Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][O:6][C:7]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=1.Cl.[CH3:36][NH2:37]>C(Cl)Cl>[CH3:36][NH:37][C:13]([C:12]1[C:7]([O:6][CH2:5][C:4]2[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=2)=[N:8][C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:11]=1)=[O:14]
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Reactant: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a portion of the methylene chloride (1 mL) solution of 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonyl chloride (0.044 mmol) was added methylamine hydrochloride (6 mg, 0.088 mmol) and TEA (0.018 mL, 0.13 mmol). The reaction was stirred at rt for 16 h and was then evaporated. The residue was purified by preparative TLC eluted with 25% ethyl acetate in hexanes to yield N-(methyl)-2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3carboxamide. HPLC/MS: 533 (M+1), 535 (M+3); Rt=4.77 min
Reaction SMILES: [P:1]([O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]3[O:32][CH2:31][O:30][C:27]=3[CH:28]=2)[N:23]=[C:22]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.[Pd]>[P:1]([OH:3])([OH:11])([O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]3[O:32][CH2:31][O:30][C:27]=3[CH:28]=2)[N:23]=[C:22]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:21]=1)=[O:2]
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1cc(-c2cccc3ccccc23)nc2cc3c(cc12)OCO3
Agent: [Pd]
Solvent: CO
Product: O=P(O)(O)Oc1cc(-c2cccc3ccccc23)nc2cc3c(cc12)OCO3
Yield: 94.1 %

Procedure:
A suspension of 152 (894.8 mg, 1.55 mmol) in anhydrous MeOH (40 mL) was hydrogenated in the presence of 10% Pd/C (456.7 mg) at 25° C. for 15 min. The catalyst and precipitate were collected and dissolved in 10% NaHCO3 solution and then filtered. The filtrate was acidified with dil aq HCl and the precipitate was then collected and washed with acetone to give 153. Yellow solid; yield: 94.1%; ESI-MS (Negative mode): m/z 394 [M−H]−; 1H-NMR (D2O+NaOD, 500 MHz): δ 6.13 (2H, s), 7.26 (1H, s), 7.50 (1H, ddd, J=8.23, 7.33, 1.20 Hz), 7.55-7.58 (2H, m), 7.62-7.70 (3H, m), 7.98 (1H, d, J=8.53 Hz), 8.02 (1H, d, J=8.96 Hz); 13C-NMR (D2O+NaOD, 125 MHz): δ 98.65, 102.15, 103.54, 109.80, 110.00, 118.35, 125.66, 126.37, 126.84, 127.40, 128.34, 128.97, 130.89, 133.50, 138.15, 146.58, 147.34, 151.27, 158.15, 158.23.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:15][CH:14]=4)[C:8]1([CH3:31])[CH3:30])[CH3:5])[CH3:2].[CH3:32][C:33]([CH3:36])([O-])[CH3:34].[K+].C1OCCOCCOCCOCCOCCOC1.ClCC(C)=C>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:16]([C@H:17]([CH3:20])[CH2:18][O:19][CH2:34][C:33]([CH3:36])=[CH2:32])[CH2:15][CH:14]=4)[C:8]1([CH3:31])[CH3:30])[CH3:5])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO)[C@@]1(C)CC3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C=C(C)CCl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)COC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(C)OCC)C(C)(C)[C@@H]1CC3
Temperature: 70 °C
Yield: 107.5 %

Procedure:
vii)—A mixture of (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-dien-21-ol (1.0 g), dry toluene (67 ml), potassium t-butoxide (3.34 g), 18-crown-6 (0.581 g) and 3-chloro-2-methyl-1-propene (1.14 ml) was heated at 70° C. for 1.5 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-oxacholesta-8,14,25-triene (1.21 g), which was used in the following step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([OH:10])[CH:9]=1.CN(C)C=O.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][C:31](=[O:38])/[C:30]/2=[CH:39]/OC>CCOCC>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH3:12])[CH2:3][NH:2][CH:39]=[C:30]1[C:29]2[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH3:25])[CH:28]=2)[C:33](=[O:37])[NH:32][C:31]1=[O:38]
Reactant: COc1ccc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(OC)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(=CNCc1ccc(OC)c(O)c1)C(=O)NC2=O
Reaction time: 0.25 h

