19]=2)[CH2:21][CH2:22]1)=[O:28])([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)Cl
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Product: CC(C)OC(=O)N1CCC(c2cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3o2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and isopropyl chloroformate following a procedure analogous to that described for Example 19. LC (method 6): tR=1.45 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: FC1C(F)=C(F)C(F)=C2C=1[NH:4]C(=O)C(=O)N2.[Br:17][C:18]1[CH:27]=[C:26]([Br:28])[CH:25]=[C:24]2[C:19]=1[NH:20][C:21](=[O:30])[C:22](=[O:29])[NH:23]2.[OH-].[K+].NOS(O)(=O)=O>O>[NH2:4][N:23]1[C:24]2[C:19](=[C:18]([Br:17])[CH:27]=[C:26]([Br:28])[CH:25]=2)[NH:20][C:21](=[O:30])[C:22]1=[O:29]
Reactant: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Reactant: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c(Br)cc(Br)cc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
The procedure of Shin, S. C. and Lee. Y. Y., Taehan Hwahakhoe Chi 27 (5): 382-4 (1983) was adapted. 5,7-Dibromo-1,4-dihydroquinoxaline-2,3-dione (46 mg, 0.144 mmole) was dissolved into 3N KOH (2 mL) at 60° C. for 1 h, and NH2OSO3H (20 mg, 0.172 mmole, Aldrich) in distilled water (0.5 mL) was dropwise added into above solution with stirring at 60° C. Some precipitate came out after 15 mins, then a second 20 mg NH2OSO3H portion was added. The mixture was stirred at room temperature for 1 h. The white precipitate was collected by filtration, washed with cold distilled water (0.5 mL), affording crude 1-amino-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (38 mg, 79%) after drying in the air at 60° C. for 2h (contains the isomeric 4-amino-5,7-dibromo-2,3-quinoxalinedione, by NMR, but it is not known which is produced in a greater amount). A 38 mg sample of crude 1-amino-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione was dissolved into distilled water (4 mL) at 60° C., the insoluble material was removed by filtration, and the filtrate was acidified with AcOH to pH=5 to give a white precipitate, which was collected by filtration and washed with cold distilled water (2×1 mL). The precipitate was dried at 60° C. for 2h affording 1-amino-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (28 mg, 58.5%) as a white powder with some isomer. Mp: 273°-5° C. (dec. from 270° C.). IR (KBr, cm-1): 3435; 3289; 3190; 1719; 1672; 1625; 1584. NMR (1H, DMSO-d6): δ 5.831 ((s, 2H); 7.672 (d, J=15 Hz, 1H); 7.810 (d, J=15Hz, 1H); 11.275 (s, 1H). HRMS: calcd for C8H3N3O2Br2 (M+) m/z: 332.8746; Found: 332.8744.
Reaction SMILES: Cl.[F:2][C:3]([F:10])([F:9])[CH2:4][CH2:5][C:6]([NH2:8])=[NH:7].BrBr.C[O-].[Na+].[S-:16][C:17]#[N:18].[K+]>CO>[F:2][C:3]([F:10])([F:9])[CH2:4][CH2:5][C:6]1[N:8]=[C:17]([NH2:18])[S:16][N:7]=1
Reactant: N=C(N)CCC(F)(F)F
Reactant: N#C[S-]
Agent: BrBr
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: Nc1nc(CCC(F)(F)F)ns1
Temperature: 5 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of 4,4,4-trifluoro-butyramidine hydrochloride (2.1 g, 0.012 mol) in methanol (10 mL) at 0° C. under vigorous stirring was added dropwise bromine (0.61 mL, 0.012 mol) and a 5.4M sodium methylate solution in methanol (4.4 mL, 0.012 mol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (1.16 g, 0.012 mol) in methanol (10 mL) over 10 min at 0-10° C. The resulting mixture was stirred for 2 h at 0-10° C. and filtered. The isolated material was washed with methanol and dried which afforded a brown solid which was purified by flash chromatography (150 g silica gel 60 5% methanol/diethyl ether) and crystallized from diethyl ether/hexanes which afforded 3-(3,3,3-trifluoro-propyl)-[1,2,4]thiadiazol-5-ylamine (1.43 g, 61%) as a brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:11]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:11][C:5]1[C:6]([OH:10])=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][NH:1]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2[nH]ncc2c1
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2[nH]ncc2c1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of the 1H-indazol-5-ol (1.60 g, 0.0119 mol) obtained in Reference Example 4 in tetrahydrofuran (50 ml) was added N-chlorosuccinimide (1.59 g, 0.0119 mol) at room temperature. After 1 hour, the mixture thus obtained was heated to 40° C., and after another 2 hour, the mixture was heated to 50° C. After 5 hours, the reaction solution was poured into water (100 ml) and extracted with ethyl acetate (100 ml×3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-chloro-1H-indazol-5-ol (1.7365 g, 86%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH3:18][C:19]1C=CC=C(C)[C:20]=1CN1C2C(=CC=C(C(O)=O)C=2)C=C1>>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: Cc1cccc(C)c1Cn1ccc2ccc(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Product: C=CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (5.7 g) as a colorless oil was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate (7.5 g) obtained with the method described in the document (WO 1998/43956 A) according to the method of the process (2) of Example 66.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[CH:15][C:16]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([S:18][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: Fc1ccc(S)cc1Cl
