Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:25][C:26]([F:31])([CH2:29][NH2:30])[CH2:27][NH2:28]>>[O:24]=[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:28][CH2:27][C:26]([F:31])([F:25])[CH2:29][NH2:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC(F)(F)CN
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 7.93 (s, 1 H), 7.81-7.79 (m, 1 H), 7.76-7.74 (d, 2 H), 7.62-7.52 (m, 3 H), 6.25 (s, 1 H), 5.45-5.41 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.45 (m, 1 H), 4.23-4.16 (m, 2 H), 3.72-3.64 (t, 2 H), 3.50 (m, 2 H), 2.47 (s, 3 H).
Reaction SMILES: [Li].C1C2C(=CC=CC=2)C=CC=1.Br[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1.BrCCBr.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.O.[Cu]I>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([C@@H:20]2[CH2:24][NH:23][C:22](=[O:25])[CH2:21]2)=[C:13]([C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C[C@H](c2ccc(Cl)cc2Br)CN1
Agent: [Cu]I
Agent: [Li]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: O=C1C[C@H](c2ccc(Cl)cc2C(=O)c2ccccc2)CN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of lithium wire (30 mg, 4.28 mmol), naphthalene (52 mg, 0.66 mmol), and MnBr2 (0.64 g, 2.08 mmol) was cannulated anhydrous tetrahydrofuran (THF) under a nitrogen atmosphere. The mixture was stirred for 2 h at room temperature before (4R)-4-(2-bromo-4-chlorophenyl)pyrrolidin-2-one in anhydrous THF (2 mL) was added dropwise. After stirring for 1 h, the reaction mixture was cooled to 0° C. and 1,2-dibromoethane (0.3 mL, 1.89 mmol) was added. The reaction mixture was warmed to room temperature before a solution of CuI (11.4 mg, 0.06 mmol) in THF (1 mL) was introduced via cannulation. The mixture was then stirred for 5 min and benzoyl chloride (0.1 mL, 0.66 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction was diluted with water (1.5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed in vacuo to provide (4R)-4-[4-chloro-2-(phenylcarbonyl)phenyl]pyrrolidin-2-one. The crude residue was treated with a 6N HCl aq. solution and heated overnight. The crude residue was purified by HPLC to afford the title compound (11). 1H-NMR (400 MHz, CD3OD): δ 2.71-2.87 (m, 2H), 3.44-3.59 (m, 3H), 7.27 (s, 3H), 7.37-7.41 (m, 2H), 7.46-7.48 (m, 1H), 7.66-7.68 (m, 2H); MS (ESI) m/z 318.09 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:26])/[CH:5]=[C:6](\[CH3:25])/[CH:7]=[CH:8]/[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]#[C:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:25]/[C:6](/[CH:7]=[CH:8]/[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]#[C:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])=[CH:5]\[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1=C(C#CC2=C(C)CCCC2(C)C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1=C(C#CC2=C(/C=C/C(C)=C/C(=O)O)CCC2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
(2E,4E)-3-Methyl-5-[2-(2,6,6-trimethyl-cyclohex-1-enylethynyl)-cyclopent-1-enyl]-penta-2,4-dienoic acid ethyl ester (1. 47 g) was dissolved in 14 ml of THF/EtOH=1/1. 3N aqueous NaOH (7.0 ml) was added and the reaction flask kept in the dark. After stirring for 16 hours at ambient temperature, the mixture was poured onto crushed ice/HCl, extracted twice with EtOEt, washed with water, dried over Na2SO4, and evaporated to dryness. Crystallization from EtOEt/pentane afforded 1.31 g of (2E,4E)-3-Methyl-5-[2-(2,6,6-trimethyl-cyclohex-1-enylethynyl)-cyclopent-1-enyl] -penta-2,4-dienoic acid as yellow crystals of mp. 173-174° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4]>[Ni]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[N:7][CH:8]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Product: CC(C)(C#N)c1ccc(N)cn1

