Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:21]=[C:20](O)[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[C:20]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:21]=[C:12]([C:11]([O:10][CH3:9])=[O:23])[CH:13]=1
Reactant: OCCCCCCCl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCCCCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 22 h
Yield: 54.6 %

Procedure:
13.02 g (95.3 mmol) of 6-chlorohexanol were added to a solution of 20.04 g (95.3 mmol) of 5-hydroxyisophthalic acid dimethyl ester and 47.4 g (180.5 mmol) of triphenylphosphine in 300 ml of tetrahydrofuran. The colourless solution was cooled to 0° C. and then 79 ml (180.5 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene were added dropwise over a period of 2 hours and 45 minutes. The mixture was allowed to react for another 30 minutes at 0° C. and then for 22 hours at room temperature. The reaction mixture was concentrated by evaporation under vacuum. The residue was filtered through silica gel using dichloromethane:diethylether (85:15) as eluent. The filtrate was concentrated in vacuum and further purified by column chromatography on silica gel with hexane:ethyl acetate (9:1) to give 17.12 g (55%) of 5-[(6-chlorohexyl)oxy]isophthalic acid dimethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[N:7]=1.C[Al](C)C.[CH:20]([NH2:23])([CH3:22])[CH3:21]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:13])[N:10]=2)[N:7]=1
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (250 mg, 1.11 mmol) was taken up in tetrahydrofuran and cooled to 0° C. Trimethylaluminum (6.6 mL, 13.3 mmol) was added dropwise followed by the addition of isopropylamine (0.4 mL, 2.2 mmol). The cold bath was removed and the reaction was allowed to proceed overnight at room temperature. The reaction was then quenched slowly with methanol, and stirred for 10 minutes. The resulting mixture was filtered, washing the solids with ethyl acetate and water. The filtrate was collected, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were concentrated under and purified via flash chromatography (0-15% methanol in dichloromethane) to afford the title compound.
Reaction SMILES: CCN(CCCC([NH:11][C:12]1[C:13]2[CH:14]=[CH:15][C:16](Cl)=[CH:17][C:18]=2[N:19]=[C:20]2[CH:25]=[CH:24][C:23](OC)=[CH:22][C:21]=12)C)CC.NCCCCN.ClC1C=C2C(=CC=1)C(Cl)=C1C(C=CC(OC)=C1)=N2.[OH-].[Na+]>C1(O)C=CC=CC=1>[CH:23]1[CH:24]=[CH:25][C:20]2[N:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([NH2:11])[C:21]=2[CH:22]=1
Reactant: CCN(CC)CCCC(C)Nc1c2ccc(Cl)cc2nc2ccc(OC)cc12
Agent: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Agent: NCCCCN
Agent: [Na+]
Solvent: Oc1ccccc1
Product: Nc1c2ccccc2nc2ccccc12

Procedure:
A diamine side chain is first synthesized in a manner analogous to the side chain of quinacrine. Specifically, mono-phthaloyl protected 1,4-diaminobutane (27) is reacted with 6,9-dichloro-2-methoxyacridine (28) in phenol (J. Am. Chem. Soc. 66:1921-1924, 1944). The reaction mixture is then poured into an excess of 2N NaOH and extracted with ether. The ether extract is washed with 1M NaHCO3, then H2O, and dried over MgSO4. The crude product is recrystallized from H2O-alcohol. The phthaloyl protecting group is removed using anhydrous hydrazine in MeOH (Bioconjugate Chem. 2:435-440, 1991) to yield the aminoacridine, (29). Aminoacridine (29) is then conjugated with vitamin B12 monocarboxylic acid (2, 3, 4) to yield a cyanocobalamin-acridine conjugate (30).
Reaction SMILES: ClC1C2C(=CC(OC)=[C:9]([O:12]C)C=2)C=C(Cl)N=1.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:31]([OH:33])=[O:32])[N:20]=1>>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[C:26]([O:12][CH3:9])[CH:27]=2)[CH:22]=[C:21]([C:31]([OH:33])=[O:32])[N:20]=1
Reactant: COc1cc2cc(Cl)nc(Cl)c2cc1OC
Reactant: COc1ccc2c(OC)nc(C(=O)O)cc2c1
Product: COc1cc2cc(C(=O)O)nc(OC)c2cc1OC

