Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:23]([CH3:29])([CH3:28])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:30]([O:1][C@@H:2]([C:23]([CH3:28])([CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)OC(=O)c1ccccc1

Procedure:
In analogy to Example 1(a), 1.6 g of (1S,5R,6R,7R)-6-[(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one, 8 ml of pyridine, and 1 ml of benzoyl chloride yield 2 g of the dibenzoate as a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C1(C)C=CC=CC=1.CN(C)C=O.CN1C(=O)CCC1>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=1)=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccccc1Br
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Thionyl chloride (120.5 g) was added to a stirred mixture of 2-bromobenzoic acid (194 g) in toluene (500 ml) and N, N-dimethylformamide (DMF) (5 ml) and the mixture heated at 80° C. for 4 hours. The solution was cooled to 20° C. and added slowly to a solution of 4-nitroaniline (133.1 g) in toluene (500 ml) and NMP (120 ml), maintaining the temperature of the reaction mixture between 20°-25° C. The reaction mixture was then stirred for 24 hours when a solid precipitated. Water (360 ml) was added with rigorous stirring and the suspended solid collected by filtration, and washed successively with water, toluene and acetonitrile to give 2-bromo-N-(4-nitrophenyl)benzamide (B) as a solid, in 87% yield; m.p. 200°-202° C.; NMR(d6 -DMSO): 7.4-7.8(m, 7H), 8.0(d, 2H), 8.3(d, 2H), 11.5(brs, 1H); which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]3[C:14]([OH:19])=[CH:15][C:16](=[O:18])[O:17][C:5]=3[C:4]=2[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O.C(O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]3[C:14]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[C:16](=[O:18])[O:17][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cn1c(=O)c2c(O)cc(=O)oc2c2cc(Cl)ccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: Cn1c(=O)c2c(O)c([N+](=O)[O-])c(=O)oc2c2cc(Cl)ccc21
Temperature: 20 °C

Procedure:
0.02 Mole 9-chloro-5,6-dihydro-6-methyl-2,5-dioxo-2H-pyrano[3,2-c]quinoline-4-ol from Example 7 (5.6 g) is suspended in 25 ml of glacial acetic acid. 4 ml of nitric acid (d=1.40) are added dropwise at 25° C., while stirring, and the magma-like reaction batch is then heated for 60 minutes to 95° C. It is then cooled to 20° C. During cooling, 36 ml of a mixture of water and isopropanol (1:1) is added. The whole is then filtered. The filter residue is washed with water to neutrality and after washing with isopropanol and petroleum ether, it is dried. 5.5 g (85% of the theory) of a crystalline residue are obtained, the crystals of which have a melting point of 241°-243° C. (decomp.) after recrystallization from a mixture of isobutanol and dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:18]=2[C:19]([O:21]CC)=[O:20])=[CH:12][C:11]=1[CH3:29].[OH-].[Na+]>C(O)C.O.CO.N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:18]=2[C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[CH3:29]
Reactant: CCOC(=O)c1cc(C)ccc1Nc1cnc(-c2cc(OC)ccc2F)c(C)c1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: COc1ccc(F)c(-c2ncc(Nc3ccc(C)cc3C(=O)O)cc2C)c1
Temperature: 60 °C
Yield: 67 %

Procedure:
The solid residue obtained in step A was dissolved in 2 ml of ethanol and 0.150 ml of aqueous solution 2N NaOH were added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SCX cartridge eluting with MeOH/NH3 10:1 affording 0.030 g (yield 67%) of the expected product.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[O:23][C:22]([F:21])([F:32])[F:33])[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccccc1OC(F)(F)F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 2-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 410.01 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+].[CH3:20][N:21]([CH3:32])[C:22]1[N:27]=[C:26]([N:28]([CH3:30])[CH3:29])[N:25]=[C:24](Cl)[N:23]=1.Cl>CN(C)C=O.O>[CH3:29][N:28]([CH3:30])[C:26]1[N:27]=[C:22]([N:21]([CH3:32])[CH3:20])[N:23]=[C:24]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[C:5]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6]2)[N:25]=1
