Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:59]([CH3:61])[CH3:60].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:59]([CH3:61])[CH3:60])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (69 mg in 3 ml 33% methylene chloride in cyclohexane), isopropyl trichloroacetimidate (22 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (12 mg).
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10].N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[CH3:7][C:8]([CH3:12])([CH3:11])[CH2:9][CH2:10][S:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5]
Reactant: C=CC(C)(C)C
Reactant: OCC(O)CS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: CC(C)(C)CCSCC(O)CO
Reaction time: 20 h

Procedure:
A mixture of 3-mercapto-1,2-propanediol (10.8 g), 3,3-dimethyl-1-butene (9.6 g) and 2,2'-azobis(2-methylpropionitrile) (0.5 g) is heated under reflux with vigorous stirring for 20 hours, then is diluted with hexane, extracted with water and stripped to give 3-(3,3-dimethylbutylthio)-1,2propanediol.
Reaction SMILES: C1(O)[C:13]2[C:12]3[C:8](=[CH:9][NH:10][CH:11]=3)[CH:7]=[CH:6][C:5]=2NCN1.[ClH:15].[CH2:16]([OH:18])[CH3:17]>>[ClH:15].[Cl:15][C:5]1[CH:6]=[CH:7][C:17]([C:16]2([OH:18])[C:13]3[C:12](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:11]3=[N:10][CH2:9][CH2:8][CH2:9][N:10]23)=[CH:12][CH:13]=1
Reactant: CCO
Reactant: OC1NCNc2ccc3c[nH]cc3c21
Agent: Cl
Product: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCCN21

Procedure:
The above prepared tetrahydropyrimidoisoindolol is dissolved in ethanol and admixed with an aqueous solution containing an equivalent amount of hydrochloric acid. The mixture is stirred for ten minutes and the solvent removed by evaporation. In this manner, is obtained 6-(4-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol hydrochloride, m.p. 232°-4°C., as a white crystalline solid, which is soluble in hot water.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C=CC(S(O[CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:33][C@H:34]4[CH2:38][CH2:37][CH2:36][O:35]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 5-fluoro-6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (42%) as a colorless solid: mp 106-116° C.; 1H NMR (300 MHz, CDCl3) δ7.28 (dd, J=7.6, 7.6 Hz, 1H), 7.14-6.98 (m, 3H), 6.58 (d, J=6.8 Hz, 1H), 6.49-6.40 (m, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.31-4.19 (m, 1H), 3.98-3.64 (m, 7H), 2.09-1.80 (m, 3H), 1.76-1.61 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.7, 177.5, 157.1, 149.3, 149.1, 148.9, 146.1, 142.8, 131.9, 131.7, 129.0, 128.9, 123.7, 123.6, 123.3, 119.3, 119.2, 110.6, 110.5, 110.3, 110.2, 109.8, 109.6, 96.3, 80.6, 76.7, 68.2, 68.1, 58.0, 56.4, 44.6, 29.2, 29.0, 25.7, 25.5; MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: [NH:1]([C:3]1[C:4]([O:11][CH3:12])=[N:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)[NH2:2].[F:13][C:14]([F:26])([F:25])[C:15](=O)[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:10][O:9][C:6]1[N:5]=[C:4]([O:11][CH3:12])[C:3]([N:1]2[C:15]([C:14]([F:13])([F:25])[F:26])=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:2]2)=[CH:8][N:7]=1
Reactant: COc1ncc(NN)c(OC)n1
Reactant: CCOC(=O)C(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)c1cc(C(F)(F)F)n(-c2cnc(OC)nc2OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using 5-hydrazinyl-2,4-dimethoxypyrimidine (Step 46.8) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (hexane/30% EtOAc). tR: 1.09 min (LC-MS 2); ESI-MS: 347 [M+H]+ (LC-MS 2); Rf=0.31 (hexane/30% EtOAc).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH2:21][C:22]1[N:26](C(OC(C)(C)C)=O)[N:25]=[C:24]([CH2:34][CH2:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:21][C:22]4[CH:23]=[C:24]([CH2:34][CH2:35][C:36]5[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[CH:37]=5)[NH:25][N:26]=4)=[O:16])=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CC3)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C5CC5)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 12 %