Procedure:
2-methyl-2-(5-nitropyridin-2-yl)propanenitrile (15.70 mmol) was subjected to hydrogenation using Raney-Ni (0.6 g) at 40 psi for 4 h. Reaction mixture was filtered and washed with methanol. Filtrate was concentrated and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J=2.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.03 (dd, J=2.7, 8.7 Hz, 1H), 3.36 (brs, 2H), 1.74 (s, 6H); MS m/z: 162 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:17]2[C:4]([CH2:5][CH2:6][C@@H:7]3[C:16]=2[C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]([CH2:34][C:35]([F:44])([F:43])[C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])[CH3:33])=[O:31])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:45])=[CH:3]1.[C:46](OC(=O)C)(=[O:48])[CH3:47].C(Br)(=O)C>>[C:46]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]([CH2:34][C:35]([F:43])([F:44])[C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40])[CH3:33])=[O:31])([CH3:13])[C:11](=[O:45])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:48])[CH3:47]
Reactant: CN(CC(F)(F)C(F)(F)C(F)(F)F)C(=O)CCCCCCCCCC[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CCC3=C12
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)Br
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](CCCCCCCCCCC(=O)N(C)CC(F)(F)C(F)(F)C(F)(F)F)C[C@]2(C)C(=O)CC[C@@H]12

Procedure:
One operates as in Stage B of Example 3 starting with 345 mg of the product obtained in Stage A above using 0.4 cm3 of acetic anhydride and 0.2 cm3 of acetyl bromide. One obtains 323 mg of expected product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:24]CC2C=CC(OC)=CC=2)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:22])([F:23])[F:21])=[CH:11][C:10]=1[Cl:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(c2ccc(OCc3ccccc3)c(Cl)c2)(C(F)(F)F)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc(OCc2ccccc2)c(Cl)c1)(C(F)(F)F)C(F)(F)F
Yield: 9.5 %

Procedure:
82 mg (0.2 mmol) of crude 1-benzyloxy-2-chloro-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-benzene were treated with 3 mL of a mixture of dichloromethane/trifluoroacetic acid (1:3) at room temperature for 1 h. The solvent was evaporated and the residue was redissolved in a mixture of diethyl ether and a solution of Na2CO3. The inorganic phase was extracted with diethyl ether and the combined organic phases were washed with brine and dried (Na2SO4). After filtration and evaporation of the solvent, the crude product was purified by column chromatography to give 7.3 mg (12%) of 2-(4-benzyloxy-3-chloro-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol as a yellow gum, MS: 383 (M−H, 1Cl)−.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>>[NH:20]1[C:19]([NH:18][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=2)=[O:13])=[N:23][N:22]=[N:21]1
Reactant: CCCCc1cccc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: CCCCc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 34.5 %

Procedure:
2.4 g of 6-n-butyl-2-pyridinecarboxylic acid, 15 ml of thionyl chloride and 0.97 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.97 g of N-(5-tetrazolyl)-6-n-butyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[C:10](=[O:24])[C:11]2[C:16]([C:17](=[O:20])[C:18]=1Cl)=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=[CH:13][CH:12]=2>C(O)C>[O:20]=[C:17]1[C:18]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[C:9]=2[C:10](=[O:24])[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[C:16]1=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=C1c2nc3ccccn3c2C(=O)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 4.5 %

Procedure:
1.73 g (18 mmol, 1 eq) of 2-aminopyridine are added to a suspension of 5.00 g (18 mmol), 1 eq) of 2,3-dichloro-1,4-dihydro-1,4-dioxo-5-nitronaphthalene in 400 mL of ethanol. The mixture is brought to reflux for 5 h. After an orange precipitate appears, the reaction is allowed to cool to ambient temperature and the precipitate is filtered and purified on a flash column (support: silica 6-35 μm, h=45 cm, δ=16 cm; conditioning: heptane/ethyl acetate, 50/50; eluant: heptane/ethyl acetate, 50/50 to 70/30) to obtain 0.54 g of 6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine or 6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine, which after recrystallization in 1,2-dichlorobenzene produces 0.24 g of the expected product in the form of orange crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[CH2:14](Br)[C:15]#[CH:16].C([O-])([O-])=O.[K+].[K+].CC(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:16][C:15]#[CH:14])[CH:10]=2)[C:5]([CH3:13])=[N:4][N:3]=1
Reactant: Cc1nnc(Cl)c2cc(O)ccc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc2c(C)nnc(Cl)c2c1
Temperature: 68 °C
Reaction time: 23 h
Yield: 55.4 %

