Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C@@H:11]2[C@@H:18]3[C@@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C@@H:11]2[C@@H:18]3[C@@H:14]([CH2:15][N:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=4)[CH2:17]3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(F)c1)[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1cccc(Br)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 80 °C

Procedure:
The title compound was prepared by combining (3aS,4S,6aS)—N-(3-fluorophenyl)octahydrocyclopenta[c]pyrrole-4-carboxamide (98 mg, 0.395 mmol) from Example 55, 2-bromo-6-(trifluoromethyl)pyridine (125 mg, 0.553 mmol), and triethylamine (0.165 mL, 1.184 mmol) in ethanol (0.2 mL). The reaction mixture was heated at 80° C. for 72 hours. The reaction was quenched with water (1 mL) and the resulting brown oil was purified using a 12 g silica gel cartridge eluting with 1-100% ethyl acetate/hexanes over 20 minutes to give a solid. The solid was recrystallized from ethyl acetate/heptane (10%) to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 11.06 (s, 1H), 8.21 (dt, J=11.7, 2.2, 1H), 7.60-7.59 (m, 1H), 7.54-7.47 (m, 1H), 7.30 (td, J=8.2, 6.8, 1H), 6.98 (d, J=7.3, 1H), 6.91 (tdd, J=8.6, 2.6, 0.6, 1H), 6.41 (d, J=8.6, 1H), 3.46 (dd, J=10.3, 7.6, 3H), 3.23-3.14 (m, 1H), 3.06 (dd, J=10.8, 5.7, 1H), 2.90-2.72 (m, 2H), 2.22-2.12 (m, 1H), 2.12-1.95 (m, 2H), 1.39 (dtd, J=10.4, 8.0, 5.4, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][CH:52]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH3:53]>C1COCC1.C(OCC)(=O)C>[C:57]([O:56][C:55]([NH:54][CH:52]([CH3:53])[CH2:51][N:37]1[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]1)=[O:61])([CH3:60])([CH3:59])[CH3:58]
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Reactant: CC(CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(I)nn(CC(C)NC(=O)OC(C)(C)C)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred suspension of PPh3 (12.41 g, 47.3 mmol) in THF (100 mL) was added DIAD (9.20 mL, 47.3 mmol) at 10° C. and allowed to stir at 0° C. for 0.5 h. Intermediate 104C (8.0 g, 23.66 mmol) was added as a solution in THF (10 mL) at 0° C. and stirred at RT for 45 min. The reaction mixture was cooled again to 0° C. and tert-butyl (1-hydroxypropan-2-yl)carbamate (5.39 g, 30.8 mmol) was added as a solution in THF (10 mL) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford the Intermediate 340A as a brown liquid (7.0 g) contaminated with impurities arising from the coupling reagents. MS(ES): m/z=496 [M+H]+. The crude intermediate was taken to the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45](I)=[CH:44][CH:43]=2)=[CH:26]/[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:18][C:19]1[CH:20]=[CH:21][C:22](/[C:25](/[C:42]2[CH:43]=[CH:44][C:45]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:46][CH:47]=2)=[CH:26]/[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(CO)cc1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(I)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2ccc(C#Cc3ccc(CO)cc3)cc2)cc1C
Temperature: 25 °C

