Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:8](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH2:7][CH2:6]2.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:24][C:23](=[O:25])/[CH:22]=[CH:21]/[C:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: COc1ccc(C2=C(/C=C/C(=O)O)CCc3cc(OC)ccc32)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C2=C(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)CCc3cc(OC)ccc32)cc1
Yield: 43.3 %

Procedure:
As in Example 113, (E)-3-[3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid (1.7 g) was reacted with 4-nitrophenol (0.775 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (1.04 g) overnight at room temperature. After the normal work up, the crude ester was triturated with diethyl ether and then crystallized from 2-propanol to give 1 g of (E)-3-[3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester as a yellow solid, mp 151°-152° C. Anal. Calcd for C27H23NO6 : C, 70.89; H, 5.07; N, 3.06 Found: C, 70.52; H, 5.10; N, 3.08
Reaction SMILES: C([NH:4][C:5]1[C:24]([Br:25])=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH2:14][CH2:15][N:16]([CH3:22])[CH2:17]3)=[O:10])=[C:7]([O:26][CH3:27])[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C.O>[CH3:22][N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[CH:21][C:12]=2[NH:11][C:9](=[O:10])[C:8]2[CH:23]=[C:24]([Br:25])[C:5]([NH2:4])=[CH:6][C:7]=2[O:26][CH3:27])[CH2:17]1
Reactant: COc1cc(NC(C)=O)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Br)cc1C(=O)Nc1cccc2c1CCN(C)C2
Yield: 7.9 %

Procedure:
To a solution of 4-acetylamino-5-bromo-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide (0.888 g, 2 mmol) in ethanol (30 ml) and water (10 ml) was added 10% aqueous sodium hydroxide (1.25 ml). The mixture was heated at reflux for 1.25h before pouring into water and extracting with chloroform. The organic layer was dried over sodium sulfate, concentrated in vacuo and the residue recrystallised from ethyl acethate to afford the title compound as a brown solid (0.062 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:12]([C:14]1[CH:48]=[CH:47][C:17]2[N:18]([CH2:34][CH2:35][CH2:36][N:37]([CH3:46])[CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[C:19]([NH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)=[N:20][C:16]=2[CH:15]=1)=O)[CH:8]([CH3:10])[CH3:9].C(OCC)(=O)C>O1CCCC1>[CH2:7]([N:11]([CH2:12][C:14]1[CH:48]=[CH:47][C:17]2[N:18]([CH2:34][CH2:35][CH2:36][N:37]([CH3:46])[CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[C:19]([NH:21][C:22]3[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=3)=[N:20][C:16]=2[CH:15]=1)[CH2:49][CH:50]([CH3:51])[CH3:52])[CH:8]([CH3:10])[CH3:9]
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3cc(CN(CC(C)C)CC(C)C)ccc3n2CCCN(C)CCc2ccccn2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A molar solution of lithium aluminium hydride in tetrahydrofuran (0.83 ml, 5 eq) is added dropwise to a solution of N,N-diisobutyl-1-{3-[methyl(2-pyridin-2-ylethyl) amino]propyl}-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (105 mg, 1 eq. prepared according to Example A1) cooled down to 0° C., in tetrahydrofuran (3 ml). After stirring for 15 minutes at 0° C., the mixture is heated at 60° C. for 3 hours then cooled down to 0° C. and hydrolysed. After adding ethyl acetate, decanting and extraction, the combined organic phases are washed with salt water, followed by drying over sodium sulphate and concentrating under reduced pressure. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a foam (63 mg, 62% yield).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH3:30][C:31]1([CH2:34]O)[CH2:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:30][C:31]3([CH3:34])[CH2:33][CH2:32]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC1(CO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(C)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (1-methylcyclopropyl)methanol (0.44 g) and tributylphosphine (1.9 mL) in THF (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:34]([O:36]C)=O)[CH3:9].[NH3:38]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:34]([NH2:38])=[O:36])[CH3:9]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Br
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Br