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(SCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Picolyl chloride hydrochloride (3.03 g) was added to a stirred suspension of 3-chloro-4-fluorobenzenethiol (3.0 g) and cesium carbonate (12.0 g) in DMF (50 ml) and the mixture stirred at RT overnight. Mixture poured into water, organics extracted into ether and the ether extracts washed (brine), dried (MgSO4) and evaporated under reduced pressure to a green oil (4.0 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)(=[O:30])=[O:29])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Solvent: c1ccncc1
Product: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccccn2)c1-c1ccc(C)cc1
Reaction time: 72 h

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (750 mg) in dry pyridine (5 ml) at room temperature was added pyridine-2-sulphonyl chloride (748 mg), the mixture was stirred for 72 hours. The reaction was concentrated under reduced pressure and the residue re-evaporated from toluene. The residue was then partitioned between ethyl acetate (20 ml) and water (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][N:7]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8](=[O:19])[CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])C>C1COCC1.[Li+].[OH-]>[C:25]([O:24][C:22]([NH:21][CH2:20][N:7]([C:8](=[O:19])[CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CCN(CNC(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)N(CCC(=O)O)CNC(=O)OC(C)(C)C)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of N-(N-tert-butyloxycarbonyl-aminomethyl)-N-(N1-thyminylacetyl)-β-alanine ethylester (5.45 g, 13.2 mmol) in THF (80 mL) and aqueous LiOH (0.5 M, 80 mL) was stirred at room temperature for 1 hour and extracted with ethyl acetate. The aqueous layer was acidified to pH 3.5 by dropwise addition of hydrochloric acid (4 M) and kept at 4° C. for 3 hours. The colorless precipitate was filtered, rinsed with water and dried in vacuo to give 4.40 g of the title compound, mp 196° C. (dec.). The filtrate was extracted with ethyl acetate, the organic phase dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was crystallized from MeOH/ethyl acetate/hexane to give 280 mg additional title compound for an overall yield of 92%. TLC (CHCl3/MeOH/NEt3 7:2:1, UV-detection): Rf(N-(N-tert-butyloxycarbonyl-aminomethyl)-N-(N1-thyminylacetyl)-β-alanine ethylester)=0.94, Rf(the title compound)=0.52). 1H NMR (DMSO-d6) (two rotamers, ratio 3:1) δ1.46, 1.50* (2s, 9H, t-Bu), 1.83 (s, 3H, T-CH3), 2.52*, 2.73 (2t, J=7.5 Hz, 2H, NCH2CH2), 3.54*, 3.64 (2t, J=7.3 Hz, 2H, NCH2CH2), 4.64, 4.69 (2d, J=6.4 Hz, J=7.0 Hz. 13C NMR (major rotamer) (DMSO-d6) δ11.9 (T, CH3), 28.1 (t-Bu-CH3), 32.2 (CH2CO), 41.6 (NCH2CH2), 48.1 (T(N1)CH2), 53.2 (NCH2N), 60.0 (OCH2), 78.9 (C(CH3)3) 108.2 (T, CCH3), 142.0 (CH), 151.1(T, NC(O)N), 155.7 (carbamate C═O), 164.4 (T, C═O), 166.9 (tert. amide C═O), 172.7 (carboxylic acid C═O) ppm. FAB-MS: m/z=385.15 (M+H)+. Anal. Calcd. for C16H24N4O7 (384.39): C, 50.00; H, 6.29; N, 14.58. found C, 49.95, H, 6.40; N, 14.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:14]([CH2:23][CH2:24][CH3:25])[CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH3:16])[S:11][C:12]=2[CH3:13])=[C:4]([O:26]C)[CH:3]=1>Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:14]([CH2:23][CH2:24][CH3:25])[CH:15]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH3:16])[S:11][C:12]=2[CH3:13])=[C:4]([OH:26])[CH:3]=1
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2OC)c(C)s1)C(C)c1ccncc1
Agent: Br
Product: CCCN(c1nc(-c2ccc(Cl)cc2O)c(C)s1)C(C)c1ccncc1
Yield: 67 %

Procedure:
Bring to reflux for 24 hours 700 mg of 4-(4-chloro-2-methoxyphenyl)-5-methyl-2-{N-propyl-N-[1-(4-pyridyl)ethyl]amino}thiazole, the compound of Example 22, dissolved in 30 ml of concentrated hydrobromic acid. Evaporate to dryness and take up the residue in Water saturated with potassium carbonate. Extract with methylene chloride and then evaporate off the organic solvent. Purify the residue by chromatography on a silica column, using a mixture of ethyl acetate and methanol (9:1 V/V) as eluent, to obtain the expected product in the form of an oil.