Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C:16](O)([CH3:18])[CH3:17].Cl>C(COC)OC.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C:16]([CH3:18])([C:16]([C:9]1[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[F:7])([CH3:18])[CH3:17])[CH3:17]
Reactant: COc1ccc(C(C)(C)O)c(F)c1
Agent: [Ti+3]
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(C)(C)C(C)(C)c2ccc(OC)cc2F)c(F)c1
Reaction time: 0.17 h

Procedure:
4.63 g (0.03 mole) titanium trichloride are suspended under nitrogen in 150 cm3 anhydrous dimethoxyethane (glyme) and 0.38 g (0.01 mole) LiAlH4 rapidly added to the resulting suspension while cooling with ice. The dark suspension thus obtained is stirred for 10 minutes. 1.84 g (0.01 mole) 2-(2-fluoro-4-methoxyphenyl)-2-propanol dissolved in 10 cm3 anhydrous dimethoxyethane are then added dropwise with stirring and the mixture heated under reflux for 16 hours. After cooling, the reaction product is decomposed with 2N HCl, diluted with water and extracted with ether. The ether extracts are washed (NaHCO3, H2O) and dried over MgSO4. After removal of the ether, the 2,3-bis-(2-fluoro-4-methoxyphenyl)-2,3-dimethylbutane obtained is recrystallized from toluene/ligroin.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]([NH:13][NH2:14])([NH2:12])=[NH:11].[ClH:15]>CO.C(O)(=O)C>[ClH:15].[NH2:9][C:8]1[N:13]([C:10]([NH2:12])=[NH:11])[N:14]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(N)n(C(=N)N)n1
Yield: 33.8 %

Procedure:
A solution of 1.26 g of pivaloylacetonitrile and 1.37 g of aminoguanidine hydrochloride in 15 ml of methanol and 15 ml of acetic acid was heated under reflux for 5 hours. The solvents were removed by distillation under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ethanol-ether to obtain 0.74 g of 5-amino-3-(1,1-dimethylethyl)-1H-pyrazole-1-carboxamidine hydrochloride having the following physico-chemical properties:
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[Cl:29][C:30]1[CH:46]=[CH:45][C:33]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Reactant: OB(O)c1ccc(OCc2ccc(Cl)cc2)cc1
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: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(Cl)cc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0473 g, 0.104 mmol), (4-((4-chlorobenzyl)oxy)phenyl)boronic acid (0.041 g, 0.156 mmol) and 2M Na2CO3 (0.130 ml, 0.260 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 10.39 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110 C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(5-(4-((4-chlorobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0368 g, 0.062 mmol, 59.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.38-7.44 (m, 4H), 7.16-7.19 (m, 1H), 7.02-7.09 (m, 3H), 6.01 (br. s., 1H), 5.09-5.16 (m, 2H), 4.24-4.31 (m, 1H), 4.19 (qd, J=7.1, 10.8 Hz, 1H), 3.04-3.27 (m, 1H), 2.83 (br. s., 1H), 2.67 (br. s., 3H), 2.28 (br. s., 4H), 1.94-2.13 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (s, 9H), 0.88 (m, 3H), 0.68 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=593.3.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:39]=[CH:38][O:37][CH:36]=2)=[O:34])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[O:37]1[CH:38]=[CH:39][C:35]([C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([CH3:25])=[C:31]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:30]=2)=[O:34])=[CH:36]1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.53 min, MH+ 510. NMR: δH [2H6]-DMSO 11.64, (1H, b), 10.02, (1H, s), 9.23, (1H, s), 8.38, (2H, m), 8.31, (1H, d), 7.86, (1H, s), 7.80, (1H, s), 7.76, (2H, m), 7.38-7.29, (3H, m), 7.11, (1H, t), 7.01, (1H, s), 3.77, (2H, s), 2.66-2.20, (11H, m), 2.16, (3H, s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([CH2:34][O:35][CH2:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>[Pd].C(O)C.CO>[CH2:36]([O:35][CH2:34][C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:37]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Yield: 87.7 %