Procedure:
This intermediate was prepared from 1,3-dichloro-6,7-dimethoxy-isoquinoline in three steps according to the preparation of 1,6-dimethoxy-isoquinoline-3-carboxylic acid.
Reaction SMILES: O[CH:2]1[NH:8][C:7](=O)[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.C(OCC)C>[CH:12]1[C:5]2[N:4]3[CH:13]=[CH:14][CH:15]=[C:3]3[CH2:2][NH:8][CH2:7][C:6]=2[S:10][CH:11]=1
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: c1cc2n(c1)-c1ccsc1CNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A solution of 5.3 g (0.024 mol) of 6-hydroxy-5,6-dihydro-4-oxo-4H-pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine in 400 ml of dichloromethane is added in small portions to a suspension of 3.66 g (0.096 mol) of lithium aluminum hydride in 20 ml of ethyl ether. The reaction mixture is stirred at room temperature for 30 minutes and then heated to reflux for 6 hours. After cooling, the solution obtained is poured onto 250 g of ice. The emulsion formed is drained and the organic phase is then separated after settling has taken place. The aqueous phase is extracted with 200 ml of dichloromethane. The organic phases are combined, dried over calcium chloride, purified with animal charcoal and evaporated under vacuum. The residual oil is dissolved in 300 ml of ethyl ether and a stream of gaseous HCl is bubbled into this ethereal solution for 15 seconds. The precipitate is drained, washed with ether and recrystallized. 3.2 g of 5,6-dihydro-4H-pyrrolo[1,2-a]thieno -[2,3-f][1,4]diazepine are thereby obtained in the form of beige crystals, melting point 260° C. (isopropanol).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]1([CH:44]=O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:44][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3cccc4ccccc34)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.5 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (150 mg, 0.34 mmol) in anhydrous DCE (3 mL) were added 1-naphtaldehyde (Fluka, 70 μL, 0.51 mmol) and sodium triacetoxyborohydride (110 mg, 0.51 mmol). The reaction mixture was stirred at rt for 72 hrs. The solvent was removed under reduced pressure. The residue was taken up with an aqueous solution of NaOH (2 mL, 1N) and extracted with Et2O (6 ml). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (pentane/DCM (2/3)) gave 72 mg (36%) of the title compound as a yellow oil. HPLC, Rt: 6.2 min (purity: 100%). 1H NMR (CDCl3) δ: 7.91-7.80 (m, 3H), 7.54-7.27 (m, 11H), 7.17 (d, J=7.9 Hz, 2H), 7.08 (m, 1H), 6.78 (d, J=8.7 Hz, 1H), 5.20 (s, 2H), 4.70 (s, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.69 (s, 6H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:18]([NH:6][C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC=O
Reactant: COC(=O)[C@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCN[C@H](CC(C)C)C(=O)OC
Yield: 40.3 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using D-leucine methyl ester hydrochloride (1.5 gm, 8.25 mmol), THF (20 mL), MgSO4 (1.68 gm, 14.02 mmol), decanal (3.1 mL, 16.5 mmol), Et3N (1.15 mL, 8.25 mmol), sodium borohydride (624 mg, 16.5 mmol), and methanol (30 mL) to give 11o (950 mg, 40%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.86-0.96 (9H, m), 1.2-1.34 (16H, m), 1.38-1.52 (4H, m), 1.69 (1H, heptet), 2.39-2.48 (1H, m), 2.5-2.58 (1H, m), 3.27 (1H, t, J=7.08 Hz), 3.71 (3H, s). ESI-MS: 308.1 (M+23).
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C@@:11]([CH3:37])([OH:36])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[CH3:37][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[O:36][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(CN2CCN(C3CCN(c4ccc(OC(F)(F)F)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
(S)-1-(2-bromo-4-nitroimidazol-1-yl)-2-methyl-3-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazin-1-yl}propan-2-ol (790 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (4 ml), sodium hydride (69 mg, 1.74 mmol) was added while cooling on ice, and the solution was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate (1.3 ml) and water (10 ml) were added in this order, and the precipitated crystals were filtered off and washed with water. The crystals were purified by silica gel column chromatography (methylene chloride/methanol=10/1) and recrystallized from ethyl acetate/isopropyl ether to obtain (S)-2-methyl-6-nitro-2-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazin-1-ylmethyl}-2,3-dihydroimidazo[2,1-b]oxazole (270 mg, yield 40%) as a white powder.
Reaction SMILES: CON(C)[C:4]([C:6]1([C:20]([F:23])([F:22])[F:21])[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.C(Cl)Cl>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH:9]1[CH2:10][CH2:11][C:6]([C:20]([F:23])([F:21])[F:22])([CH:4]=[O:5])[CH2:7][CH2:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CON(C)C(=O)C1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(C=O)(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
4.15 g (11.2 mmol) of 4-(tert-Butyl-dimethyl-silanyloxy)-1-trifluoromethyl-cyclohexanecarboxylic acid methoxy-methyl-amide (70) were dissolved in 40 ml of anhydrous THF. Afterwards, 28.1 ml (28.1 mmol) of a 1M solution of diisobutylaluminium hydride in CH2Cl2 was added at 0° C. and the mixture was stirred at 0° C. for 30 minutes. 40 ml of a 10% aqueous solution of potassium sodium tartrate tetrahydrate were added and the mixture was stirred for 1 h at ambient temperature. The reaction mixture was then extracted twice using 50 ml of ethyl acetate each. The organic layer was dried over MgSO4 and evaporated to give 3.40 g of 71. Rt=0.98 min (Method Q).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:11][C:10]([NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:9][C:10](=[O:13])[CH2:11][N:23]2[CH2:22][CH2:21][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[CH2:25][CH2:24]2)=[O:13])[CH2:24][CH2:25]1
Reactant: Cc1ccc(C)c(NC(=O)CCl)c1
Reactant: c1ccc(N2CCNCC2)nc1
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1NC(=O)CN1CCN(c2ccccn2)CC1
Yield: 74 %