Procedure:
(4-Ethynylphenyl)methanol (200 mg, 1.51 mmol) and diisopropylamine (360 mg, 3.56 mmol) were added to a solution of methyl (Z)-[4-[3-(4-bromophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (445 mg, 0.75 mmol) in anhydrous tetrahydrofuran (15 mL). The solution was degassed and bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) and copper(I) iodide (15 mg, 0.078 mmol) were added. The reaction solution was degassed again and then stirred under inert atmosphere at ambient temperature over night. The reaction mixture was filtered through a paddle of silica gel; the paddle was thoroughly washed with ethyl acetate (4×20 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (E)-[4-[3-(4-bromophenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]([CH3:42])[C:34]1=[O:43].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH3:42][N:35]1[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:33]([CH2:32][CH2:31][CH2:30][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:34]1=[O:43]
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C)c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400 mg, 0.962 mmol, 1 equiv), 1-(3-iodopropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (304.8 mg, 0.962 mmol, 1 equiv), and potassium carbonate (399 mg, 2.88 mmol, 3 equiv) was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using preparatory thin layer chromatography in 5% methanol in dichloromethane to afford the title compound as an oil (427 mg, 78%); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (d, 2H, J=13.2 Hz), 1.85 (t, 2H, J=7.2 and 6.8 Hz); 2.34 (d, 2H, J=6.4 Hz); 2.64-2.66 (m, 2H); 2.89 (s, 3H); 3.843 (s, 3H); 3.91 (t, 2H, J=6.4 and 6.8 Hz); 4.58 (s, 2H); 4.62 (s, 2H); 6.78 (t, 1H, J=7.2 Hz); 6.86 (d, 2H, J=8.8 Hz); 7.01-7.07 (m, 2H); 7.13-7.14 (m, 1H); 7.21-7.26 (m, 3H); 7.52-7.58 (m, 2H); 7.88 (s, 1H); 7.90 (s, 1H); MS for C33H37N5O4 m/z 568.13 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH:12]=O)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([C@H:24]([NH2:26])[CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[C:14]1([C@H:24]([NH:26][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[CH:9][CH:10]=2)[CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=Cc1ccnn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCc1ccnn1-c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-phenyl-1H-pyrazole-5-carbaldehyde 38 (0.517 g, 3 mmol) in DCE (10 mL) at room temperature was added (R)-1-(naphthalen-1-yl)ethanamine 39 (0.625 g, 4 mmol), acetic acid (0.208 g, 3 mmol), and NaBH(OAc)3 (0.946 g, 4 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched with saturated NaHCO3, diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 20% to 70% EtOAc in hexanes) gave (1R)-1-(1-naphthalenyl)-N-((1-phenyl-1H-pyrazol-5-yl)methyl)ethanamine 40. Mass spectrum: calculated for C22H21N3 327.2; found 328.2 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-])=O)[C:5]1=[O:17].CO.[H][H]>>[NH2:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][N:4]([CH2:3][CH2:2][OH:1])[C:5]2=[O:17]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Reactant: [H][H]
Solvent: CO
Product: Nc1cccc2c(=O)n(CCO)ccc12
Reaction time: 8 h

Procedure:
Into a 500 ml round bottom flask was combined 2-(2-hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (2.0 g, 0.0085 mol) palladium on C (0.09 g, 0.0008 mol), and methanol (100 mL, 2 mol). The vessel was charged with hydrogen and evacuated three times and stirred under hydrogen at 1 atm. overnight. The mixture was filtered over Celite and the filtrate was removed under reduced pressure to yield the title compound as a light brown solid. It was taken onto the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[N:5][CH:4]=1.C([N:18]=[C:19]=[S:20])(=O)C1C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:19]([NH2:18])=[S:20])[CH:6]=[N:5][CH:4]=1
Reactant: COc1cncc(N)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Product: COc1cncc(NC(N)=S)n1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
6-Methoxy-pyrazin-2-ylamine (0.85 g, 6.8 mmol) is dissolved in ethanol (7 ml) and benzoylisothiocyanate (0.91 ml) is added dropwise. The mixture is heated to 80° C. with stirring for 10 minutes then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting solid dissolved in 1M sodium hydroxide (15 ml) and heated under reflux for 1 hour. The resultant suspension is filtered and the solid washed with water and a little cold ethanol. The solid is dried in vacuo to yield the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]([CH3:19])([CH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16])[CH3:12]>C(O)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][C:11]([CH3:19])([CH2:13][CH2:14][C:15]([NH:18][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([CH3:17])[CH3:16])[CH3:12]
Reactant: CC(C)(N)CCC(C)(C)N
Reactant: O=Cc1ccccc1O
Agent: [Ni]
Solvent: CCO
Product: CC(C)(CCC(C)(C)NCc1ccccc1O)NCc1ccccc1O
Yield: 5.3 %

