Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])([CH3:7])[CH:4]([CH3:6])[CH3:5])=[O:2].[CH3:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1>C1COCC1>[OH:2][CH:1]([C:25]1[CH:26]=[C:21]([CH3:20])[CH:22]=[CH:23][CH:24]=1)[C:3]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH3:18])([CH3:7])[CH:4]([CH3:5])[CH3:6]
Reactant: Cc1cccc([Mg]Br)c1
Reactant: COc1cccc(C(=O)NC(C)(C=O)C(C)C)c1C
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NC(C)(C(C)C)C(O)c2cccc(C)c2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
An oven-dried vial equipped with a stir bar was flushed with N2, charged with N-(1-formyl-1,2-dimethyl-propyl)-3-methoxy-2-methyl-benzamide (IX, R1=2-Me-3-MeO—Ph, R2=i-Pr, R3=Me, 131 mg, 0.5 mmol) in dry THF (1 mL) and cooled in dry ice acetone. 3-methylphenyl-magnesium bromide (1.0 M, 2 mL, 2.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NaHCO3 (5 mL) and poured onto a 10 mL Chem Elut cartridge. After 5 min the cartridge was eluted with CH2Cl2 (25 mL). The eluate was evaporated to leave a secondary alcohol, N-[1-(hydroxy-m-tolyl-methyl)-1,2-dimethyl-propyl]-3-methoxy-2-methyl-benzamide (VIII, R1=2-Me-3-MeO—Ph, R2 =i-Pr, R3=Me, R4=3-Me—Ph, 180 mg). 1H and 13C NMR showed complete consumption of aldehyde.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)CCCCl)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52b, 1-(4-chlorophenyl)-1-methylethylamine hydrochloride (2.5 g) was treated with 4-chlorobutyryl chloride (1.7 g) in dichloromethane (30 ml) containing triethylamine (3.4 ml) to give 4-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]butyramide which was used directly in part (b) below.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:2]2.[Cl:27][CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30].C(#N)C>CCOC(C)=O>[Cl-:27].[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29](=[O:30])[C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])=[CH:20][CH:21]=1
Reactant: O=C(CCl)c1cccs1
Reactant: COc1ccc(C(OC(=O)C2CN3CCC2CC3)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(OC(=O)C2C[N+]3(CC(=O)c4cccs4)CCC2CC3)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of (4-methoxyphenyl)(phenyl)methyl quinuclidine-3-carboxylate (37 mg, 0.10 mmol) in EtOAc (1.5 ml), 2-chloro-1-(thiophen-2-yl)ethanone (19 mg, 0.12 mmol) was added. Acetonitrile was added until complete dissolution, and the reaction was stirred at room temperature overnight. The organic solvents were removed under vacuum, and the residue was purified by flash chromatography (DCM/MeOH=9/1) to obtain 3-(((4-methoxyphenyl)(phenyl)methoxy)carbonyl)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (16 mg, mixture of diastereoisomers).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:11]([O-])([OH:13])=[O:12].CC(CC(C1C(O)=CC(O)=C(CC=C(C)C)C=1[O-])=O)C.ClC1C(Cl)=CC([N+]([O-])=O)=CC=1C=O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: CC(C)=CCc1c(O)cc(O)c(C(=O)CC(C)C)c1[O-]
Agent: O=Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 22.5 °C

Procedure:
A solution of 40 g of 2,3-dichlorobenzaldehyde (compound IX) in 160 mL of concentrated sulfuric acid (95-98% w/w) is heated to 40° C. and stirred to form a solution, then cooled to 20-25° C. Concentrated nitric acid (69-71 % w/w; 24.7 g) is added to this solution over 20 minutes (an ice bath is used to maintain a reaction temperature of 20-30° C.). The reaction mixture is stirred at room temperature for 1 hour, and then added in portions to 600 mL of water. The resulting suspension is stirred for 2 hours and filtered. The filter cake is washed (3×50 mL of water). The filter cake is agitated with 200 mL of water for 2 hours and filtered. The filter cake is washed (3×50 mL of water) and dried in vacuo to give a mixture of the compound X and the isomer, 2,3-dichloro-5-nitrobenzaldehyde.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.O>C(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 4-(methylsulfonyl)acetophenone (4.85 g, 24.5 mmol) in CHCl3 (70 ml) was added aluminum chloride (1 mg) and bromine (1.1 mL) in CHCl3 (8.5 mL) dropwise. The mixture was stirred overnight, and poured into water. The whole was extracted with ethyl acetate (50 mL×2), the combined organic layer was dried over MgSO4, and concentrated in vacuo. The resulting residue was recrystallized from ethyl acetate/hexane (1/1) to give the subtitle compound (5.28 g, 78% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:26][CH3:25])=[CH:35][CH:34]=3)=[O:37])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(=O)N[C@H]3CCN(C(=O)c4cc(Cl)cc(Cl)c4)[C@H](Cc4ccccc4)C3)cc2c1