Reactant: CN(C)c1nc(Cl)nc(N(C)C)n1
Reactant: O=C(O)CCC(=O)c1c[nH]c2ccc(Br)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(N(C)C)nc(-n2cc(C(=O)CCC(=O)O)c3cc(Br)ccc32)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A solution of 4-(5-bromo-1H-indol-3-yl)-4-oxobutyric acid (148 mg, 0.5 mmol) in anhydrous dimethylformamide (5 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 50 mg, 2.0 mmol) in dimethylformamide (5 mL). After 30 mins, a solution of N2,N2,N4,N4-tetramethyl-6-chloro-[1,3,5]-triazine-2,4-diamine (100 mg, 0.5 mmol) in dimethylformamide (5 mL) was added dropwise. The reaction mixture was stirred at 70° C. for 16 hours, cooled to room temperature and then poured carefully into water (20 mL), acidified to pH 4 with 0.5N hydrochloric acid and extracted with ethyl acetate (3×25 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5% methanol in dichloromethane) afforded the title compound as a white solid (111 mg, 48%), Rf: 0.40 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 8.96 (1H, s, ArH), 8.55 (1H, d, J=9 Hz, ArH), 8.33 (1H, d, J=2 Hz, ArH), 7.47 (1H, dd, J=9, 2 Hz, ArH), 3.22 (2H, t, J=7 Hz, CH2), 3.18 (6H, s, 2×Me), 3.12 (6H, s, 2×Me), 2.59 (2H, t, J=7 Hz, CH2); ESI-LCMS e/z calculated for C19H21BrN6O3 461.318, found 461 [M+H (79Br)]+, 463 [M+H (81Br)]+, 483 [M+Na (79Br)]+, 485 [M+Na (81Br)]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[Cl:23])=[N:15]1)[CH2:11][C:12]#[CH:13]>>[Cl:23][C:20]1[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: C#CCCn1cc2c(Cl)cccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3c(Cl)cccc3n2)n1
Yield: 629.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (51 mg, 0.027 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mmol, Example 150(B)). Reaction time: 3 hours the crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 54 mg (0.17 mmol, 70%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:23]=[CH:22][C:8]([C:9](=[O:21])[CH2:10][N+:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:38](#[N:41])[CH:39]=[CH2:40]>CN(C)C=O>[C:38]([C:39]1[CH:40]=[C:10]([C:9](=[O:21])[C:8]2[CH:22]=[CH:23][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=12)#[N:41]
Reactant: C=CC#N
Reactant: O=C(C[n+]1cccc2ccccc21)c1ccc([N+](=O)[O-])cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared from 1-(4-nitro-phenacyl)-quinolinium bromide (119 mg, 0.319 mmol), tetrapyridinecobalt(II) dichromate (205 mg, 0.336 mmol), sodium bicarbonate (68.3 mg, 0.813 mmol), acrylonitrile (100 μL, 1.52 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 55.0 mg (50%) as a yellow solid. 1H NMR (CDCl3): 8.43 (dd, J=9.07, 2.20 Hz, 2H), 8.21 (dd, J=8.88, 2.13 Hz, 2H), 8.12 (d, J=8.52 Hz, 1H), 7.89 (dd, J=7.70, 1.64 Hz, 1H), 7.82 (d, J=9.07 Hz, 1H), 7.71 (d, J=9.06 Hz, 1H), 7.67 (ddd, J=8.17, 7.08, 1.58 Hz, 1H), 7.59 (td, J=7.49, 1.10 Hz, 1H), 7.44 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH:10]=[CH:9]2)([O-:3])=[O:2].[Li+].[OH-].Cl>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: COC(=O)Cn1ccc2cccc([N+](=O)[O-])c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1ccc2cccc([N+](=O)[O-])c21
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of methyl 2-(7-nitro-1H-indol-1-yl)acetate (0.37 g, 1.580 mmol) in THF (20 ml), LiOH 1N (3.16 ml, 3.16 mmol) was added at room temperature. The reaction was stirred at the same temperature for 16 hours. Aqueous 2N HCl was added and the solvent was partially removed under vacuum. The remaining aqueous phase was extracted with ethyl acetate; the organic phase was dried over sodium sulfate and the solvent was evaporated under vacuum affording 2-(7-nitro-1H-indol-1-yl)acetic acid (0.33 g, 1.499 mmol, 95% yield). MS/ESI+ 220.9 [MH]+. This compound was used without any additional purification.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=O)=[CH:25]2.N1CCCCC1>C(O)C>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:25]2
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 6-phenyl-2-oxindole (45 mg, 0.21 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 68 mg (76%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.[NH2:36][OH:37]>C(O)C>[OH:37][NH:36][C:14]([C:13]1[C:8]2[N:7]=[C:6]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[N:5]([CH2:4][C:3]3[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[C:9]=2[CH:10]=[CH:11][CH:12]=1)=[NH:15]