Procedure:
55.0 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of 2,5-diamino-2,5-dimethylhexane and with a melting point of 111°-112° C. are hydrogenated for 2 hours in 250 ml of ethanol in an autoclave in the presence of 5.5 g of Raney nickel at 100° C. and under a pressure of 80 atmospheres. The catalyst is filtered off and the filtrate is concentrated. The residue is recrystallised from 220 ml of ispropanol, collected by filtration, washed with n-hexane and dried in vacuo, affording 18.9 g (34% of theory) of N,N'-bis-(2-hydroxybenzyl)-2,5-diamino-2,5-dimethyl-hexane with a melting point of 102°-106° C. Two recrystallisations from a mixture of cyclohexane and ethanol yield 15.2 g of pure product with a melting point of 124°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[NH2:5].[C:22]1([C:28]2[CH:42]=[CH:41][C:31]([C:32]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3=O)=[O:33])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:5][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:42][CH:41]=1)=[O:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: O=C1CCCCC1C(=O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(-c2ccccc2)cc1
Yield: 32.3 %

Procedure:
The title compound (830 mg) was prepared from 1.83 g (5.7 mmol) O-benzyl-L-tyrosine methyl ester and 1.59 g (5.7 mmol) of 2-(4-phenylbenzoyl)cyclohexanone (Child, R. G. et.al. J. Pharm Sci 1977, 66(4), 466-76) according to the method of Intermediate 23 followed by purification via silica gel chromatography eluting with 1/9 EtOAc/hexanes: Low resolution MS (Cl) m/e 452 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=3)[C:14](=[O:24])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[Br:23][C:18]1[CH:17]=[C:16]([N:15]2[C:14](=[O:24])[O:13][N:12]=[C:11]2[C:7]2[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])=[N:10][O:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
A 22 L flask was charged with 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to −15° C. with an ice/salt bath, the solution of tert-butyl [chlorosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed −10° C. (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed −5° C. (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10° C., split into two portions, and neutralized with 10% conc HCl (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (˜25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off-white solid. The solid was triturated with MTBE (2×1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][CH3:43])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][N:42]([CH3:43])[C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:28])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN(C)C(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)cc1OC
Yield: 47.1 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol) prepared in Example 1d was reacted with [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine (58.6 mg, 0.3 mmol), HATU (76.0 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amide (57.3 mg, 48.26%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].COCCOCCN(CCOCCOC)CCOCCOC.[OH-].[K+].[F:34][C:35]1[CH:40]=[C:39](F)[C:38]([F:42])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]>C(OCC)(=O)C.O>[F:42][C:38]1[CH:37]=[C:36]([N+:43]([O-:45])=[O:44])[C:35]([F:34])=[CH:40][C:39]=1[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: OCc1cccc(F)c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(OCc2cccc(F)c2)cc1F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A mixture of 2.35 g (18.6 mmol) of 3-fluorobenzylalcohol and 0.55 g (1.7 mmol) of tris[2-(2-methoxyethoxy)ethyl]amine is treated portionwise under stirring with 1.06 g (18.6 mmol) of potassium hydroxide. Stirring is continued for 10 min if necessary under slight heating to reach a homogenous reaction mixture. Thereafter, 3.0 g (16.9 mmol) of 2,4,5-trifluoronitrobenzene are added dropwise. The reaction mixture becomes solid and is heated to 100° C. for 2 hours. For the working-up, the mixture is cooled to RT, then 25 ml water and 25 ml ethyl acetate are added and stirring continued for 30 min. The organic layer is separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are washed with water, then twice with 2N hydrochloric acid and finally with water. After drying over magnesium sulfate, the solution is evaporated under reduced pressure. During evaporation, the byproduct, 1-fluoro-2,4-bis-(3-fluorobenzyloxy)-5-nitro-benzene precipitates. For purification, the material obtained is chromatographed on silica gel using a 4:1-mixture of n-hexane and ethyl acetate as the eluent. There are obtained 2.63 g (55% of theory) of the 1,4-difluoro-2-(3-fluorobenzyloxy)-5-nitro-benzene as an off-white solid. MS: m/e=283 (M)+.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[OH-].[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23]>>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])[CH2:4][CH:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O
Yield: 97 %