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 126 mg (0.661 mmol) of 5-methoxyindole-2-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR88## is obtained (118 mg, 41%) as white crystals of melting point 251° C. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.81, FD-MS: M+ =535, 537; IR: 3440, 3280, 1625 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH:19][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (500 mg, 2.35 mmol), 2-diethylaminoethylamine (300 mg, 0.363 mL, 2.59 mmol) and triethylamine (262 mg, 0.359 mL, 2.59 mmol) in CH2Cl2 (7 mL) was stirred at room temperature for 18 hours. The mixture is then diluted with dichloromethane, and washed with brine. The organic layers is dried (MgSO4) and the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C>[CH2:39]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 10.0 g (25.34 mmol) of bendamustine hydrochloride, 5.85 g (25.6 mmol, 1.01 eq) of pentadecanol, 5.3 g (25.6 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 100 mL of MDC and 0.31 g (2.54 mmol, 0.1 eq) of DMAP. The reaction was stirred at room temperature overnight at which time an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 25 mL of MDC. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2×100 mL), DI water (1×100 mL) and brine (1×100 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo to an off-white solid. This solid was triturated with 25 mL of MDC and the solid impurities were removed by vacuum filtration and washed with 5 mL of MDC. The filtrate was concentrated to dryness in vacuo to yield 10.8 g (19.0 mmol, 75%) of the product as an off-white solid with an HPLC purity of 94.6 A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.76 Hz, 1H), 7.08 (d, J=2.32 Hz, 1H), 6.78 (dd, J=2.4, 8.76 Hz, 1H), 4.05 (t, J=6.8 Hz, 2 H), 3.72 (m, 4H), 3.69 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.4 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 24H), 0.88 (t, J=6.68 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH3:16][Zn]C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd]Br>[F:8][C:6]1[CH:7]=[C:2]([CH3:16])[CH:3]=[C:4]([F:15])[C:5]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)c1c(F)cc(Br)cc1F
Reactant: C[Zn]C
Agent: Br[Pd]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)C(C)c1c(F)cc(C)cc1F
Yield: 77.4 %

Procedure:
Compound (30b) (5.4 g, 19.3 mmol) and dimethyl zinc (2M-solution in toluene, 38.7 mL, 77.4 mmol), and a solution (40 mL) of trans-dibromobis(triphenylphosphine)palladium(II) [trans-Pd(PPh3)2Br2] (0.085 g, 5.6 mol %) in 1,4-dioxane (40 mL) were treated in the same manner as in (k) above. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 3.2 g (77%) of compound (31b) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]([OH:23])=O)=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[C:61]1([NH:60][C:21]([C:12]2[S:11][C:10]([N:7]3[C:6]4[CH:24]=[C:25]([O:26][CH3:27])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=[CH:8]3)=[N:14][C:13]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)O)s3)c2cc1OC
Reactant: Nc1ccccc1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)Nc4ccccc4)s3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid (30 mg, 0.075 mmol) in dimethylformamide (1 ml) was added diethylisopropylamine (15.6 μL, 0.09 mmol) and HATU (28.5 mg, 0.075 mmol). The mixture was stirred under ambient temperature for 5 min. Aniline (6.8 μL, 0.075 mmol) was added. The mixture was stirred for 1 hr. Ethyl acetate (5 ml) was added. The mixture was washed with water (2×3 ml), brine, dried with magnesium sulfate and concentrated in vacuo. The crude was purified with flash chromatography (0 to 2% methanol dichloromethane) to afford 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid phenylamide (30 mg, 86.4%) as a yellow solid. MS m/z 457 (M+1).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[S:17][C:16]2[S:15](=[O:19])(=[O:18])[NH:14][CH2:13][C:12](=[O:20])[C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C(OCC)C.N(CCO)CCO>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[S:17][C:16]2[S:15](=[O:19])(=[O:18])[NH:14][CH2:13][C@@H:12]([OH:20])[C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2=O
