Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18](C(NCCCCCCCCCCC)=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].FC(F)(F)C(O)=[O:44]>ClCCl>[NH2:1][C@H:2]([C:18]([OH:19])=[O:44])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCCCCNC(=O)C(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O

Procedure:
The 7,2 g of 1j were dissolved in 30 ml of dichloromethane and 15 ml of trifluoroacetic acid were added. The Boc group was immediately removed. After concentration, adding of ether and washing with NaHCO3, the organic phase was dried and concentrated. The Lys(Z) [C(O)NH(CH2)10CH3 ][NH2 ] formed was allowed to reactwith C8F17CH2CH2CO2H (7,6 g, 1,34.10-2 mole); 2.7 g of DCC (1.34.10-2 mole) and 100 mg of HOBT. The peptidiccoupling was carried out in dimethylformamide (DMF). After 24 h the DCU wasfiltered and the product was crystallized.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH2:23])=[O:22]>>[C:9]1([C@H:20]2[C@H:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[F:13])[C:21](=[O:22])[NH:23][C:21]2=[O:22])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccccc1F
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1F

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2-fluorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2-fluorophenylacetamide. Yield 30.6 mg, 8.8%. 1H NMR (DMSO-d6) 400 MHz δ: 11.64 (s, 1H), 7.36 (m, 3H), 7.17 (m, 3H), 6.84 (m, 2H), 4.44 (d, 1H, J=7.2 Hz), 4.40 (d, 1H, J=7.6 Hz), 4.10 (s, 2H), 2.88 (s, 2H), 2.09 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH2:1][Br:25])=[CH:17][CH:16]=2)=[O:7])=[CH:9][CH:10]=1)#[N:13]
Reactant: Cc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Heat a mixture of 4-(4-methyl-benzoyl)-benzonitrile (300 mg, 1.356 mmol), NBS (386 mg, 2.169 mmol), and AIBN (22 mg, 0.136 mmol) in carbon tetrachloride (10 mL) for 14 h at reflux. Add additional NBS (121 mg) and AIBN (11 mg) and reflux the mixture for 3 h. Cool the reaction mixture to ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to provide the title compound as a solid (286 mg, 70%). GC-MS m/z: 300 (M+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2O.C(N(CC)CC)C.C(Cl)[Cl:25]>P(Cl)(Cl)(Cl)=O>[Cl:25][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: Oc1ncnc2ccc(OC(F)(F)F)cc12
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Preparation D4, Step 5: A suspension of 6-(trifluoromethoxy)quinazolin-4-ol (515 mg, 2.23 mmol) in phosphorous oxychloride (1.9 mL) was treated with triethylamine (3 mL, 21.1 mmol), and the mixture was heated at reflux for 2 h. The resulting solution was cooled to room temperature, and stripped 3× from methylene chloride to remove residual phosphorous oxychloride. The residue was dissolved in 100 mL methylene chloride, 100 mL saturated sodium bicarbonate was carefully added, causing vigorous gas evolution, and the mixture was stirred for 10 min, until gas evolution had ceased. The layers were separated, and the organic phase was washed with saturated sodium bicarbonate (2×30 mL), followed by brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 40% EtOAc/heptane, to yield 377 mg of 4-chloro-6-(trifluoromethoxy)quinazoline as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 1H), 8.16 (d, J=9.23 Hz, 1H), 8.10 (s, 1H), 7.83 (dd, J=9.23, 2.20 Hz, 1H). MS (ES+)=249 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11]C)[C:6]#[N:7].[Cl-].[NH4+].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[NH:20][N:19]=[N:18][N:7]=2)[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11]
Reactant: COc1cc(C#N)cc([N+](=O)[O-])c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnn[nH]2)cc([N+](=O)[O-])c1O
Reaction time: 31 h