Procedure:
In a similar manner as described for example A5, 2.11 g of methyl 3-[(1R)-1-(2-bromophenyl)ethoxy]-5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxylate and 168 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[CH:6][C:5]=1[F:14]>C1COCC1>[F:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([NH:2][CH3:1])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of MeNH2 in THF (5.7 mL, 2 M, 11 mmol) was added dropwise to a solution of 1,2,4-trifluoro-5-nitrobenzene (1.0 g, 5.7 mmol) in THF (10 mL) at −20° C. The mixture was stirred at −20° C. for 1 h, concentrated, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc/PE gave the sub-title compound. Yield: 1.0 g (81%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:18]([NH2:22])(=[O:21])[CH:19]=[CH2:20]>O>[S:1]=[C:2]1[N:6]([CH2:20][CH2:19][C:18]([NH2:22])=[O:21])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1
Reactant: Sc1nc2ccccc2s1
Reactant: C=CC(N)=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)CCn1c(=S)sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a stirred solution at 50° C. containing 86 g (0.5 mol) of 2-mercaptobenzothiazole, 60.8 g (0.6 mol) of triethylamine and 500 ml of water, 43 g (0.6 mol) of acrylamide was added in one portion. After stirring at 60°-70° C. for 24 hours, the stirred reaction mixture was cooled to 25° C., the solid collected by filtration, washed with water until neutral and airdried at 50° C. The product, 2-thioxo-3(2H)-benzothiazole-propanamide, mp 226°-227° C. was obtained in 77% yield.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[C:7]2[CH:14]=[CH:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1>CO>[CH3:1][O:2][C:6]1[C:7]2[CH:14]=[CH:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ncnc2[nH]ccc12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of sodium methoxide prepared by adding portion wise the sodium (2 g) in methanol (100 mL) under an inert atmosphere, was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Reference: Gerster, John F.; Hinshaw, Barbara C.; Robins, Roland K.; Townsend, Leroy B. Study of electrophylic substitution in the pyrrolo[2,3-d]pyrimidine ring. J. Heterocycl. Chem. (1969), -(2), 207-13.) (3.5 g). The solution was stirred at 65° C. for 16 hours and then partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (1.2 g) as an amorphous solid. MS: 150 [MH]+. LCMS (Method B) RT=2.39 minutes.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[N+](C1C=CC([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:28]([N:15]2[CH2:16][CH2:17][CH:12]([C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)[CH2:13][CH2:14]2)=[O:27])=[CH:31][CH:32]=1)([CH3:39])[CH3:38]
Reactant: Ic1ccc2ncnc(C3CCNCC3)c2c1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(NC(=O)N2CCC(c3ncnc4ccc(I)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A solution of impure 6-iodo-4-piperidin-4-yl-quinazoline (4.00 g, “11.8 mmol”), as prepared in the preceding step, in CHCl3 (20 mL) was treated with (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (4.10 g, 13.0 mmol), prepared as described in Example 1a, in one portion at rt under air. DIEA (2.15 mL, 13.0 mmol) was then added in one portion, and residual nitrophenyl ester and DIEA was transferred to the reaction with additional CHCl3 (20 mL). After 8 h rt stirring, the reaction was washed in succession with 1 M NaH2PO4 (50 mL) and 2 M K2CO3 (1×50 mL). The organic phase was filtered, the filter cake was washed with DCM (2×10 mL), and the combined filtrates were dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (1:2 hex/EtOAc) afforded the title compound as a beige foam (2.58 g, 42%). 1H-NMR (300 MHz, CDCl3) δ 9.26 (s, 1H), 8.52 (d, 1H), 8.13 (dd, 1H), 7.80 (d, 1H), 7.25 (m, 2H), 6.83 (m, 2H), 6.33 (br s, 1H), 4.48 (heptet, 1H), 4.32-4.22 (m, 2H), 3.68 (tt, 1H), 3.17 (td, 2H), 2.21-1.92 (m, 4H), 1.32 (d, 6H). LC/MS (ESI): calcd mass 516.1, found 517.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:11])=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.BrN1C(=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]=[O:18])=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1csc2ccc(Cl)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1csc2ccc(Cl)nc12
Temperature: 100 °C
Yield: 28.1 %