Procedure:
The mixture of 4-chloro-6-hydroxy-1-methylphthalazine (5) (195 mg, 1.00 mmol), 80% propargyl bromide (1.30 mmol) in toluene (145 μL), K2CO3 (187 mg, 1.35 mmol), and acetone (8 mL) is stirred at 68° C. under argon for 23 h, then cooled to room temperature, and concentrated. The residue is diluted with H2O (50 mL) and extracted with ethyl acetate (70 mL and 60 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (33% to 50% ethyl acetate/hexane) to give 129 mg (55%) of 6 as a light-yellow solid, mp 169-171° C. IR 3077, 1401, 1217 cm−1; 1H NMR (CDCl3) δ 2.66 (t, J=2.4 Hz, 1H, C≡CH), 2.97 (s, 3H, CH3), 4.96 (d, J=2.4 Hz, 2H, CH2C≡CH), 7.62 (dd, J=9.3, 2.7 Hz, 1H, 7-PhthH), 7.69 (d, J=2.7 Hz, 1H, 5-PhthH), 8.05 ppm (d, J=9.3 Hz, 1H, 8-PhthH).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.CN(C)[C:17](=O)[CH3:18].C(Cl)(=O)C>O>[CH3:17][C:18]1[O:1][N:2]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[N:14]=1
Reactant: CC(=O)N(C)C
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)=NO
Solvent: O
Solvent: CC(=O)Cl
Product: Cc1nc(Cc2ccc([N+](=O)[O-])cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a mixture of N′-hydroxy-2-(4-nitrophenyl)ethanimidamide (2.38 g) and N,N-dimethylacetamide (30 mL) was added acetyl chloride (0.96 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of obtained residue and xylene (100 mL) was heated under reflux for 24 hrs. The reaction mixture was concentrated and ethyl acetate was added to the obtained residue. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 5-methyl-3-(4-nitrobenzyl)-1,2,4-oxadiazole as orange crystals (1.00 g, yield 37%) from a fraction eluted with hexane-ethyl acetate (4:1-3:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave orange prism crystals. melting point: 66-67° C.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([S:6][CH2:7][C:8]#[N:9])[S:3][CH:2]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C)C=O>[S:3]1[CH:2]=[CH:1][CH:5]=[C:4]1[S:6][CH2:7][C:8]1[NH:12][N:11]=[N:10][N:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCSc1cccs1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1csc(SCc2nnn[nH]2)c1

Procedure:
A mixture of 7.76 g. (50 millimoles) of thiophene-2-thioacetonitrile, 4.30 g. (66 millimoles) of sodium azide, 3.55 g. (66 millimoles) of ammonium chloride, and 0.38 g. (9 millimoles) of lithium chloride is maintained for 5 hours at 120° in 50 ml. of dry dimethylformamide. The dimethylformamide is withdrawn under vacuum, the residue is combined with 500 ml. of cold 0.2 N sodium hydroxide solution and extracted with ether. The aqueous phase is adjusted to pH 3 and extracted three times with respectively 150 ml. of ether. The ether phase yields, after drying (Na2SO4) and concentration, the crude, solid tetrazole which is recrystallized once from acetonitrile/water and once from ethanol/water.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH2:14][CH2:13]3)[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.[CH3:28][NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)=[O:31]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][CH:12]2[N:8]2[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]3[N:3]=[C:2]([C:36]4[CH:35]=[CH:34][C:33]([NH:32][C:30]([NH:29][CH3:28])=[O:31])=[CH:38][CH:37]=4)[N:11]=[CH:10][C:9]2=3)=[CH:16][CH:17]=1
Reactant: COc1ccc2c(c1)C(N1C(=O)C3COCCN3c3nc(Cl)ncc31)CC2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2C(=O)N3C2CCc3ccc(OC)cc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 84 using 2-chloro-5-(6-methoxy-2,3-dihydro-1H-inden-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x43, 70 mg, 0.181 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (100 mg, 0.362 mmol) and PdCl2(dppf) (6.62 mg, 9.05 μmol) in dioxane (3 mL) and aqueous saturated NaHCO3 (0.6 mL). 1H NMR (400 MHz, DMSO-d6) δ 2.23-2.45 (m, 3H), 2.60-2.66 (m, 3H), 2.87-3.17 (m, 4H), 3.55-3.72 (m, 4H), 3.95-4.10 (m, 1H), 4.16-4.34 (m, 1H), 4.38-4.64 (m, 2H), 6.04-6.15 (m, 1H), 6.49-6.91 (m, 3H), 7.23-7.34 (m, 1H), 7.41-7.50 (m, 2H), 8.04-8.14 (m, 2H), 8.72-8.81 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C27H28N6O4, 501.22. found 501.5.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH2:38]O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:38][CH:31]([C:28]3[CH:27]=[CH:26][C:25]([C:24]([NH:23][CH2:22][CH2:21][C:20]([OH:41])=[O:19])=[O:40])=[CH:30][CH:29]=3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCCC(COc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Example 8, using 4′-tert-butyl-biphenyl-4-ol and 3-[4-(1-hydroxymethyl-heptyl)-benzoylamino]-propionic acid methyl ester as starting materials. MS (ES): 528.3 [M+H]−.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][C:5]([C:10](O)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[ClH:16].[N:2]12[CH2:9][CH2:8][C:5]([C:10]([Cl:1])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C12CCN(CC1)CC2