Procedure:
4-(4-cyclopropylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate (193 mg, 0.7 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292 mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (acidic) using a 16-36% gradient of acetonitrile in water containing 0.1% TFA. The clean fractions were neutralised and evaporated to afford the title compound as a white solid (40 mg, 12%); 1H NMR (500.13 MHz, DMSO-d6+d4 Acetic Acid) δ 0.46 (2H, d), 0.50 (2H, d), 1.79-1.84 (1H, m), 2.78 (4H, t), 2.90 (4H, s), 3.24-3.31 (4H, m), 3.75 (6H, s), 6.32 (1H, s), 6.33 (1H, t), 6.42 (2H, d), 6.94-6.96 (2H, m), 7.86-7.88 (2H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl-].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[CH2:13][NH3+:14])([O-:9])=[O:8].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C[NH3+])cc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.4 ml (0.244 mol) of methanesulfonyl chloride are metered over 30 minutes with ice-cooling to a solution of 30.1 g (0.122 mol) of 3-nitro-4-methoxycarbonyl-benzylammonium chloride and 34 ml (0.244 mol) of triethylamine in 300 ml of dichloromethane, and stirring of the mixture is continued for one hour. For work-up, the reaction mixture is treated with ice water, the phases are separated, and the aqueous phase is reextracted twice more with dichloromethane. After drying (Na2SO4), filtration and concentration, 31.3 g (89%) of methyl 4-methanesulfonylaminomethyl-2-nitrobenzoate remain as a syrupy oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[CH2:10][O:9][CH:8]([CH2:11]Br)[O:7][C:6]=2[CH:13]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17]>CCO>[Br:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:18][CH2:15][CH2:16][CH3:17])[O:7][C:6]=2[CH:13]=1
Reactant: Fc1cc2c(cc1Br)OC(CBr)OC2
Reactant: CCCN
Solvent: CCO
Product: CCCNCC1OCc2cc(F)c(Br)cc2O1
Yield: 41.1 %

Procedure:
Preparation according to Example 3. 7-bromo-2-(bromomethyl)-6-fluoro-4H-1,3-benzodioxine (0.60 g, 1.84 mmol), propan-1-amine (1.0 ml, 12.2 mmol) and EtOH (3.0 ml) was Heated at 130° C. for 40 min. Twice purification by flash column chroma-tography (EtOAc) gave the pure title compound (0.23 g, 41%). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 182° C. MS m/z (rel. intensity, 70 eV) 305 (M+, 3), 303 (M+, 3), 205 (8), 203 (8), 96 (6), 95 (10), 72 (bp).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1)(=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C(C)C)cc1)N2
Yield: 68 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol,) in dichloromethane (5 mL) was added isobutyryl chloride (0.04 mL, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 61 mg, yield: 68%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][NH:28]1>>[O:32]=[S:27]1(=[O:33])[CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 92.6 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.24 g) described in Preparation Example 246 and isothiazolidine 1,1-dioxide (0.47 g) and by the reaction and treatment in the same manner as in Example 262, the title compound (1.26 g) was obtained.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[N:5]1)(C)C.I[CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH2:34]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[N:5]1)[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)n1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CC(C)CI
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Iodo-2-methyl-propane provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (m, 2H), 8.18 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.73 (t, J=6.6 Hz, 1H), 7.54 (s, 1H), 7.52 (m, 1H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (m, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H) 3.93 (d, J=7.5 Hz, 2H), 4.29 (m, 1H), 0.95 (d, J=6.6 Hz, 6H); MS: (M+H m/z=435.2).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][S:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.O>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)[S:11](/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)(=[O:13])=[O:12]