Procedure:
The procedure described in Example 181 was followed, substituting 2-chloro-N-[2-(2-chloroacetylamino)phenyl]acetamide (Aldrich) for N-(2,5-dimethylphenyl)-2-chloroacetamide and using 2.4 equivalents of 1-pyridin-2-yl-piperazine to provide the title compound (74% yield) as a light tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.59 (m, 8H), 3.18 (s, 4H), 3.52 (m, 8H), 6.63 (dd, 2H, J=5.1, 5.1 Hz), 6.78 (d, 2H, J=8.5 Hz), 7.20 (dd, 2H, J=5.8, 3.4 Hz), 7.51 (dd, 2H, J=8.5, 8.5 Hz), 7.60 (dd, 2H, J=5.8, 3.7 Hz), 8.10 (d, 2H, J=3.7 Hz), 9.64 (br s, 2H); MS (DCI/NH3) m/e 515 (M+H)+; Anal. calcd for C28H34N8O2.0.4 C4H8O2.0.1 H2O: C, 64.44; H, 6.83; N, 20.31. Found: C, 64.42; H, 6.67; N, 20.12.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=O.COC1C=CC(/C=[C:38]2/[C:39]([NH:41][C:42]([S:44]/2)=[NH:43])=[O:40])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:43][C:42]1[S:44]/[C:38](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])/[C:39](=[O:40])[N:41]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: COCCOCCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOCCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 130 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
The suspension of 6-formyl-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (example 28b, 50 mg, 0.17 mmol), pseudothiohydantoin (19.3 mg, 0.17 mmol), and sodium acetate (55 mg, 0.68 mmol) in acetic acid (180 uL) was stirred at 130° C. for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-7% methanol in methylene chloride in 30 min) afforded 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (16.2 mg, 24%) as a slight yellow solid. LC-MS m/e 399 (MH+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2=[CH:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:23]=[C:17]2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1.[C:35](=[O:37])=[O:36]>O1CCCC1>[CH3:13][N:14]1[C:19](=[O:20])[C:18]2=[CH:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]([C:35]([OH:37])=[O:36])=[C:17]2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1
Reactant: O=C=O
Reactant: CC(C)Cc1nn(C)c(=O)c2cn(Cc3ccccc3)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Cc1nn(C)c(=O)c2cn(Cc3ccccc3)c(C(=O)O)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (2.5M in hexanes, 2.35 m) was added dropwise to a stirred solution of diisopropylamine (0.85 ml) in dry tetrahydrofuran (10 ml) at 0° C., under nitrogen. The reaction was stirred at 0° C. for 30 minutes, then cooled to −78° C. To this was added a solution of 2,6-dihydro-2-methyl-4-(2-methylpropyl)-6-(1-phenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one (1.5 g, prepared as in Example 14 step b) in dry tetrahydrofuran (10 ml), and stirring was continued for 30 minutes. This anion was then added to an excess of solid carbon dioxide. The reaction was allowed to warm to room temperature overnight, and was then quenched by the addition of water. The mixture was extracted into ethyl acetate, washed with brine, dried and evaporated to give a yellow oil, which was chromatographed, eluting with ethyl acetate:isohexane(3:7), to give the sub-title compound as a yellow solid (0.91 g).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2[F:27])[CH:6]=1.[OH-].[Na+]>CO>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:18]=2[F:27])[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:42])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2F)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2F)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(2-fluoro-3-trifluoromethyl-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4a) (0.84 g, 0.0014 mol) in methanol (7.5 mL) was treated with 2N NaOH (5.0 ml) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was diluted with EtOAc (25 mL), water (10 mL) was added, and the solution acidified to pH 2 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil. Solidification of the waxy oil from 9:1 ether/pet ether gave white solid (5a) 0.67 g in 85% yield, mp: 181.4° C. 1H NMR (CD3OD) δ 7.84 (d, 2H), 7.46 (m, 11H), 6.88 (d, 2H), 6.68 (d, 2H), 4.67 (s, 2H), 4.64 (t, 1H), 4.11 (s, 2H), 3.99 (d, 2H), 3.54 (s, 2H), 3.45 (d, 2H), 2.27 (t, 2H); 13C NMR (CD3OD) δ 175.3, 159.5, 141.3, 139.1, 137.6, 131.1, 130.6, 130.5, 128.9, 126.8, 126.7, 123.6, 116.9, 114.0, 66.4, 59.0, 53.9, 52.0, 41.5, 23.5. Anal. Calcd for C33H31F4NO3.2H2O: C, 65.87; H, 5.19; N, 2.33; F, 12.63. Found: C, 65.80; H, 5.34; N, 2.08; F, 12.51.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)nc1)C(=O)c1ccccc1
Reactant: FC(F)(F)c1ccc(CCBr)cc1
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1)c1ccccc1