Procedure:
A mixture of 5-chloro-3-methyl-thieno[3,2-b]pyridine (0.5 g, 2.7 mmol), N-bromosuccinimide (0.48 g, 2.7 mmol) and benzoyl peroxide (50 mg) in carbon tetrachloride (3 mL) was heated at 100° C. in a microwave reactor for 15 minutes. The supernatant was decanted and evaporated under reduced pressure, the residue was suspended in toluene (3 mL) and pyridine-N-oxide (0.5 g) was added, followed by sodium bicarbonate (0.4 g) and diisopropylethylamine (3 drops). The reaction mixture was heated at 150° C. in a microwave reactor for 5 minutes, was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 20/80) to give 150 mg of 5-chloro-thieno[3,2-b]pyridine-3-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH3:31])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[NH:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>N1C=CC=CC=1>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4]([C:3]1[CH:26]=[CH:27][C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[CH3:31])=[CH:29][C:2]=1[NH:1][C:43]([C:39]1[NH:38][CH:42]=[CH:41][CH:40]=1)=[O:44])=[O:5]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(N)c1
Solvent: c1ccncc1
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(NC(=O)c2ccc[nH]2)c1
Yield: 65 %

Procedure:
2-Amino-N-[5-(3,5-difluoro-benzyloxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide (115 mg, 0.23 mmol) in pyridine (2.2 mL), cooled to 4° C., was treated with solid 1H-pyrrole-2-carbonyl chloride (34 mg, 0.27 mmol). The reaction was stirred until clear and left to room temperature over night. After removal of the volatiles, the crude was purified over silica gel to afford 90 mg of title compound in 66% yield.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1>C(O)CCC>[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:10][CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]2)=[CH:18][CH:19]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: CN1C(C)(C)CC(Nc2ccc(Cl)nn2)CC1(C)C
Temperature: 120 °C