Procedure:
A mixture of tert-butyl 4-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate (15 g, 29.7 mmol) and 10% palladium on carbon (4.5 g, wetted with ethanol) in 1:1 ethanol/methanol (400 mL) was hydrogenated using a Parr apparatus at 28 psi (1.9×105 Pa) for 16 hours. The mixture was filtered through CELITE filter agent, which was subsequently washed with methanol. The filtrate was concentrated under reduced pressure to afforded 10.8 g of tert-butyl 4-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate as a green-yellow solid.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([C:19]1[CH:31]=[C:30]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:32](Cl)=[O:33])=[CH:27][C:28]=3[CH2:29]2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCOCC1>[C:1]([NH:9][NH:10][C:32]([C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:30](=[CH:31][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)[CH2:29][C:28]=2[CH:27]=1)=[O:33])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)Cl)ccc1-2
Reactant: CCCCCCC(=O)NN
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)NNC(=O)CCCCCC)ccc1-2
Temperature: 0 °C
Yield: 69.8 %

Procedure:
Then, in a 50 ml-three-necked flask, 0.32 g (2.22 mM) of heptanohydrazide and 15 ml of dioxane were placed. To the mixture, a solution of the above-prepared 7-octyl-2-fluorenecarbonyl chloride in 5 ml of dioxane was added, followed by addition of 0.84 ml of pyridine at about 85° C. under stirring and further stirring for 30 minutes at 85°-88° C. After the reaction, the reaction mixture was cooled and poured into 200 ml of ice water to precipitate a crystal. The crystal was recrystallized from a mixture solvent of toluene-acetone to obtain 0.68 g of N-heptanoyl-N'-(7-octyl-2-fluorenecarbonyl) hydrazine (Yield: 69.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccccc1C1N(CC(=O)NC2CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 30.9 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.23 mmol) prepared in example 34a was reacted with cyclopropylamine (0.1 g, 1.8 mmol) (Aldrich), N-methylmorpholine (48 mg, 0.47 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(cyclopropylamino)-carbonyl-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.039 g, 30%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[N:5]2.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C1COCC1.O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH3:28])[CH:20]=3)=[O:27])=[CH:17][CH:18]=1)=[N:5]2
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(C#Cc2ccc3nccn3n2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(C#Cc3ccc4nccn4n3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A reaction mixture of 4-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline (93.6 mg, 0.4 mmol, 1 eq) and m-tolyl isocyanate (0.051 mL, 1 eq) in anhydrous THF (4 mL) was stirred at room temperature for four hours. It was then diluted with water and a solid which precipitated was filtered. The solid was further triturated with ethyl acetate and 1-[4-(imidazo[1,2-b]pyridazin-6-ylethynyl)phenyl]-3-(3-methylphenyl)urea was obtained as a yellow solid upon filtration in amount of 125 mg.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Yield: 66.2 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (30 mg, 0.044 mmol), 1-methylpiperazine (44.4 mg, 0.44 mmol, 10 eq) and acetic acid (2.54 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 22.15 mg (59.1%) of the title compound. LC-MS m/z 761 (M+H)+, 1.38 min (ret time).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CS(=O)(=O)c1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(S(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a solution of 3-iodo-5-(methylsulfonyl)-1H-indazole (400 mg, 1.24 mmol) in THF (15 mL) was added t-BuOK (208 mg, 1.86 mmol) slowly at 0° C., mixture stirred for 30 minutes, then iodomethane (262 mg, 1.86 mmol) was added at 0° C., then warmed to room temperature and stirred for 2 hours. Reaction quenched with water (40 mL) and product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a solid which was purified by column chromatography (silica gel, 200-300 mesh, eluting with dichloromethane/methanol=10:1) to give 3-iodo-1-methyl-5-(methylsulfonyl)-1H-indazole (210 mg, 50.6%) as a white solid. LCMS: (M+H)+=337; 1H NMR (300 MHz, DMSO): δ 7.97-7.94 (m, 3H), 4.13 (s, 3H), 3.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1.[Br:13]Br>ClCCl>[Br:13][C:3]1[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: Cc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-1H-pyrazole (8.0 g, 50.6 mmol) in dichloromethane (150 mL) was added bromine (8.08 g, 50.6 mmol) dropwise at 0° C., The reaction was stirred at that temperature for 30 min and continued at room temperature for 2 h. After the reaction was quenched with an aqueous solution of Na2SO3 (10% w/w, 10 mL), the organic solvent was removed and the aqueous mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow oil (9.5 g). LCMS m/z=236.9 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 7.30-7.57 (m, 5H), 13.12 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28])(=O)C.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:27]([C:26]1[C:9]2[CH2:10][C:11]([CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[CH:20][CH:21]=3)([CH3:13])[O:12][C:8]=2[CH:7]=[C:6]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:5]=1[OH:4])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(NC(=N)N)cc1)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(COc2ccc(NC(=N)N)cc2)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.6 %