Procedure:
A mixture of 5-aminomethyl-2-methoxy-phenol hydrochloride (145 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 □L, 0.54 mmole) is stirred for 15 minutes. Then (4E)-6-methoxy-4-methoxymethylene-4H-isoquinoline-1,3-dione (117 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is diluted with ether, filtered washed with water, washed with ether and dried to give an light beige solid, 161 mg, (91%), mp 240-2° C. dec; MS (ESI): m/z 355.2 (M−H).
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[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1>>[CH3:34][O:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2-methoxypyridine (169 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (85 mg, 18%). MS (ISP) 463.2[(M+H)+]; mp 166-168° C.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5](=[O:21])[N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:7]=1)#[N:2].[ClH:22].O1CCOCC1>C(OCC)(=O)C>[ClH:22].[O:21]=[C:5]1[NH:4][C:3]([C:1]#[N:2])=[CH:7][N:6]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1cn(C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(4-cyano-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (45 mg, 0.154 mmol) was dissolved in ethyl acetate (5.0 mL). 4M Hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol) was added to the mixture. Reaction was stirred at room temperature for 18 hours. Liquids were decanted off. Remaining solids were dissolved in methanol and then transferred to a smaller flask. Material was concentrated by roto-vap. Residue was treated with dichloromethane and then concentrated to dryness. Title compound was obtained as yellow solid in quantitative yield. MS (M+H)+=193.0.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[CH3:17].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]2[CH2:27][CH2:28][N:29]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=3[CH3:17])[CH2:30][CH2:31]2)[CH:20]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1cc(C)nc(N2CCNCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3C)CC2)c1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
Caesium carbonate (10.19 g, 31.38 mmol), 1-chloro-2-methyl-4-nitro-benzene (0.98 g, 5.75 mmol) and 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (1.0 g, 5.23 mmol) were taken in toluene (35 mL) and degassed with argon for 15 min. A slurry of 2-dicyclophosphino-2′-(N,N-dimethylamino)-biphenyl (0.2 g, 0.52 mmol) and palladium acetate (0.116 g, 0.52 mmol) in toluene (5 mL) was added, the mixture degassed for another 10 min and then heated at reflux for 16 h. The mixture was cooled to room temperature and filtered, washing with ethyl acetate. The filtrate was washed with 2N hydrochloric acid, water, and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain the crude compound. Purification by column chromatography over silica gel (100-200 mesh) using 0-12% ethyl acetate in petroleum ether as eluent gave 1-(4,6-dimethyl-pyridin-2-yl)-4-(2-methyl-4-nitro-phenyl)-piperazine (0.463 g, 27%) as a solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[C:12]([CH3:29])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][C:12]1[CH:11]=[C:10]([S:7]([NH:6][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(C)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCCC[C@@H]1c1ccnn1C
Yield: 81.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (79 mg, 0.14 mmol) prepared in Example 54a, triethylsilane (0.1 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield the title compound (49 mg, 84%) as a colorless solid.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9]2)[CH:4]([OH:15])[CH2:3][CH2:2]1.Cl.Cl[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22]>>[CH:21]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18][O:15][CH:4]1[CH:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH:10]2[CH2:1][CH2:2][CH2:3]1)([CH3:23])[CH3:22]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: OC1CCCC2Oc3ccccc3OC12
Agent: Cl
Product: CC(C)N(CCOC1CCCC2Oc3ccccc3OC12)C(C)C
Yield: 82.2 %

Procedure:
Working as described in Example 3, but starting with 12.4 g (0.06 mole) of the alcohol of Example 1 and 10 g (0.05 mole) of 1-chloro-2-diisopropylaminoethane hydrochloride, there were obtained 13.7 g of the title-compound of melting point 63.4° C., having the elementary analysis:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[O:18]([CH2:25][CH2:26][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCCOc1ccccc1
Reactant: N#Cc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C3CCN(CCCOc4ccccc4)CC3)c2c1
Yield: 44.3 %