Procedure:
A mixture of 1,2,2,6,6-pentamethylpiperidin-4-amine (14.2 g, 83 mmol) and 3,6-dichloropyridazine (6.2 g, 41.6 mmol) in n-butanol (10 mL) was heated at 120° C. for 120 min. The crude material solidified and was re-suspended in n-butanol (15 mL) and heated at 120° C. for 1 h. This crude material was combined with batch 1 for workup and purification. Water and CH2Cl2 were added to the combined crude material and the organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material was recyrstallized from CH3CN (400 mL) to give 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-5 (15.5 g, first crop). Recrystallization was repeated using CH3CN to give a 2nd crop of 6-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-5 (3.98 g). LCMS Rt=1.10 min (condition B); MS (M+1)=283.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 (d, J=9.3 Hz, 1H), 6.65 (d, J=9.3 Hz, 1H), 4.70 (d, J=7.3 Hz, 1H), 4.08-4.26 (m, 1H), 2.31 (s, 3H), 1.89-2.09 (m, 2H), 1.42 (apparent t, J=12.1 Hz, 2H), 1.21 (s, 6H), 1.15 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.O>N1C=CC=CC=1>[C:32]12([C:42]([O:1][C:2]3[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]4[C:3]=3[C:4](=[O:31])[O:5][CH2:6]4)=[O:43])[CH2:39][CH:38]3[CH2:37][CH:36]([CH2:35][CH:34]([CH2:40]3)[CH2:33]1)[CH2:41]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Solvent: c1ccncc1
Solvent: O
Product: COc1c(C)c2c(c(OC(=O)C34CC5CC(CC(C5)C3)C4)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (10.0 g) was dissolved in pyridine (50.0 ml) followed by the addition of 1-adamantanecarbonyl chloride (10.0 ml). The mixture was stirred at room temperature for 90 minutes, then poured into water and extracted with ethyl acetate. The organic solution was dried and evaporated to give morpholinoethyl E-6-[1,3-dihydro-4-(1-adamantoyloxy)-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl]-4-methyl-4-hexenoate.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[S:24][C:25]2[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=2[N:31]=1)=[O:22])=O)(C)(C)C.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](C(O)=O)=[CH:38]2>C(O)C>[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:5])=[CH:38]2
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH:36]1[CH2:40][CH2:39][CH:38]([CH3:41])[NH:37]1.O>C(#N)C>[CH3:35][CH:36]1[CH2:40][CH2:39][CH:38]([CH3:41])[N:37]1[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC1CCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1CCC(C)N1CC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and 2,5-dimethylpyrrolidine (81 μl). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. The product was purified by column chromatography using gradient elution with methanol-dichloromethane (2%->5%). 1H-NMR (300 MHz; d6-DMSO) δ: 9.66 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.06 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd, 1H, J 2.1, 9.9 Hz), 3.22 (s, 2H), 3.05-2.88 (m, 1H), 2.78-2.66 (m, 3H), 2.22-2.12 (m, 1H), 2.08-1.92 (m, 1H), 1.90-1.79 (m, 2H), 1.43-1.34 (m, 2H), 1.06 (d, 6H, J 6.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18](=[O:23])[NH:19][CH:20]2[CH2:22][CH2:21]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[N:7]([CH:14]3[CH2:16][CH2:15]3)[C:6]=2[CH:17]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:18](=[O:23])[NH:19][CH:20]2[CH2:21][CH2:22]2)=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH:14]3[CH2:16][CH2:15]3)[C:6]=2[CH:17]=1
Reactant: COC(=O)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2n1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CC1)c1cc2nc(C(=O)O)n(C3CC3)c2cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.65 g (4.9 mmol) of methyl 6-chloro-1-cyclopropyl-5-(cyclopropylcarbamoyl)-1H-benzimidazole-2-carboxylate were dissolved in 82 ml of THF and admixed at 0° C. with 0.24 g (9.89 mmol) of lithium hydroxide predissolved in 18 ml of water, and the reaction mixture was stirred at room temperature for 18 hours. The THF was distilled off and the aqueous phase was extracted three times with ethyl acetate; the aqueous phase was adjusted to pH=3 with HCl. The solid which precipitates out was filtered off with suction. Due to its relative instability, the acid was used for subsequent reactions without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:11][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: OCC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (25.5 mL) was added dropwise to a solution of cyclopentanemethanol (32.4 mL) and triethylamine (46 mL) in dichloromethane (500 ml) at 0° C. After stirring overnight at room temperature, the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again. Following drying over sodium sulfate, the solvent was removed under vacuum, affording crude cyclopentylmethyl methanesulfonate (ca. 50 g) as a colourless oil. A mixture of this product and sodium iodide in acetone (600 ml) was heated at reflux in the dark for 16 hours. After cooling to room temperature, the reaction mixture was poured into petrol ether/water 2:1 (1.5 L) under stirring. The organic layer was washed twice with water, dried (Na2SO4) and carefully concentrated under reduced pressure (50 mm; temperature of the bath <30° C.). The residue was distilled in vacuo. The title product was obtained as a light yellow oil (39 g), by collecting the fraction boiling at 101-102°/70 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:12])=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.C1(O)C=CC=CC=1.[CH3:23][O:24][C:25](=[O:29])[CH:26](Br)[CH3:27]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[C:5]([O:12][CH:26]([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: CCC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: CCC(=O)c1cc(Br)cc([N+](=O)[O-])c1OC(C)C(=O)OC

Procedure:
Using 1-(5-bromo-2-hydroxy-3-nitrophenyl)propan-1-one as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted 2-nitrophenols gives the title compound as a gold oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.10 (m, 3H) 1.44 (d, J=6.82 Hz, 3H) 3.00-3.12 (m, 2H) 3.59 (s, 3H) 4.56 (q, J=6.82 Hz, 1H) 8.07 (d, J=2.53 Hz, 1H) 8.34 (d, J=2.53 Hz, 1H). ESI-MS: m/z 361.1 (M+H)+.