Procedure:
4.0 g of 3,4-dimethoxy-5-nitro-benzonitrile are dissolved in 50 ml of dimethylformamide, whereupon the solution is treated with 1.66 g of ammonium chloride and 2.02 g of sodium azide and stirred at 125° for 31 hours. After in each case 8 and 15 hours the same amounts of ammonium chloride and sodium azide are added thereto. After cooling the mixture is poured on to ice. The separated precipitate is filtered under suction, washed with water and dried. There is obtained 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol in the form of orange crystals of m.p.>240° (dec.).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])(C)(C)C.Cl.[C:20]([O:24][C:25]([NH:27][C:28]1[CH:29]=[C:30](C(O)=O)[N:31]([CH3:33])[CH:32]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(Cl)CCl.CCN(C(C)C)C(C)C>C(O)C.C1(C)C=CC=CC=1.CC(N(C)C)=O>[C:20]([O:24][C:25]([NH:27][C:28]1[CH:29]=[C:30]([C:6]([NH:8][C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[N:12]([CH3:14])[CH:13]=2)=[O:7])[N:31]([CH3:33])[CH:32]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1nc(NC(=O)OC(C)(C)C)cn1C
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(NC(=O)c2cc(NC(=O)OC(C)(C)C)cn2C)cn1C
Reaction time: 0.75 h
Yield: 73.5 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-imidazole-2-carboxylate (2.50 g, 9.80 mmol) in 30 ml of EtAc was added 6 ml of HCl (conc.). After stirring for 45 min, the mixture was diluted with ethanol and toluene, concentrated and co-evaporated with ethanol/toluene (1:1, 3×50 ml) to dryness without further purification. To the dry compound was added 4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxylic acid (2.35 g, 9.8 mmol), EDC (5.60 g, 29.1 mmol), DIPEA (1.70 ml, 9.8 mmol) and 80 ml of DMA. The mixture was stirred under Ar overnight, concentrated, diluted with THF/EtAc (1:2, 150 ml), and washed 1M NaH2PO4/NaCl (conc) and NaHCO3 (conc) separately. The organic solvent layer was separated and dried over MgSO4, filtered, concentrated and purified on SiO2 chromatography eluted with EtAc/DCM (1:25 to 1:15) to afford 2.72 g (73%) of the title product. 1H NMR (DMF-d7) 10.27 (s, 1H), 9.08 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.07 (s, 1H), 4.10 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.47 (s, 9H); 13C NMR 162.62, 161.20, 153.82, 145.32, 144.12, 132.56, 128.46, 124.39, 119.83, 79.51, 52.75, 36.06, 35.83, 28.88; MS m/z+ 400.2 (M+Na).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13]([O-])=[O:14]>>[Cl:8][C:5]1[S:4][C:3]2=[N:2][C:11]([CH2:10][Cl:9])=[CH:12][C:13](=[O:14])[N:7]2[CH:6]=1
Reactant: O=C([O-])CC(=O)CCl
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Product: O=c1cc(CCl)nc2sc(Cl)cn12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-amino-5-chloro-thiazole hydrochloride (8 g) was reacted with 4-chloroacetoacetate (15.8 g) in polyphosphoric acid (40 g) under stirring at 110° C. for 1 hour. After cooling, dilution with water and neutralization with 35% NaOH, the precipitate was filtered and washed with water. Crystallization from isopropyl ether gave 2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 123°-125° C. (7.45 g), which was reacted with triphenylphosphine (9.42 g) in acetonitrile (100 ml) under stirring at reflux temperature for 10 hours. After cooling the precipitate was filtered and washed with acetonitrile to give (2-chloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphonium chloride, m.p. 300°-310° C. dec. (10 g) which was suspended in dimethylsulfoxide (40 ml) and treated with potassium tert-butoxide (2.48 g) dissolved in dimethylsulfoxide (40 ml) at room temperature under stirring for 10 minutes. To the solution of the ylide so obtained 5 -formyl-2-methyl-thiazole (3.1 g) dissolved in dimethylsulfoxide (20 ml) was added and the reaction mixture was kept under stirring at room temperature for 15 minutes: after dilution with ice water and neutralization with NaH2PO4 the precipitate was filtered and crystallized from CH2Cl2 -methanol to give 3.4 g of 2-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 224°-226° C., NMR (CDCl3) δ ppm: 2.97 (s) (3H, --CH3), 6.61 (s) (1H, C-6 proton), 6.78 (d) (1H, β-ethenyl proton), 7.82 (d) (1H, α-ethenyl proton), 7.88 (s) (1H, C-3 proton), 8.02 (s) (1H, C-4 thiazolyl proton); JHαHβ =16 Hz.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH2:7][CH:8]([OH:13])[CH2:9][N:10]=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH2:7][CH:8]([OH:13])[CH2:9][NH2:10]
Reactant: CN(C)c1cccc(OCC(O)CN=[N+]=[N-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(OCC(O)CN)c1
Yield: 83.9 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 2.41 g of 3-(3-dimethylaminophenoxy)-2-hydroxypropylazide (prepared as described in Preparation 80), 0.76 g of lithium aluminum hydride and 50 ml of anhydrous tetrahydrofuran were used, to give 1.80 g of the title compound having an Rf value of 0.9 (on silica gel thin layer chromatography, using a 4:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=O)=[O:4].Cl.[NH2:32][NH2:33]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[NH:32][N:33]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CC1
Reactant: NN
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)n[nH]1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-thiopropionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 398a) was reacted with hydrazine hydrochloride (CAS Reg. No. 2644-70-4) to give the title compound as brown oil.
Reaction SMILES: C(OC1C=CC(COC(N2CCNCC2)=O)=CC=1)C1C=CC=CC=1.[F:25][C:26]1[CH:66]=[CH:65][C:29]([CH2:30][O:31][C:32]2[CH:64]=[CH:63][C:35]([CH2:36][O:37][C:38]([N:40]3[CH2:45][CH2:44][N:43](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:42][CH2:41]3)=[O:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.N1CCOCC1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][O:31][C:32]2[CH:64]=[CH:63][C:35]([CH2:36][O:37][C:38]([N:40]3[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]3)=[O:39])=[CH:34][CH:33]=2)=[CH:65][CH:66]=1
Reactant: O=C(OCc1ccc(OCc2ccc(F)cc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCNCC1
Solvent: C1COCCN1
Product: O=C(OCc1ccc(OCc2ccc(F)cc2)cc1)N1CCNCC1