Procedure:
Quinuclidine-4-carboxylic acid hydrochloride (0.192 g, 0.001 mole) was suspended in dichloromethane (5 ml) and dimethylformamide (1 drop) and oxalyl chloride (0.436 ml. 0.635 g, 0.005 mole) were added. The resulting suspension was heated to reflux under an atmosphere of argon for six hours. Following concentration of the suspension in vacuo the residue was suspended in dichloromethane, concentrated in vacuo and finally dried in vacuo to give the title compound as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NC1CCCCC1
Solvent: CO
Product: Nc1nc(Cl)cc(NC2CCCCC2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 108.5 %

Procedure:
In a 25 mL sealable tube under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and cyclohexylamine (0.87 mL, 7.62 mmol) and CH3OH (10 mL). The vial was sealed, and the reaction mixture was stirred for 2 days at 50° C. The reaction was cooled to room temperature and concentrated. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (750 mg, 99%) as an orange oil. LC-MS (ES) m/z=227 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH2:20][C:19](=[O:35])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=3[N:7]=2)=[CH:24][C:25]=1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccnc(-c3cccnc3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-(3-[2,3′]bipyridinyl-4-yl-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M294) (230 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (147 mg, 84%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[C:17]([N:18]([CH3:20])[CH3:19])=[O:21]
Reactant: CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-[1-Dimethylcarbamoyl-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (5.7 g, 18.5 mmol) was dissolved in 4M HCl-dioxane (7 mL) at 0° C. The mixture was stirred at 25° C. for 3 hours, concentrated and the residue triturated with ether. Yield, 5.23 g; HPLC (60/40) 3.32 minutes (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:4]=1.[Sn]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/c2ccc([N+](=O)[O-])cc2)c1
Agent: [Sn]
Product: COc1cccc(/C=C/c2ccc(N)cc2)c1

Procedure:
In an analogous manner to that described in Example 37b), the reduction of (E)-1-methoxy-3-[2-(4-nitrophenyl)ethenyl]-benzene using tin yields the (E)-4-[2-(3-methoxy-phenyl)-vinyl]-phenylamine as a brown oil; MS: m/e=226 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][CH:10]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])=[CH:23][CH:22]=1
Reactant: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Cc1cc(N2CCC(N3CCC[C@H]3C)C2)ccc1NC(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(R)-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-fluorobenzoyl chloride. LCMS: RT=1.57 minutes, MS: 382 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[Li].CO.C1COCC1>O>[CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Li]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (90 mg, 0.2 mmol), lithium hdroxide monohydrate (24 mg, 1.0 mmol), methanol (2 ml), THF (3 ml), and water (1 ml) was stirred at +45° for 18 hours. The mixture was concentrated, diluted with 8 ml of water and 2 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate-heptane (1:1), extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the target product as a white solid (84 mg, 99%). MS (M+1): 419.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Br)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 54.2 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.3 g, 6.5 mmol) prepared in Example 63a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 54%).