Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([O:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:23]3)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
447 ml of methanesulphonyl chloride were added portionwise within 20 minutes while cooling with an ice bath to a mixture of 1157 g of trans-N-(7-chloro-quinolin-4-yl)-4-aminocyclohexanol and 868 ml of triethylamine in 6.1 l of dichloromethane. After a clear solution formed transiently the product began to separate. After 2 hours the mixture was filtered and the filtrate was evaporated to dryness. Filter residue and evaporation residue were combined and triturated. in 8 l of water. The mixture was again filtered, washed with a further 8 l of water and thereafter with 4 l of isopropanol and the product obtained was dried at 50° C./12 mbar. Yield: 2028 g (90%) of trans-N-(7-chloro-quinolin-4-yl)-4-methanesulphonyloxy-cyclohexylamine, m.p.: 154-159° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:36][C:35](=O)[CH:34]=[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[O:32]1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:35](=[O:36])[CH2:34][C:33](=[O:32])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C(F)(F)F)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Yield: 67.6 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (203 mg, 0.52 mmol) and 2,2-dimethyl-6-(3-trifluoromethyl-phenyl)-[1,3]dioxin-4-one (Example J5) (150 mg, 0.55 mmol) according to the general procedure K. Obtained as an off-white solid (213 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:19]([CH3:20])=[C:18](B2OC(C)(C)C(C)(C)O2)[C:17]([CH3:30])=[N:16]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:12][N:11]([CH3:13])[CH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:18]3[C:17]([CH3:30])=[N:16][N:15]([CH3:14])[C:19]=3[CH3:20])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)C1CCc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(N(C)C)CC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(Method 3): (6-Bromo-indan-1-yl)-dimethyl-amine (0.82 mmol) was dissolved in DME/H2O 1/1 (10 mL) under argon atmosphere. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.82 mmol), K2CO3 (3.08 mmol), and tetrakis-(triphenylphosphine)palladium (3 mol %, 0.025 mmol) were added and the reaction mixture was stirred at 100° C. for 3 h. Then, a second fraction of 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.41 mmol) was added and the reaction mixture was stirred at 100° C. for 2 h more. The reaction mixture was evaporated to dryness, then dissolved in CHCl3 and filtered through Celite® to give the crude product dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine. The crude was purified by flash column chromatography (CH2Cl2 and MeOH as eluents) by using a CombiFlash Companion™ system to yield the base of the title compound. The obtained product was diluted in ethyl acetate and a solution of hydrogen chloride 2.0 M in diethylether was added. The resulting precipitate was filtered and dried under vacuum to yield the title compound dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine dihydrochloride (75%). MS [MH]+=270.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:21]=[N+]=[N-])[N:3]=1.C(O)=O.N>[Pd].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:14][O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18]2)=[C:4]([NH2:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O=CO
Product: CC1(C)OCC(CCn2cnc3c(N)nc(N)nc32)CO1
Yield: 65 %

Procedure:
A mixture of 2-amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (318 mg, 1.0 mmol), formic acid (0.15 ml, 4.0 mmol), concentrated ammonia (0.22 ml, 4.0 mmol), 10% palladium-on-charcoal (30 mg) and methanol (10 ml) was heated under reflux for 1 hour. The solution was allowed to cool, filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (20:1 and 15:1) to give 2,6-diamino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (190 mg, 65%), m.p. 202°-204° C.); νmax (KBr) 1670, 1640, 1595, and 1410 cm-1 ; δH (CDCl3 -CD3OD) 1.42 (6 H, s, C(CH3)2), 1.6-2.0 (3 H, m, CHCH2CH2), 3.5-4.2 (6 H, m, 2×CH2O and CH2N), and 7.68 (1 H, s, 8-H) (Found: C, 52.88; H, 6.78; N, 28.36%; M+ 292.1652, C13H20N6O2 requires C, 53.41; H, 6.90; N, 28.75%; M+ 292.1648).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH2:23][CH:24](C)C)[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:27](N(C)CCC(O)C(C)C)C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH:11]([CH:23]([CH3:24])[CH3:27])[CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:15])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CC(C)C(O)CCN(C)Cc1ccccc1
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Product: CC(C)C(CCN(C)Cc1ccccc1)Oc1cccc2sccc12