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: NO
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 87.3 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (0.60 g, 1.57 mmol) dissolved in ethanol (15 mL) and triethylamine (0.5 mL) was added hydroxylamine (0.14 g, 130 M%). After 24 h at reflux, the reaction was concentrated. The residue was redissolved in CH2Cl2 and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 4% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of N-hydroxy 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxamidine (0.57 g, 1.37 mmol, 87% yield). M.p. 214-216° C. 1H NMR (200 MHz, CD2Cl2): δ7.84 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.57 (m, 1H, H4′), 7.54 (dd, J=1.1, 8.2 Hz, 11H, H7), 7.30 (dd, J=7.7, 8.2 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.83 (m, 2H, H3″,5″), 6.61 (br, 2H, NH2), 5.39 (s, 2H, CH2PhF2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][S:20]2(=[O:26])=[O:25])[N:12]([CH3:18])[C:13](=[O:17])[C:14]=1[O:15]C)=[O:8].[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][S:20]3(=[O:25])=[O:26])[N:12]([CH3:18])[C:13](=[O:17])[C:14]=2[OH:15])=[O:8])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: COc1c(C(=O)NCc2ccc(Cl)c(Cl)c2)nc(N2CCCCS2(=O)=O)n(C)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c1=O
Yield: 75.9 %

Procedure:
Reaction of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-methoxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid 3,4-dichloro-benzylamide (0.160 g, 0.337 mmol) in 2,4,6-collidine with lithium iodide gave 0.118 g (76% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.70–1.85 and 2.06–2.15 (2×1H, 2 m, CH2), 2.3–2.4 (2H, m, CH2), 3.2–3.33 (2H, m, CH2 ), 3.64 (3H, s, NCH3), 3.7–3.85 (2H, m, CH2), 4.58 (2H, AB part of ABX system, JAB=15.5 Hz, Δν=49.6 Hz, JAX=6.6 Hz, JBX=6.1 Hz, NCH2), 7.18 (1H, broad dd, aromatic), 7.42 (1H, broad d, aromatic), 7.45 (1H, d, J=8.1 Hz, aromatic, 7.57 (1H, broad NH). HRMS (FAB POS) calculated for C17H19Cl2N4O5S [M+H+]: 461.045322. found: 461.045599.
Reaction SMILES: N1CCC[CH2:2]1.[CH2:6]([N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[CH3:25])[CH:15]([NH2:26])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[CH3:25])[CH:15]([NH:26][CH3:2])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)ccc1C1CN(Cc2ccccc2)CC1N
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1C

Procedure:
In analogy to the procedure described for the synthesis of pyrrolidine intermediate VIII-1 (step c), the title compound [(3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine was prepared from (3RS,4SR)-1-benzyl-4-(4-chloro-2-methyl-phenyl)-pyrrolidin-3-ylamine instead of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine and was obtained as a colorless oil. MS m/e: 315.1 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[NH:29][NH2:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:33]([O:32][C:28]([NH:29][NH:30][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)=[O:11])[CH2:13][CH2:14]2)=[CH:27][CH:26]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NNC(=O)OC(C)(C)C)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 420 mg (0.93 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid, 156 mg (1.18 mmol) of tert-butyl carbazate, 272 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 192 mg (1.42 mmol) of 1-hydroxybenzotriazole, and 574 mg (5.67 mmol) of N-methylmorpholine in 10 ml of dichloromethane was stirred for 3 h at room temperature. After evaporation, the mixture was diluted with AcOEt, washed with water and saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 0.46 g (quant.) of the title compound. MS (m/e): 489.4 (MH+).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)=O.[OH-].