Reactant: Clc1cccc(CBr)c1
Reactant: O=S(=O)(/C=C/c1cccc(Cl)c1)Nc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(/C=C/c1cccc(Cl)c1)N(Cc1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a well-stirred suspension of NaH (23.2 mg, 0.92 mmol, 5.6 eq.) in 4 mL of THF, a THF solution (1.5 mL) of compound 2 (53.9 mg, 0.16 mmol, 1 eq.) was added and the mixture was stirred for 1 hour at room temperature. Afterwards, the reaction mixture was cooled at 0° C. and a THF solution (1.5 mL) of 3-chlorobenzylbromide (52.2 mg, 0.25 mmol, 1.5 eq.) was added. After the reaction mixture was stirred at room temperature for 22 h, water was added and the product was extracted three times from the aqueous phase with EtOAc. The resulting organic phase was washed with brine, dried under Na2SO4 and the solvent evaporated. After the product was purified from the crude by flash column chromatography (15% EtOAc/hexanes), compound ef-rs-03-075 (26.1 mg, 0.06 mmol) was obtained in a 35% yield. 1H NMR (400 MHz, CDCl3) δ 7.46 (s, ArH, 1H), 7.42 (dt, J=7.6, 1.7 Hz, ArH, 1H), 7.36 (m, ArH, 3H), 7.23 (m, ArH, 6H), 7.14 (m, ArH, 2H), 6.78 (d, J=15.4 Hz, C═CH, 1H), 4.76 (s, CH2, 2H). 13C NMR (100 MHz, CDCl3, δ): 141.55 (CH), 140.00 (C), 137.62 (C), 135.26 (C), 134.81 (C), 134.51 (C), 134.14 (C), 131.04 (CH), 130.45 (CH), 130.24 (CH), 129.92 (CH), 128.91 (CH), 128.56 (CH), 128.49 (CH), 128.27 (CH), 127.97 (CH), 127.03 (CH), 126.59 (CH), 126.55 (CH), 124.48 (CH), 54.36 (CH2).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:17]([N:11]1[CH:10]=[CH:9][C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Yield: 67.2 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), β-alanine (956 mg, 10.7 mmol) and NaOMe solution (16 mL, 8.06 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and then extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 20 mg of the title compound. MS: (+) m/z 368.00 (M+1).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]C[O:11][CH2:10]1)C1C=CC=CC=1.N[CH2:48]C1(N(CC2C=CC=CC=2)CC2C=CC=CC=2)COC1>>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH:33]([CH3:48])[C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13][O:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3C)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-6-methylquinoline) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (dd, J=7.96, 1.39 Hz, 1 H), 7.90 (d, J=6.57 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.46 (ddd, J=8.15, 6.63, 1.64 Hz, 2 H), 7.33 (dd, J=8.59, 1.77 Hz, 1 H), 6.15 (s, 1 H), 5.86 (d, J=6.82 Hz, 1 H), 4.64-4.53 (m, 4 H), 4.40-4.25 (brs, 2 H), 3.70 (d, J=8.59 Hz, 1 H), 3.62-3.58 (m, 2 H), 3.57-3.49 (m, 1 H), 2.43 (s, 3 H), 2.00 (d, J=7.07 Hz, 3 H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]2[C:12]3[C:17]([CH2:18][CH:4]2[CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:29](OCC)=[O:30].O>O1CCCC1>[OH:30]/[CH:29]=[C:3]1\[CH:4]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:5]2[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]\1=[O:1]
Reactant: CCOC=O
Reactant: CCOC(=O)N1C(=O)CC2Cc3ccccc3C21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1C(=O)/C(=C/O)C2Cc3ccccc3C21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Ethyl 2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (200 mg, 0.81 mmol) was dissolved in tetrahydrofuran (8 mL) was cooled to −78° C. Then, lithium bis(trimethylsilyl)amide (1 mol/L in THF, 1.22 mL, 1.22 mmol) was added. After 1 h at −78° C., ethyl formate (0.198 mL, 2.446 mmol) was added. The mixture was stirred for another 30 min and then allowed to warm to room temperature. After another 30 min, water was added. The mixture was extracted with diethylether, the pH of the aqueous layer was adjusted to 1 and the solution was extracted with EtOAc (2*20 mL), dried (Na2SO4) and concentrated to give a colourless oil ethyl (3E)-3-(hydroxymethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D12 (120 mg, 54%) which was used without further purification in the next step. LCMS (Method A): RT: 1.53 min; ES− 272 [M−H]