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NC[C@H]2O
Temperature: -35 °C
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A solution of (+)-diisopinocamphenylchloroborane (3.8 g, 11.8 mmol) was dissolved in anhydrous THF (10 mL) under nitrogen and cooled to -35° C.; the product from Step A (0.8 g, 2.36 mmol) was added and this mixture was stirred at -35° C. for 24 hr. The solvent was evaporated and the residue was mixed with diethyl ether (15 mL) and diethanol amine (0.62 g, 5.9 mmol) was added followed by stirring for 2 h, filtration, and evaporation. The residue was purified by column chromatography (silica, hexane then hexane/ethyl acetate gradient) to give a colorless solid (0.60 g, 75%): mp 57°-58° C. The optical purity was established to be >90% ee by HPLC analysis of the diastereomeric esters formed with (S)-α-methoxyphenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(Cl)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-Methoxy-3,4-dihydro-2H-naphthalen-1-one (5.0 g, 28.37 mmol) in THF (25 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (25 ml; prepared from 4.0 ml of diisopropylamine (28.37 mmol) and 17.7 ml of 1.6 M n-BuLi in hexane (28.37 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (5.41 g, 28.37 mmol) in THF (25 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 920:80 to 880:120) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.54-2.63 (m, 1H), 2.68-2.75 (m, 1H), 3.04-3.12 (m, 1H), 3.38-3.46 (m, 1H), 4.02 (s, 3H); 4.72-4.76 (m, 1H), 6.87 (s, 1H), 7.00-7.04 (m, 1H), 8.22 (d, J=10 Hz, 1H). ES+-MS: 279.1, 280.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([CH3:16])=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC)c1nc(N)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CON=C(C(=O)O)c1nc(N)sc1C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.5 %

Procedure:
A mixture of ethyl 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 4.0 g.), 2N-aqueous sodium hydroxide (25 ml.), ethanol (30 ml.) and tetrahydrofuran (15 ml.) was stirred at room temperature for 75 minutes. The reaction mixture was adjusted to pH 6 with hydrochloric acid, and the organic solvent was distilled off in vacuo. The remaining aqueous solution was washed with ethyl acetate and adjusted to pH 3 with hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried to give 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([O:19][C:20]([F:23])([F:22])[F:21])[CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([O:19][C:20]([F:23])([F:22])[F:21])[CH:12]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)c(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(-n2nnnc2CO)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
(1-{4-Cyano-3-[(trifluoromethyl)oxy]phenyl}-1H-tetrazol-5-yl)methyl acetate (Intermediate 53, 7.0 g, 21.4 mmol) was dissolved in MeOH:THF:H2O (1:2:1) and the solution was cooled to 0° C. Lithium hydroxide (770 mg, 32.2 mmol) was added at 0° C. The reaction was slowly allowed to reach room temperature and stirred for 3 hr. The solvent was removed under reduced pressure. The residue was diluted with DCM, and washed with ice-cooled water, saturated aq. NaHCO3 and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to give the title compound (3.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[O:4].[C:13]([C:15]1C=CC(C=O)=CC=1)#[N:14].[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:3](=[O:4])([O:2][CH3:1])[O:5][C:6]1[CH:12]=[CH:11][C:9]([N:10]=[C:15]([C:13]#[N:14])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: c1ccccc1