Procedure:
Under a nitrogen atmosphere, 1.4 g of 1-{4-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methoxy]phenyl}guanidine was dissolved in 50 ml of toluene. To the solution was added 12 ml of diisobutyl aluminum hydride (1.0 M in toluene) and the mixture was stirred at room temperature for 14 hours. After further addition of 6 ml of diisobutyl aluminum hydride (1.0 M in toluene) at room temperature, the mixture was heated under reflux for 2 hours. After reaction, a saturated aqueous ammonium chloride solution was added, and insoluble matters were filtered off on Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 0.67 g of 1-{4-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)methoxy]phenyl}guanidine as a pale yellow oil (yield 52%).
Reaction SMILES: [C:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[C:4]=1[CH2:9]O)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl>[Br:31][CH2:9][C:4]1[C:5]([CH3:8])=[N:6][S:7][C:3]=1[C:1]#[N:2]
Reactant: Cc1nsc(C#N)c1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nsc(C#N)c1CBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Cyano-4-hydroxymethyl-3-methyl-isothiazole (50% purity) (1.14 g, 3.7 mmol) was dissolved in dichloromethane (10 ml) and triphenyl phosphine (1.07 g, 4.0 mmol) and carbon tetrabromide (1.18 g, 3.6 mmol) were added at 0° C. The mixture was stirred at 0° C. for 2 hours, concentrated and the crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane). The colourless oil (0.65 g) consisted of a 1:1 mixture of methyl ester (see Example I14) and product. The mixture was used without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.CCCCCCC=CCCC>CN(C)C=O>[CH:13]1([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
A mixture of N-hydroxypthalimide (10.00 g, 61.3 mmol), cyclopentylbromide (8.21 mL, 76.63 mmol), and 1,8-diazabicyclo)5.4.0]undec-7-ene (13.75 mL, 76.6 mmol) were combined under an Argon atmosphere in dimethylformamide (50 mL). The mixture was heated to 55° C. and stirred vigorously for 1.5 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. After separating the phases, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate, saturated aqueous brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with hexane, filtered, and dried under high vacuum to provide 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (11.37 g, 80%). HL-NMR (chloroform-D3): 1.61 (m, 2H), 1.77 (m, 2H), 1.97 (m, 4H), 4.91 (m, 1H), 7.73 (m, 2H), 7.82 (m, 2H). MS(ESI): 254 (M+Na).
Reaction SMILES: Cl.[CH3:2][S:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])(=[O:5])=[O:4].[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[CH:32][C:31]([C:34]([O-])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)[CH3:21].[Na+].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(Cl)(Cl)Cl>[S:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:34]([C:31]1[CH:32]=[N:33][C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:27][CH2:26]2)=[CH:29][CH:30]=1)=[O:35])([CH3:2])(=[O:5])=[O:4]
Reactant: CS(=O)(=O)OCCCCCCCCCCCCN
Reactant: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 3.77 g of 12-aminododecyl methanesulfonate hydrochloride in 100 ml of methylene chloride were added successively under ice-cooling 3.60 g of sodium 6-(4-ethyl-1-piperazinyl)pyridine-3-carboxylate, 2.89 g of 1-hydroxybenzotriazole (HOBt), 1.99 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI) and then the mixture was stirred overnight. The reaction solution was diluted with chloroform and washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue thus obtained was chromatographed over a silica gel column to afford 4.96 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[S:19][CH:20]=2)=[CH:9][C:8]=1[CH3:30])C.[Li+].[OH-]>>[CH2:32]([O:31][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[S:19][CH:20]=2)=[CH:9][C:8]=1[CH3:30])[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid as colorless liquid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[CH3:33]>CN(C)C=O>[CH2:32]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:3]1)[CH3:33]
Reactant: CCBr
Reactant: O=C(C1CCCNC1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCCC(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-(piperidin-3-ylcarbonyl)-4-[3-(trifluoromethyl)phenyl]piperazine hydrochloride (600 mg) in N,N-dimethylformamide (10 ml) was stirred at room temperature. Potassium carbonate (800 mg) was added followed by ethyl bromide (158 mg) and the mixture was stirred overnight. The mixture was filtered through a sinter and then through a SCX-2 column eluting with methanol and then a 7M solution NH3 in methanol. The basic fraction was concentrated at reduced pressure. This gave 1-[(1-ethylpiperidin-3-yl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperazine as a colourless oil (420 mg)