Procedure:
In analogy to the procedure described for the synthesis example 43 (step 2), the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide (MS m/e: 433.2 [M+H]+) was prepared from N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide and 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([NH2:22])=[O:21])[CH:4]=1.O=[CH:24][C:25](Cl)([Cl:27])[Cl:26]>C1C=CC=CC=1>[Cl:26][C:25]([Cl:27])=[CH:24][NH:22][C:20]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=1)=[O:21]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(N)=O)c1
Solvent: c1ccccc1
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC=C(Cl)Cl)c1

Procedure:
1.0 g (0.0032 mol) of 4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in benzene and mixed with 0.93 g (0.0032×2.0 mol) of chloral, followed by treating the obtained solution under reflux for about 5 hours. The reaction solution was concentrated and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH2:20][CH2:21]Br>>[Br:19][CH2:20][CH2:21][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCOc1ccccc1O
Reactant: BrCCBr
Product: CC(C)(C)OC(=O)NCCOc1ccccc1OCCBr

Procedure:
Reacting crude o-(2-tertiary butoxycarbonylaminoethoxy)-phenol with 1,2-dibromoethane analogously to Example 2 b yields 1-(2-bromoethoxy)-2-(2-tertiary butoxycarbonylaminoethoxy)-benzene, which has a melting point of 74°-75° (from isopropanol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>ClCCl>[N:1]1([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: O=C(Cn1ccnc1)OCc1ccccc1
Yield: 89.6 %

Procedure:
A solution of 1.4 g (21 mmol) of imidazole and 1.0 ml (6.3 mmol) of benzyl 2-bromoacetate in 40 ml of dichloromethane was stirred at ambient temperature for 16 h. The resulting solution was washed with water, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue using 5% methanol in chloroform provided 1.22 g (89%) of the desired compound as an oil. 1H NMR (CDCl3) δ 4.73 (s, 2H), 5.21 (s, 2H), 6.96 (t, J=1 Hz, 1H), 7.11 (t, J=1 Hz, 1H), 7.36 (m, 5H), 7.51 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:19][C:20]#[N:21])[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:17]([CH:15]1[CH2:16][C:13]([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[N:7]=3)[CH:9]=[N:10]2)([CH2:19][C:20]#[N:21])[CH2:14]1)#[N:18]
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CC(C#N)C1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(C(=O)O)cc4)n3)cn2)CC(C#N)C1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-cyclobutanecarbonitrile (300 mg, 0.00100 mol), p-aminobenzoic acid (206 mg, 0.00151 mol), and p-toluenesulfonic acid (150 mg, 0.00085 mol) in dry 1,4-dioxane (8 mL) was refluxed overnight, cooled to room temperature. The solid was filtered and collected to give the titled compound as a cis- and trans-isomer mixture, which was used directly in next step (310 mg, 77.3%). LCMS (M+H) 400.4.