Procedure:
Using a method similar to that for [3-(Benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine, 1-(benzyl-methyl-amino)-4-methyl-pentan-3-ol affords the title compound: mass spectrum (ion spray) m/z=354.3(M+1); 1H NMR (CDCl3) δ 7.49 (d, 1H), 7.43 (d, 1H), 7.31-7.19 (m, 7H), 6.85 (d, 1H), 4.48-4.44 (m, 1H), 3.51-3.43 (m, 2H), 2.61-2.48 (m, 2), 2.19 (s, 3H), 2.11-1.85 (m, 3H), 1.03 (d, 3H), 0.99 (d, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[CH:12].N>>[C:13]1([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: c1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-benzene (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.37 (s, 1H), 7.46-7.68 (m, 4H), 7.85-8.00 (m, 2H), 8.37 (dt, J=7.9, 2.0 Hz, 1H), 8.66 (dd, J=4.9, 1.5 Hz, 1H), 9.10 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 223 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][N:21]([CH3:29])[CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:28][CH:25]1[CH2:26][CH2:27][CH:22]([N:21]([CH3:29])[CH3:20])[CH2:23][CH2:24]1)[C:11]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[N:10]2
Reactant: Clc1cc2nc(Cl)c(-c3cccnc3)nc2cc1Cl
Reactant: CN(C)C1CCC(N)CC1
Solvent: Cc1ccccc1
Product: CN(C)C1CCC(Nc2nc3cc(Cl)c(Cl)cc3nc2-c2cccnc2)CC1

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-3-yl-quinoxaline (1.0 g) and N,N-dimethyl-cyclohexane-1,4-diamine in toluene (25 mL) was refluxed for 24 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give the product as a yellow solid (0.43 g); mp 158-161° C.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C1(C)C=CC(S(O[CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])(=O)=O)=CC=1>O>[N+:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH:15]=[CH:16][C:17]=1[OH:23])([O-:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)OCCCCO[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)OCCCCO[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a mixture comprising DMF (200 ml), 5-t-butoxycarbonylaminosalicylic acid (4.37 g, 17.3 mmol) and 4-nitrooxybutyl p-toluenesulfonate (5 g, 17.3 mmol), at room temperature and under stirring triethylamine was added (2,6 ml; 19 mmol). The reaction mixture was maintained 3 days under stirring at room temperature. It was then poured in water and extracted with ethyl ether. The combined organic phases were washed with a sodium carbonate solution and then with water. After drying on sodium sulfate, the evaporation of the solvent yields a raw product that purified by silica gel chromatography gives the title compounds with a yield of 65%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.B(F)(F)F.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>C1COCC1>[Cl:17][CH2:16][CH:18]([OH:20])[CH2:19][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: ClCC1CO1
Reactant: O=C1CCCN1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCCN1CC(O)CCl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
2-Pyrrolidinone (4.47 g, 52.5 mmol) was mixed with THF (25 mL) and cooled to −78° C. Butyllithium (1.6 M in hexanes) (32.8 mL, 52.5 mmol) was added slowly then and the mixture was agitated for 10 minutes. Boron trifluoride ethereate (6.59 mL, 52.5 mmol) was added dropwise, followed by dropwise addition of epichlorohydrin (4.11 mL, 52.5 mmol). The resulting mixture was allowed to warm up overnight, then cooled and quenched with saturated sodium bicarbonate solution, and extracted 3 times with ethyl acetate. The extracts were washed with brine, dried and evaporated to give ˜4 g of crude oil. The crude oil was purified by chromatography on silica gel, eluting with 1-2% methanol/dichloromethane, to provide the title compound (1.53 g, 16.4% yield) as clear oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[O:11][C:10]([C:12]([CH3:14])=[CH2:13])=[CH:9][C:8]2=[C:15]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH:16]=1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[O:11][C:10]([CH:12]([CH3:14])[CH3:13])=[CH:9][C:8]2=[C:15]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH:16]=1)([CH3:2])[CH3:3]
Reactant: C=C(C)c1cc2c(C(=O)Nc3ccc(C)cn3)cc(OC(C)C)cc2o1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(OC(C)C)cc3oc(C(C)C)cc23)nc1
Yield: 54.2 %