Procedure:
A stirred solution of 3-(4-piperidinyl)-5-cyanoindole (0.71 g, 2.2 mmol), 3-phenoxypropyl bromide (0.52 g, 2.4 mmol), and triethylamine (0.6 ml, 4.4 mmol) in methanol (10 mL) was heated at reflux for 18 hours. The solution was concentrated in vacuo. Purification by flash chromatography yielded the product (0.35 g, 44%). 1H-NMR δ(CD3OD) 8.11 (s, 1 H), 7.49 (d, 1 H), 7.40 (d, 1 H), 7.28 (m, 3 H), 6.94 (m, 3 H), 4.12 (t, 2 H), 3.59 (br d, 2 H), 3.26-3.18 (m, 3 H), 3.04 (br t, 2 H), 2.25 (m, 4 H), 2.02 (br q, 2 H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2].FC(F)(F)C(O)=O.CO[CH2:22][N:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][Si](C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:9][C:7]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=[C:3]([CH:1]2[CH2:2][CH2:24][N:23]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22]2)[N:8]=1
Reactant: C=Cc1ccc([N+](=O)[O-])c(C)n1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
To a solution of crude 6-ethenyl-2-methyl-3-nitropyridine (440 mg, 2.68 mmol) in dichloromethane (DCM) (5 mL) was added trifluoroacetic acid (0.268 mL, 3.48 mmol). To this stirred solution was added [(methyloxy)methyl](phenylmethyl)[(trimethylsilyl)methyl]amine (2.74 mL, 10.72 mmol) (carefully) and the reaction mixture was stirred under nitrogen for 1.5 hours. The reaction mixture was diluted with DCM and then treated with saturated sodium bicarbonate solution. The organic phase was separated and passed through a hydrophobic frit. The organic solvent was evaporated in vacuo and the residue was dissolved in DCM (5 mL). This was purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane with 0-20% methanol gradient). The appropriate fractions were combined and evaporated in vacuo to give the crude product (201 mg) as a brown liquid. Used directly in next step without further purification. LCMS (2 min, formic) Rt 0.71 min, m/z (ES+) 298 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH2:16]1[C:29]2[C:20](=[N:21][C:22]3[C:23](=O)[CH2:24][CH2:25][CH2:26][C:27]=3[CH:28]=2)[C:19](=O)[CH2:18][CH2:17]1>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]=[C:19]2[C:20]3[C:29](=[CH:28][C:27]4[CH2:26][CH2:25][CH2:24][C:23](=[N:6][C:5]5[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=5)[C:22]=4[N:21]=3)[CH2:16][CH2:17][CH2:18]2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: FC(F)(F)c1cc(N=C2CCCc3cc4c(nc32)C(=Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCC4)cc(C(F)(F)F)c1

Procedure:
was synthesized by methods similar to those in Examples 3 and 4: 3,5-bis-trifluoromethylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis[3,5-bistrifluoromethylphenylimino]-1,2,3,4,5,6,7,8-octahydroacridine (5). The complexation of (5) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of the final complex was proved by direct probe GC. Exact mass direct probe calculated for C29H19Cl2F12FeN3: 763.01. Found: 763.01.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.FC1C=CC(N2CCNCC2)=CC=1.[CH:30]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[N:39]=[N:40][C:41](Cl)=[CH:42][CH:43]=2)=[O:37])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[N:39]=[N:40][C:41]([N:12]3[CH2:13][CH2:14][N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:10][CH2:11]3)=[CH:42][CH:43]=2)=[O:37])[CH2:32][CH2:31]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nn1
Yield: 57 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 1-(3-trifluoromethylphenyl)piperazine to replace 1-(4-fluorophenyl)-piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 57% yield (0.210 g). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=9.5 Hz, 1H), 7.98 (t, J=5.4 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.12 (m, 3H), 7.04 (d, J=9.5 Hz, 1H), 3.96 (m, 4H), 3.55 (m, J=6.72 and 13.2 Hz, 2H), 3.40 (m, 4H), 1.51 (dd, J=6.7 and 13.8 Hz, 2H), 0.74 (m, 1H), 0.45 (m, 2H), 0.08 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 162.9, 150.8, 145.2, 129.8, 127.2, 119.19, 116.75, 112.6, 48.5, 44.7, 39.7, 34.5, 8.7, 4.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=1)=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 130 mg, 0.91 mmol) was dissolved in methanol (5 mL). 4-Trifluoromethyl-benzaldehyde (160 mg, 0.91 mmol) was added, stirred at 25° C. for 15 min, then acetic acid (0.2 mL) was added, followed by sodium cyanoborohydride (150 mg, 2.3 mmol) and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product (1R,2S)-2-(4-trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (200 mg, 0.664 mmol, 73%) as a clear oil. LC-MS (ESI) calcd for C15H18F3NO2 301.13, found 302.2 [M+H+].
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([SH:11])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Cl.[CH2:16]1[CH2:25][O:24][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:26]Cl)[C:18]=2[O:17]1>CO>[C:1]([C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[NH:8][C:9]([S:11][CH2:26][C:19]3[C:18]4[O:17][CH2:16][CH2:25][O:24][C:23]=4[CH:22]=[CH:21][N:20]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: ClCc1nccc2c1OCCO2
Reactant: CC(=O)c1cc2nc(S)[nH]c2cc1C
Agent: Cl
Solvent: CO
Product: CC(=O)c1cc2nc(SCc3nccc4c3OCCO4)[nH]c2cc1C
Yield: 79.7 %