Procedure:
Prepared in analogy to piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester (Example 41) from piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester and morpholine: colourless, waxy solid: IR (Nujol): 3341 cm−1, 1689 cm−1. 1H-NMR (CDCl3): 1.75 br, 1H; 2.85–2.90 m, 4H and 3.40–3.55 m, 4H; 5.02 s, 2H; 5.07 s, 2H; 6.94 d, J=8.4 Hz, 2H, 7.07 t, J=8.8 Hz, 2H, 7.30 d, J=8.4 Hz, 2H and 7.38–7.42 m, 2H. MS (EI): 344.3 M+.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH:16]=[C:10]3[C:9]2=[O:25])=CC=1.O=C1NCCN2N=C(COC(=O)C)C=C12>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][C:15]1[CH:16]=[C:10]2[C:9](=[O:25])[NH:8][CH2:13][CH2:12][N:11]2[N:14]=1
Reactant: COc1ccc(CN2CCn3nc(COc4ccccn4)cc3C2=O)cc1
Agent: CC(=O)OCc1cc2n(n1)CCNC2=O
Product: O=C1NCCn2nc(COc3ccccn3)cc21

Procedure:
The compound was prepared from 5-(4-methoxy-benzyl)-2-(pyridin-2-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one using the method described in the preceding example 58 (acetic acid 4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylmethyl ester).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9]Cl)=[C:4]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([F:20])[CH:16]=[CH:15][CH:14]=3)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([F:20])[C:18]=4[CH:19]=[C:11]3[C:4]=2[CH:3]=1
Reactant: Fc1cccc2[nH]c(-c3cc(Cl)nnc3CCCl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccc2c1cc1n2CCc2nnc(Cl)cc2-1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a suspension of 2-(6-chloro-3-(2-chloroethyl)pyridazin-4-yl)-4-fluoro-1H-indole (60 mg, 0.17 mmol) in DMF (1 mL) was added Cs2CO3 (124 mg, 0.34 mmol), and then the mixture was stirred for 20 minutes at 60° C. After being concentrated in vacuo, the resulting residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O and dried over Na2SO4. After concentration, the residue was purified by prep-TLC (DCM) to give the product of 2-chloro-11-fluoro-5,6-dihydropyridazino[4′,3′:3,4]pyrido[1,2-a]indole (40 mg, yield: 75%). 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 7.63 (s, 1H), 7.47 (d, J=8.22 Hz, 1H), 7.24˜7.33 (m, 1H), 6.87˜6.97 (m, 1H), 4.52 (t, J=6.4 Hz, 2H), 3.53 (t, J=6.4 Hz, 2H). MS (M+H)+: 274/276.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Br:12]N1C(=O)CCC1=O.Br>COC(C)(C)C.C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cccs2)nc1
Agent: Br
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Brc1ccc(-c2ccccn2)s1
Temperature: 35 °C
Yield: 81.7 %

