Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:38][S:39]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)(=[O:41])=[O:40]
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(S(C)(=O)=O)CC4)nc12
Yield: 32 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.009 ml methanesulfonyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.015 g (32%) 6-methanesulfonyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine as yellow solid; MS (ISP): m/e=464 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][CH2:4][NH:3]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[C:25]([F:28])([F:27])[F:26].O>O1CCCC1>[F:26][C:25]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:22])[F:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:3]1[CH2:4][CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7][C:2]1=[O:1]
Reactant: O=C1CC(C(=O)O)CCN1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 2-oxopiperidine-4-carboxylic acid (21.3 g) in tetrahydrofuran (300 mL) was added 60% sodium hydride (18 g, containing mineral oil) under cooling to 0° C. The reaction mixture was stirred for 30 min under cooling to 0° C. To the reaction mixture was added dropwise 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (46 g) under cooling to 0° C., and the mixture was further stirred at 80° C. for 2 days. Water was added to the reaction mixture under cooling to 0° C., and the mixture was extracted with ethyl acetate. To the aqueous layer was further added 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (32 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:21]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:18]([C:15]2[CH:16]=[CH:17][C:9]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[O:1][CH2:37][C:38]([NH2:40])=[O:39])[CH2:13][CH2:12][O:11][C:10]=3[CH:14]=2)(=[O:19])=[O:20])=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(N)=O)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (550 mg, 1.080 mmol), 2-bromoacetamide (704 mg, 5.108 mmol, Aldrich) in DMF (10 mL) was added potassium carbonate (528 mg, 3.83 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-60% ethyl acetate in hexane) to get 2-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (300 mg, 49.0%). MS (ESI, positive ion) m/z; 567.1 (M+1)
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>C1COCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: c1ccc2scnc2c1
Reactant: CC(C)CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes; 65.1 ml, 0.163 mol) was added to a stirred solution of benzothiazole (20.0 g, 0.148 mol) in dry THF (250 ml) under argon at -78° C. After 10 min a solution of isovaleraldehyde (17.4 ml, 0.163 mol) in dry THF (50 ml) was added slowly and the mixture stirred for 1 h at -78° C. The reaction mixture was removed from the cooling bath and after 10 min was quenched by the addition of excess water and the mixture extracted with ethyl acetate. The combined organic layers were washed with water, dried, filtered and evaporated. Chromatography (20-30% diethyl ether in hexane) gave 1-(2-benzothiazolyl)-3-methylbutanol (5.8 g, 18%) as an amorphous yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a suspension of 2,6-dichloro-3-nitropyridine (6 g, 31.1 mmol) in AcN (200 mL) at 0° C., TEA (9 mL, 62.2 mmol) and tetrahydro-2H-pyran-4-amine (3.15 g. 31.1 mmol) were added. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction crude was tempered and stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed thrice with saturated NaHCO3 aqueous solution. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was cromategraphed on a silica gel flash system (ISCO Combiflash) using hexanes/TBME mixtures of increasing polarity as eluent to afford 5.23 g of the desired product (65% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([C:19]([Br:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(Br)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 5 h

Procedure:
N-bromosuccinimide (14 mg, 0.080 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol) in chloroform (1.0 mL). After stirring for five hours the reaction was diluted with ethyl acetate, washed with NaHSO3, brine, dried over Na2SO4, and concentrated to a yellow solid (33 mg, 92%). MS APCI (+) m/z 494, 496, 498 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.55 (dd, 1H), 7.22 (dd, 1H), 6.53 (d, 1H), 3.98 (s, 3H).
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]([N:16]2[CH:20]([C:21]([OH:23])=O)[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.CS(Cl)(=O)=O.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[NH2:43]>ClCCl>[CH:7]1([CH2:12][C@@H:13]([C:14](=[O:15])[N:16]2[CH:20]([C:21]([NH:43][C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[O:23])[CH2:19][CH:18]=[N:17]2)[CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ncccn1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ncccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1-Methyl-1H-imidazole (0.24 mL, 3.0 mmol) was added into a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in dichloromethane (DCM) (5.0 mL). The resulting solution was cooled to 0° C., and then methanesulfonyl chloride (0.08 mL, 1.05 mmol) was added dropwise at 0° C. To the reaction mixture was then added 2-pyrimidinamine (105 mg, 1.1 mmol), and stirring continued for 30 min at room temperature. After this time, the solvent was removed under reduced pressure to provide a residue which was purified by Combiflash automated silica gel chromatography (80-100% EtOAc in Hex) to afford 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(2-pyrimidinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (270 mg, 0.63 mmol, 63% yield). MS: 430 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl>>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)N(CCCCCl)C1=O