[K+]>C(O)C.O>[CH2:20]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:19])[C:8]=2[CH:7]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN(C(=O)C(F)(F)F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 2,2,2-trifluoro-N-pentyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (31) (13.6 g, 37.5 mmole) in 140 mL ethanol was treated with a solution of potassium hydroxide (10.52 g) in 25 mL water. The mixture was stirred at room temperature for two hours, diluted with 100 mL water and then extracted with two 250 mL portions of ethyl acetate. The combined organic extracts were washed with six 200 mL portions of cold water or until the pH was neutral. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes) to yield 9.86 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (33) as a golden oil.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]1([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][CH:17]=[N:16]4)[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH3:3][O:5][C:6]1([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][CH:17]=[N:16]4)[N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: OC1(c2ccc3ccc4cccnc4c3n2)CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC1(c2ccc3ccc4cccnc4c3n2)CCCCC1
Yield: 89.5 %

Procedure:
Through use of General Procedure II, NaH (0.110 g 4.6 mmol), methyl iodide (0.65 mL, 4.6 mmol), and 2-[(1-hydroxycyclohexyl)]-1,10-phenanthroline (0.320 g, 1.15 mmol), prepared as described by Example 1, were reacted to provide 0.301 g (90% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.24 (dd, J=4.50, 1.80 Hz, Hp9), 8.25 (d, J=8.40 Hz, Hp4, dd, J=8.10, 2.40 Hz, Hp7), 7.96 (d, J=8.40 Hz, Hp3), 7.82 and 7.75 (two d, J=8.80 Hz, Hp5 and Hp6), 7.61 (dd, J=8.10, 4.50 Hz, Hp8), 3.11 (s, 3H, OCH3), 2.23 (m, 4H, cyclohexyl H), 1.74 (m, 6H, cyclohexyl H); 13C NMR (75 MHz) δ166.33, 150.49, 146.33, 145.11, 136.40, 136.04, 128.77, 127.41, 126.38, 126.03, 122.40, 120.45, 80.46, 50.45, 33.83, 25.08, 21.69; IR (CHCl3) 3048 (C—H Ar), 2933 ((CH), 908 (C—H Ar), cm−1; HRMS m/e Calcd for C19H21N2O (MH+): 293.1654, found: 293.1665.
Reaction SMILES: C([O:5][C:6]([CH:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9](OCC)=O)=O)(C)(C)C.CC(C)([O-])C.[Na+].ClC(F)[F:31].O.[Cl-].[Na+].O>O1CCCC1>[F:31]/[CH:9]=[C:8](\[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)/[CH2:6][OH:5]
Reactant: FC(F)Cl
Reactant: CCOC(=O)C(CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC/C(=C/F)CCc1ccc(F)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Combine ethyl 2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate (32.14 g) and sodium t-butoxide (19.81 g) in tetrahydrofuran (400 mL). Stir the mixture for 1 hour, then heat to 45° C. Add an excess of chlorodifluoromethane over about 15 minutes. After 1 hour under an atmosphere of chlorodifluoromethane, allow the temperature to fall to ambient. Pour the reaction mixture into water/brine. Extract with diethyl ether. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:7](=[O:14])[C:6]=12.C(N=C=NCCCN(C)C)C.O/[N:40]=[C:41](\[NH2:48])/[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11]3[O:13][N:48]=[C:41]([C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)[N:40]=3)[NH:8][C:7](=[O:14])[C:6]=12
Reactant: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(C(=O)O)[nH]c(=O)c12
Reactant: N/C(=N\O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(-c3nc(-c4cccnc4)no3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A solution of Example 12b (200 μL, 0.0275 g, 0.076 mmol) in N,N-dimethylformamide/pyridine (1:1 v/v), a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (200 μL, 0.0225 g, 0.145 mmol) in N,N-dimethylformamide/pyridine (1:1 v/v), and a solution of (Z)—N′-hydroxynicotinimidamide (173.0 μL, 0.103 mmol) in 1 mL of N,N-dimethylformamide/pyridine (1:1 v/v) were combined and shaken at ambient temperature overnight. Upon completion, the reaction mixture was concentrated to dryness. The residue was purified by reverse phase HPLC (C8, acetonitrile/water (0.1% ammonium acetate), 45-75%) to give 0.0031 g (9%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 9.24 (dd, J=2.14, 0.61 Hz, 1H), 8.81 (dd, J=4.88, 1.83 Hz, 1 H), 8.45 (ddd, J=8.09, 1.83, 1.68 Hz, 1 H), 7.67 (m, 1 H), 7.64 (dd, J=7.63, 1.83 Hz, 1 H), 7.59 (s, 1 H), 7.44 (m, 1 H), 7.34 (m, 3 H), 7.07 (m, 2 H), 6.95 (m, 2 H), 2.66 (s, 3 H). MS (ESI+) m/z 562.0 (M+H)+.