Procedure:
A solution of 2-thienylpyridine (1.924 kg) and N-bromosuccinimide (2.759 kg) in tert-butyl methyl ether (20.0 kg) was agitated for 15 minutes, treated with 30% HBr in acetic acid (125 g), heated to 35° C. for about 6 hours, and filtered. The wetcake was washed with tert-butyl methyl ether (12.6 kg) while maintaining the temperature of the filtrate at 30° C. to 35° C. The filtrate was washed with 5% Na2SO3 (21 kg) and 10% Na2CO3 (22 kg), concentrated to about 20 L, and diluted with isopropanol (11 kg), which caused the product to crystallize. This procedure was repeated twice more, when NMR analysis of the mother liquor indicated absence of tert-butyl methyl ether. The suspension was concentrated to about 12 L, cooled to 0° C., and filtered. The wetcake was washed with chilled (0° C.) isopropanol (7 kg) and dried in a vacuum oven with a nitrogen purge at 60° C. to provide 2.34 kg (82%) of the desired product. MS m/z 241 (M+H)+; 1H NMR δ 8.53 (m, 1H), 7.68 (m, 1H), 7.57 (m, 1H), 7.30 (m, 1H), 7.15 (m, 1H), 7.06 (m, 1H); Anal. calcd for C9H6BrNS: C, 45.01; H, 2.50; N, 5.83. Found: C, 45.14; H, 2.45; N, 5.72.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][C@@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[CH:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1>>[C:1]([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([NH:17][C@@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[CH:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Yield: 37 %

Procedure:
By using 2-acetamido-4-nitrobenzoic acid (800 mg, 3.57 mmol) and 3α-aminocholestane (1.4 g, 3.61 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (784 mg, yield; 37.0%).
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53][CH2:52][CH2:51]C[CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.ICC1CCCC1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:49][CH2:51][CH2:52][CH2:53]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: ICC1CCCC1
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and iodomethyl-cyclopentane (CAS Reg. No. 27935-87-1). Brown sticky solid (50%). MS (Turbo Spray): m/z=377.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:29](=[O:31])[CH3:30])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Nc2ccncc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
4-tert-Butyl-N-[4-chloro-2-(pyridin-4-ylamino)-phenyl]-benzenesulfonamide (103 mg, 0.25 mmol) dissolved in DCM (5 mL) was treated with acetic anhydride (26 mg, 0.25 mmol) and triethylamine (51 mg, 0.5 mmol), and the reaction mixture was allowed to stir overnight. The volatiles were evaporated and the product was purified by HPLC to afford the title compound. MS: (M+H)/z=458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH:37]([CH2:39][CH3:40])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH:37]([CH2:39][CH3:40])[CH3:38])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CCC(C)Br
Product: CCC(C)Oc1ccc(OC)c2c1C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 2-bromo-butane
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6](=[O:13])[CH2:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:4].Cl[CH:15](OCC)[CH2:16]Cl>O.C(OCC)C>[CH2:3]([O:5][C:6]([C:7]1[CH:16]=[CH:15][O:12][C:8]=1[CH:9]([CH3:10])[CH3:11])=[O:13])[CH3:4]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CCOC(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccoc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[N:22][C:23]([O:26]C)=[CH:24][CH:25]=3)[CH:15]=2)[N:10]=[CH:9]1.I[CH3:33]>C(#N)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:33])[CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: CI
Reactant: COc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Solvent: CC#N
Product: Cn1cc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)ccc1=O
Temperature: 90 °C

Procedure:
To a solution of rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one (0.025 g, 0.060 mmol) in 1 mL of acetonitrile in a screw capped vial was added iodomethane (0.031 g, 0.22 mmol). The vessel was sealed and heated at 90° C. for 48 h, cooled to rt, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.07-9.05 (m, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.94-7.92 (m, 1H), 7.75-7.72 (m, 2H), 7.45 (d, J=2.5 Hz, 1H), 7.02 (s, 1H), 6.77 (d, J=9.3 Hz, 1H), 4.68 (br s, 1H), 4.27 (s, 2H), 4.01 (br s, 1H), 3.50 (s, 3H), 2.28-1.88 (m, 5H), 1.59-1.44 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[F:12][C:2]([F:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)=[O:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(F)(F)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(F)(F)c3ccccc3)CC2)c1

Procedure:
Example 125 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.71 (s, 1H), 7.65–7.62 (m, 2H), 7.50 (s, 1H), 7.47–7.40 (m, 3H), 7.35 (d, 1H, J=7.6 Hz), 7.22 (t, 1H, J=7.2 Hz), 6.95 (d, 1H, J=7.8 Hz), 3.45 (q, 2H, J=5.3 Hz), 3.10 (d, 2H, J=10.9 Hz), 2.59–2.45 (m, 4H), 2.11–2.02 (m, 2H), 1.89–1.71 (m, 6H), 1.20 (d, 6H, J=6.9 Hz); ESMS m/e: 458.4 (M+H)+.