Procedure:
A solution of 6-isopropoxy-N-(5-methylpyridin-2-yl)-2-(prop-1-en-2-yl)benzofuran-4-carboxamide (118 mg, 0.34 mmol) in 10 mL of MeOH was passed through H-cube (10 bar of H2, 15° C., 5% Pd/C cartridge) at a rate of 1.0 mL/min. The collected solution was subsequently concentrated to give a light yellow gum (65 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1 H) 8.31 (d, J=8.56 Hz, 1 H) 8.14 (s, 1 H) 7.60 (dd, J=8.44, 2.14 Hz, 1 H) 7.29 (d, J=2.01 Hz, 1 H) 7.16 (d, J=2.01 Hz, 1 H) 6.84 (s, 1 H) 4.56-4.63 (m, 1 H), 3.04-3.13 (m, 1 H), 2.34 (s, 3H), 1.37 (m, 12 H); LCMS for C21H24N2O3 m/z 353.20 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:7]=[CH:8][C:9]=1[NH2:10])(=[O:3])[CH3:2].[Li+:17].[OH-]>C1COCC1.O>[C:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][C:13]([O-:15])=[O:14])[CH:7]=[CH:8][C:9]=1[NH2:10])(=[O:3])[CH3:2].[Li+:17]
Reactant: COC(=O)CCc1ccc(N)c(C(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(CCC(=O)[O-])ccc1N

Procedure:
Methyl 3-(3-acetyl-4-aminophenyl)propanoate (221 mg) and 4 M LiOH (0.275 mL) were added to 3 mL THF/water(v/v=3/1). The solvent was removed under reduced pressure after the reaction completed, affording lithium 3-(3-acetyl-4-aminophenyl)propanoate (X3547-1). 1H NMR (400 MHz, MeOD): δ 7.62 (d, J=2.0 Hz, 1H), 7.17 (dd, J=8.4 Hz, J′=2.0 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 2.80 (dd, J=7.6 Hz, J′=9.0 Hz, 2H), 2.55 (s, 3H), 2.41 (dd, J=7.6 Hz, J′=9.0 Hz, 2H); MS-ESI+ 207.22 (MH+).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[CH2:9]([C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C@H:16]1[CH2:20][N:19]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CC(F)(F)F
Yield: 30.6 %

Procedure:
Proceeding as in Example 1, but substituting 3,3,3-trifluoropropanoic acid and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 34, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(3,3,3-trifluoropropanoyl)pyrrolidine-2-carboxamide (9.2 mg, 30.6%). 1H-NMR (400 MHz, DMSO-D6): σ 9.98 (s, 1H), 7.54 (m, 2H), 7.22 (m, 2H), 7.17 (m, 5H), 6.93 (m, 4H), 4.49 (m, 1H), 3.60 (m, 2H), 3.26 (m, 1H), 2.65 (m, 3H), 1.91 (m, 2H). MS (EI) for C27H24F4N2O3: 501.5 (MH+).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Yield: 92 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-(1H-tetrazol-5-yl)ethyl]-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 92% of theory, C27H27N9O (493.6) ##EQU44##
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7](=[O:18])(=[O:17])[C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7](=[O:18])(=[O:17])[C:8]3[C:13]([O:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A stirred solution of 29.4 gm of 3-methoxyphenoxathiin 10,10-dioxide, 5.2 gm of tetrabutylammonium bromide (Aldrich Chemical Co.), and 500 mL of 48% aqueous HBr was refluxed in a 1 liter flask for 6 hours. It was allowed to stir overnight at room temperature and was then refluxed for one additional hour. The contents were cooled to room temperature, and a solid filtered off and washed with waster. There was obtained 26.43 gm of 3-hydroxyphenoxathiin 10,10-dioxide. This was of sufficient purity to be used for further synthetic work. Proton NMR was consistent with the structure. Recrystallization of 0.5 gm from EtOAc/Hexane yielded 0.32 gm, m.p.=213-215°.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:2][C:3](=[O:10])[C:4]([CH2:8][CH3:9])([CH3:7])[CH2:5][CH3:6]
Reactant: CCC(C)(CC)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(CC)C(=O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 93.5 %