Reactant: COC(=O)Oc1ccc(N)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [O-2]
Product: COC(=O)Oc1ccc(N=C(C#N)c2ccccc2)cc1

Procedure:
A mixture of 0.835 g. of p-methoxycarbonyloxyaniline and 0.655 g. of p-cyanobenzaldehyde is gassed with argon in 50 ml. of benzene and heated under reflux for 1 hour (bath temperature 130°). The resulting water is separated with a water separator. During an additional hour, benzene condensed in the reflux condenser is now passed back into the reaction vessel through a layer of 20 g. of aluminum oxide (act. I). After cooling, the reaction mixture is freed from solvent in vacuum at 50° C. bath temperature, whereby there remain 1.395 g. of yellowish crystals which are recrystallized several times from isopropanol up to constant melting point and clearing point and up to the disappearance of sideproducts in the gas chromatogram. The pure, slightly yellowish p-[(-cyanobenzyliden)amino]phenyl methyl carbonate obtained has a melting point of 145.1°-146.2° and a clearing point of 163.4°. UV (EtOH): ε 270 = 20250, ε 324 = 10800 (shoulders at 243 l and 221 nm; minima at 312 and 233 nm).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:16][OH:17].C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>CCCCCC.C1COCC1>[Si:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][OH:17])=[C:2]([C:24]([OH:25])([CH3:26])[CH3:23])[CH:7]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)c(Br)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1CO
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of [2-bromo-4-[tert-butyl(dimethyl)silyl]oxy-phenyl]methanol (Intermediate 9, 500 mg, 1.5758 mmol) in dry hexane (8 mL) and THF (2 mL) at −15° C. butyllithium 1.6M in hexane (2.17 ml, 3.467 mmol) was slowly added (10 min) and the reaction mixture was stirred at the same temperature for 2 hours. Then a solution of acetone (118.98 mg, 2.0486 mmol) in dry hexane (1 ml) was added at −15° C. and the reaction mixture stirred at the same temperature for additional 1 hour. The reaction was quenched with an aqueous saturated solution of ammonium chloride and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 60:40 as eluent in 12 column volumes, to give the title compound (240 mg) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[N:32]=[N:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[N:32]=[N:31][C:30]([NH2:33])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1ccc(Br)nn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)nn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl -5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 6-bromo-3-pyridazinamine (226 mg, 1.3 mmol) according to general procedure II. Obtained as a light brown solid (270 mg, 60%). MS (ISP) 449.2 [(M+H)+]; mp 214–216° C.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:23][C:24]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]>C(O)C>[Cl:23][C:24]1[CH:31]=[C:30]([N:32]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:33]2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 80 °C
Yield: 87.3 %

Procedure:
Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (Preparation 18, 2.8 g, 9.9 mmol) was suspended in ethanol (100 mL) and 2-chloro-4-hydrazinylbenzonitrile hydrochloride (Preparation 1, 2.6 g, 12.8 mmol) was added. The solution was heated to 80° C. for eight hours. The solution was returned to ambient temperature. The resulting solid was collected by vacuum filtration and washed with cold ethanol to provide the title compound largely present as (±)-(3SR,3aRS)-methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate (3.75 g, 87% yield). LC/MS on 4.6×50 mm C-18 column, tR=7.45 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 434 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.54 (m, 6H), 1.62-1.74 (m, 1H), 1.73-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.21 (dd, J=7.79, 2.15 Hz, 1H), 2.82-2.94 (m, 2H), 3.09 (d, J=16.92 Hz, 1H), 3.54-3.66 (m, 1H), 3.84 (s, 3H), 4.95 (dd, J=9.67, 5.64 Hz, 1H), 7.19 (dd, J=9.26, 1.75 Hz, 1H), 7.39 (d, J=2.15 Hz, 1H), 7.67 (d, J=8.86 Hz, 1H), 7.82 (d, J=8.32 Hz, 1H), 7.86 (s, 1H), 8.10 (d, J=8.06 Hz, 1H).