Procedure:
To a solution of 5-acetyl-6-methyl-2-mercapto-1H-benzimidazole (0.14 g, 0.66 mmol) in methanol (2 ml) aqueous NaOH (0.25 ml 5M, 1.25 mmol) and 3,4-ethylendioxy-2-chloromethyl pyridine hydrochloride (0.13 g, 0.60 mmol) dissolved in methanol (2 ml) were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over Na2SO4 and evaporated giving a yellow syrup (0.17 g, 81%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([O:15][C:16](=[O:19])[CH2:17]I)[CH3:14]>CC#N>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CI
Solvent: CC#N
Product: CCOC(=O)Cc1c[nH]c2cc(N)ccc12

Procedure:
(6-Amino-1H-indol-3-yl)-acetic acid ethyl ester (B-17) was synthesized following the general scheme above starting from 6-nitroindole and iodo-acetic acid ethyl ester. Overall yield (24%). HPLC ret. time 0.95 min, 10-99% CH3CN, 5 min run; ESI-MS 219.2 m/z (MH+).
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]O.C1(O)C=CC=CC=1>CO>[CH3:9][C:10]([CH3:14])([CH:11]=[CH2:12])[CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: COC(C)(OC)OC
Reactant: CC(C)=CCO
Solvent: Oc1ccccc1
Solvent: CO
Product: C=CC(C)(C)CC(=O)OC
Yield: 39.9 %

Procedure:
A mixture of trimethyl orthoacetate (120 g; 1 mole), 3-methylbut-2-enol (21.5 g; 0.25 mole) and phenol (1.4 g; 0.015 mole) was placed in a flask equipped with a stirrer and a 10 cm fractionating column packed with Fenske rings. The mixture was heated, with stirring, to a temperature of 95°-110° C. and maintained at this temperature for a period of 2 hours while the methanol formed was collected by distillation. The excess trimethyl orthoacetate was distilled from the reaction mixture over a period of 1 hour during which time the temperature of the reaction mixture was raised to 140°-145° C. The mixture was heated, with stirring, at a temperature of 140°-145° C. for a period of 20 hours and then the product was distilled to give methyl 3,3-dimethylpent-4-enoate (14.2 g; 40%), bp 95°-99° C. at 140 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2c(F)cccc2F)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,6-difluorobenzenesulphonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (6 mg, 24%) as a white solid. MS (ESI+) for C18H18F2N2O3S m/z 381 (M+H)+.
Reaction SMILES: [CH:1]([C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)=O.[Li].P(=O)([O-])O[CH2:24][C:25](=[O:36])[C:26](C)(C)[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[O:36]=[C:25]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)/[CH:24]=[CH:1]/[C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CC(C)(Oc1ccccc1)C(=O)CO[PH](=O)[O-]
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)COc1ccccc1
Yield: 87.5 %

Procedure:
A solution of 548 mg. of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one [J. Amer. Chem. Soc. 96: 5865 (1974)] in 20 ml. of absolute tetrahydrofuran is combined with 581 mg. of the lithium salt of dimethyl-2-oxo-3-phenoxypropyl phosphonate, and the mixture is agitated for 1.5 hours at room temperature under argon. The mixture is then combined with 0.3 ml. of glacial acetic acid, concentrated under vacuum, mixed with 100 ml. of methylene chloride, and extracted with 10 ml. of 5% sodium bicarbonate solution and twice with respectively 10 ml. of water. The product is dried with magnesium sulfate, evaporated under vacuum, and the residue of the evaporation is recrystallized from methylene chloride-isopropyl ether, thus obtaining 710 mg. of the title compound as colorless crystals (yield: 87.5% of theory).