Procedure:
50 g (0.28 mole) of 1-chloro-3-ethyl-3-methyl-pentan-2-one, dissolved in 30 ml of N,N-dimethylformamide, are added to a mixture of 38.6 g (0.28 mole) of potassium carbonate and 45.6 g (0.28 mole) of 2,4-dichlorophenol in 200 ml of N,N-dimethylformamide at the boiling point. The mixture is heated at the boiling point for 10 hours, cooled to room temperature and filtered and the solvent is distilled off under reduced pressure. Distillation of the residue gives 75.7 g (93.5% of theory) of 1-(2,4-dichlorophenoxy)-3-ethyl-3-methyl-pentan-2-one as a color less liquid of boiling point 141°-144° C./0.15 mm. ##STR64##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:19]([CH3:20])=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:10]2=[O:18]
Reactant: CC(=O)[O-]
Reactant: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2oc(C)c(-c3ccccc3)c(=O)c2c1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Intermediate 20 (4 g, 16.51 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (9.48 g, 115.57 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as yellow solid (3 g, 68% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.60(d, J=3.0 Hz, 1H), 7.45(t, J=7.1 Hz, 2H), 7.37(m, 2H), 7.29(m, 3H), 3.89(s, 3H).2.31(s, 3H).
Reaction SMILES: CS(O[CH:6]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[C-:27]#[N:28].[Na+].O>CN(C=O)C>[CH2:7]([CH:6]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:27]#[N:28])[CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC/C=C\CCCC(C#N)CCC/C=C\CCCCC
Yield: 106 %

Procedure:
A solution of (6Z,15Z)-henicosa-6,15-dien-11-yl methanesulfonate 5 (7.6 g, 19.6 mmol) and sodium cyanide (4.8 g, 98.1 mmol) in anhydrous DMF (60 mL) was heated to 60° C. overnight. Upon completion, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combine ethyl acetate extracts were washed with brine (3×100 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The product was purified by column chromatography (100% Hexanes to 1% ethyl acetate in hexanes) to afford (Z)-2-((Z)-dec-4-enyl)dodec-6-enenitrile 6 as a colorless oil (6.6 g, 97%). Rf 0.75 (10% EtOAc-Hexanes).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:11][C:12]([OH:14])=[O:13])[C:8]([OH:10])=[O:9])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C=C(CC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CC(CC(=O)O)C(=O)O)cc1
Reaction time: 40 h
Yield: 94.7 %

Procedure:
To a suspension of 2-(4-methylbenzylidene)succinic acid (4.5 g) in ethanol (50 ml) was added 10% Pd-C (100 mg) and the mixture was hydrogenated at room temperature and atmospheric pressure for 40 hours. After the catalyst was filtered off, the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from hexane-ethyl acetate (1:1) to give 4.3 g of 2-(4-methylbenzyl)succinic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Yield: 81.9 %

Procedure:
2 g 6-Hydroxymethyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is dissolved in 46 mL dichloromethane. After addition of 1.61 g activated manganese (IV) oxide the reaction mixture is heated to reflux for 1 hour. Then every two hours additional manganese (IV) oxide is added until the conversion is complete. The reaction mixture is diluted with dichloromethane and filtered over celite. 1.63 g (82%) crude product is obtained, which is directly used in the next reaction.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:2].[O:20]1CC[CH2:22][CH2:21]1>[Ni]>[C:21]([NH:2][CH2:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:20])[CH3:22]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2n1CC#N
Agent: [Ni]
Product: CCOC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Dissolve 0.34 g of the compound obtained in Step A in 10 ml of tetrahydrofuran and add a catalytic amount of Raney nickel and hydrogenate the reaction (10 bars) at ambient temperature for 24 hours. Filter over Celite and then evaporate. Take up the residue in 10 ml of tetrahydrofuran in the presence of 0.16 ml of triethylamine and, at 0° C. under argon, add dropwise 0.15 ml of acetic anhydride. Stir the reaction at ambient temperature for 22 hours. Evaporate, and take up the residue in ethyl acetate. Wash the organic phase with saturated aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution and subsequently dry over sodium sulfate. Filter and evaporate in vacuo, and then purify the compound by column chromatography on silica gel using ethyl acetate as eluant. The title compound is isolated in the form of a white solid.