Procedure:
A mixture of the N,N-dimethyl-2,6-di-t-butyl-4-aminomethylphenol (10.5 g, 40 mmols), sodium hydroxide (1.8 g, 45 mmols) and acetylacetone (24 mLs, 10% solution) was refluxed for 3 hours. Acetylacetone was distilled under reduced pressure to afford an oily residue of the 3-(3',5'-di-t-butyl-4'-hydroxybenzyl)-2,4-pentanedione compound (97% by VPC).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nccn1-c1ccc(N)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 16 h
Yield: 93.5 %

Procedure:
5-Amino-2-(2-methylimidazol-1-yl)fluorobenzene (34.25 g, 0.179 M) was dissolved in dry dichloromethane (600 ml) under nitrogen, and cooled to −5°. Pyridine (17.7 g, 0.224 M) was added, followed by benzyl chloroformate (33.7 g, 0.197 M) over 20 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 250 ml) was added, the organic layer separated, the aqueous layer re-extracted with dichloromethane (2×300 ml), and combined extracts dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (400 ml) to give title product (54.5 g). NMR (DMSO-d6) δ: 2.13 (s, 3H); 5.18 (s, 2H); 6.89 (s, 1H); 7.17 (s, 1H); 7.41 (overlapping m, 7H); 7.73 (dd, 1H); 10.21 (br, 1H). MS (ESP): 326 (MH+) for C18H16FN3O2
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:20]([O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCBr
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Solvent: CS(C)=O
Product: CCCCCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Yield: 116.5 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone (0.103 g, 0.418 mmol) in DMSO (1 mL) was alkylated with bromohexane (0.097 g, 0.585 mmol, 0.082 mL) as described in Example 21. Aqueous workup gave 1(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone 0.161 g (100% crude) as an orange oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, Ar-H), 6.82 (s, 1H, Ar-H), 4.02 (t, J=6.4 Hz, 2H, OCH2), 2.61 (s, 3H, CH3), 1.83 (m, 2H, CH2), 1.67 (app br d, 4H, 2CH2), 1.50 (m, 2H, CH2), 1.36 (m, 4H, 2CH2), 1.29 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 0.91 (t, J=7.0 Hz, 3H, CH3).
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.N([O-])=[O:23].[Na+]>C(O)(=O)C.O>[C@@H:12]1([N:8]2[C:6]3[NH:7][C:2](=[O:23])[NH:3][C:4](=[O:21])[C:5]=3[S:10][C:9]2=[O:11])[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: O=N[O-]
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of 7 (0.76 g, 2.4 mmol) in glacial acetic acid (150 mL) was added dropwise a solution of sodium nitrite (1.5 g, 21.7 mmol) in water (15 mL) with stirring. After 30 min the suspension became clear and stirring was continued at room temperature overnight. The white solid which had separated was filtered, washed with cold water and dried. Recrystallization from hot water gave fine colorless crystals of 8: yield 0.3 g, 40%: mp 250° C. dec.: UV λmax (pH 1) 293 nm (ε 5500): UV λmax (pH 7) 212 nm (ε 14,200), 301 (6100): UV λmax (pH 11) 204 nm (ε 21,900), 301 (5600). Anal Calcd. for C10H11N3O7S: C, 37.86: H, 3.49: N, 13.24: S, 10.10. Found: C, 37.81: H, 3.42: N, 13.01: S, 10.01.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([NH2:15])=O>CN1C(=O)CCC1>[I:11][C:10]1[C:9]([CH3:12])=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: Cc1ccc(C(=O)O)c(N)c1I
Reactant: NC=O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(=O)[nH]cnc2c1I
Temperature: 210 °C
Yield: 88 %

Procedure:
2-Amino-3-iodo-4-methylbenzoic acid (8.00 g, 29 mmol), formamide (11 mL, 289 mmol) and NMP (11 ml) were added to an 80 mL microwave vessel. The mixture was heated for 15 min at 210° C. The mixture was diluted with ice water and the precipitated solid collected by filtration. The solid was washed with water and dried to give 8-iodo-7-methylquinazolin-4(3H)-one (7.3 g, 88%) as a light brown solid. MS (M+H)+ 287.