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]([O:19][CH2:20][C:21]([O:23]C)=[O:22])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[K+].[Br-]>>[CH2:1]([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(-c2ccccc2)c(OCC(=O)OC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [K+]
Product: CCCCCCc1cc(-c2ccccc2)c(OCC(=O)O)c(-c2ccccc2)c1

Procedure:
The title compound was prepared as a white solid (0.559 g, 67%) from (5′-Hexyl-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid, methyl ester (0.870 g, 2.161 mmol) using a procedure similar to step 4 of example 165; mp 87-89° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.82-0.86 (m, 3H), 1.22-1.37 (m, 6H), 1.56-1.64 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 3.71 (s, 2H), 7.16 (s, 2H), 7.32-7.37 (m, 2H), 7.39-7.44 (m, 4H), 7.59 (m, 4H), 12.47 (broad s, 1H); IR (KBr) 3450, 2920, 1725, 1420, 1210 cm−1; mass spectrum [EI], m/z 388 M+; Anal. Calcd. for C26H28O3: C, 80.38; H, 7.26; N, 0.00, Found: C, 79.99; H, 7.24; N, 0.13.
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][NH:4]N=1.C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[H-].[Na+].C(#N)CC>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9](=[O:8])[CH:6]([CH3:2])[C:5]#[N:4])=[CH:11][CH:12]=1
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCC#N
Product: COc1ccc(C(=O)C(C)C#N)cc1
Yield: 62 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 4-methoxy-benzoic acid methyl ester (3.0 mL, 18.0 mmol, 1.0 eq), NaH (1.4 g, 36.0 mmol, 2.0 eq) and propionitrile (6.1 mL, 84.9 mmol, 4.7 eq). The crude was purified through Si-column (eluent exane/ethyl acetate) to give 2.1 g of title product (yield: 62%).
Reaction SMILES: BrC[CH2:3][O:4][CH3:5].[CH:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH3:3][O:4][CH2:5][C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COCCBr
Reactant: COC(=O)C1CCCCC1
Product: COCC1(C(=O)OC)CCCCC1

Procedure:
The title compound was prepared by substituting bromomethylmethyl ether for 1-bromo-2-methoxyethane and methyl cyclohexanecarboxylate for EXAMPLE 134A in EXAMPLE 134B.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([CH3:37])([CH3:36])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[N:25][N:26]=4)=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[O:23][C:22]([C:20]3[CH:19]=[CH:18][C:16]4[NH:17][C:13]([C:9]5[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][C:4]([CH3:36])([CH3:37])[C:3]([OH:38])=[O:2])=[CH:11][C:10]=5[CH3:12])=[N:14][C:15]=4[CH:21]=3)=[N:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3cc(-c4nnc(-c5ccc(OC)cc5)o4)ccc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2nnc(-c3ccc4[nH]c(-c5c(C)cc(CC(C)(C)C(=O)O)cc5C)nc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(4-{5-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid methyl ester (340 mg, 0.667 mmol) and aqueous 1M NaOH (5 mL, 5 mmol) in MeOH (5 mL) was stirred at room temperature for 18 h and then heated at 50° C. for 1 h. After the mixture was cooled to room temperature, the mixture was slowly acidified to pH 2˜3 by addition of 3M HCl. The product precipitated and was separated from the solution. The solid was dissolved in a small quantity of DMSO and purified by HPLC (basic) to give the title compound as a solid. 1H NMR (CD3OD, 400 MHz) δ ppm 8.55-8.45 (m, 1 H), 8.23 (d, J=8 Hz, 2 H), 8.22 (d, J=8 Hz, 1 H), 7.95-7.85 (m, 1 H), 7.26 (d, J=8 Hz, 2 H), 7.15 (s, 2 H), 4.02 (s, 3 H), 2.99 (s, 2 H), 2.26 (s, 6 H), 1.30 (s, 6 H). m/z 497.2 (MH+).