Procedure:
A mixture of 538 g of 5,5-dimethyl-hydantoin (4.2 mols), 290 g of anhydrous potassium carbonate (2.1 mols) and 2,130 g of 1,4-dichlorobutane (16.77 mols) is reacted for 8 hours at 138° to 141° C internal temperature (external temperature 200° C), as described under Example 1 (a). Working up is carried out according to Example 1 (a), and 830.9 g of a brown, viscous crude product (90.5% of theory) are obtained, and are purified by vacuum distillation (boiling point0.2 : 151°-153° C) and subsequent recrystallisation from diethyl ether. The pure product melts at 54.4° to 56.3° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:44])[CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:16]=1)=[O:13])C1C=CC=CC=1>C1COCC1.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:44])[CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:35]([CH3:37])[CH3:36])[CH:38]([CH3:39])[CH3:40])[CH:29]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[N:16]=1)=[O:13]
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl 3-[(3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoyl)amino]-1H-pyrazole-1-carboxylate (90 mg, 0.144-mmol) in 1:1 mixture of THF/ethanol was evacuated and purged with nitrogen (×3). 10% Palladium on carbon was added and the reaction mixture was evacuated and purged with nitrogen and then evacuated and finally purged with hydrogen gas. The reaction mixture was left to stir at ambient temperature under an atmosphere of hydrogen for 6 hours. The Palladium catalyst was filtered through diatomaceous earth. The filtrate was evaporated to give a crude solid (70 mg)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10].[CH3:12][S:13]([O-:15])=[O:14].[Na+].Cl>CN(C=O)C>[CH3:12][S:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: OB(O)c1ccccc1CBr
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccccc1B(O)O
Reaction time: 2.5 h
Yield: 28.9 %

Procedure:
A solution in DMF (2.0 ml) of [2-(bromomethyl)phenyl]boronic acid (399 mg) was added in one portion to a stirred slurry of sodium methanesulphinate (200 mg) in DMF (2.0 ml). The mixture was stirred for 2.5 h i nd then poured into 1M hydrochloric acid (100 ml) and extracted with EA (3×50 ml). the combined extracts were dried and evaporated. On standing a solid material precipitated, which was washed with ER to give white crystals of the title compound (115 mg), m.p. 133°-137°. T.l.c. (A) ER:hexane (3:2) Rf 0.51.
Reaction SMILES: [NH+:1]1([O-])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][NH+]1C=Cc2cccnc21
Product: Clc1ccnc2[nH]ccc12

Procedure:
1H-Pyrrolo[2,3-b]pyridine-N-oxide (Reference Example 65) (10.0 g) in phosphorous oxychloride (75 mL) was heated at reflux for 8 hours. The excess phosphorous oxychloride was evaporated and the residue was taken up in water and the solution was brought to a pH=8-9, the resultant precipitate was filtered and air-dried to give the title compound as an off-white solid (10.2 g). MS: 152 (MH+). 1H NMR (CDCl3): δ 8.2 (d, 1H), 7.5 (d,,1H), 7.2 (d, 2H), 6.6 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:4].S(Cl)(Cl)=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([S:26]([N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=3)[CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:25]=1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:12])[NH:39][C:36]2[CH:37]=[C:38]3[C:33]([CH2:32][CH2:31][CH2:30][N:29]3[S:26]([C:24]3[CH:25]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=3[O:40][CH3:41])(=[O:28])=[O:27])=[CH:34][CH:35]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(N)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C(=O)Nc2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Methoxycarbonylmethyl-benzoic acid (52.00 mg, 0.27 mmol) was suspended in dichloromethane (2.00 mL) and treated with thionyl chloride (95.57 mg, 0.80 mmol). The mixture was stirred at 50° C. for 18 hours, and the volatiles were evaporated. The residue was redissolved in tetrahydrofuran (2.00 mL) and treated with 1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylamine (94.48 mg, 0.27 mmol) and 4-dimethylaminopyridine (66.76 mg, 0.54 mmol). The mixture was warmed to 75° C. and stirred for 2.5 hours. The mixture was treated with HCl 1 N and the slurry extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield {4-[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid methyl ester as an off-white solid, 134.20 mg (95%), MS (ISP): m/e=529.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:31](=[O:32])[CH2:30][OH:33])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OC[C@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@H]2C[C@@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 46 %

Procedure:
The procedure described in Example 20 was repeated using (3R,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with glycolic acid (42 mg) to give the title compound as a white solid in 46% yield; NMR spectrum (DMSO-d6) 10.01 (s, 1H), 8.48 (s, 1H), 8.22 (dd, 1H), 7.74-7.69 (m, 1H), 7.43 (t, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 5.29-5.28 (m, 1H), 4.73-4.68 (m, 1H), 4.64-4.59 (m, 2H), 4.44-4.42 (m, 1H), 4.34-4.31 (m, 1H), 4.06-4.05 (m, 2H), 3.93 (s, 3H), 3.64 (dd, 1H), 3.45 (s, 1H), 2.25-2.12 (m, 1H), 1.99-1.95 (m, 1M); Mass spectrum MH+ 477.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[I-].[Na+]>CC(C)=O>[Cl:31][C:29]1[N:28]=[CH:27][N:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]3[N:15]=[C:14]4[CH:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[F:13])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]4[N:17]=3)=[CH:21][C:22]=2[O:32][CH3:33])[CH:30]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccccc3F)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccccc2F)ccc1-n1cnc(Cl)c1
Yield: 10.2 %

Procedure:
A solution of 5-(5-chloro-1-(2-fluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.47 g, 5.05 mmol), sodium iodide (3.79 g, 25.3 mmol), and diisoproplylethylamine (1.77 mL, 10.1 mmol) in acetone (40 mL) was heated in a sealed vessel at 100° C. for 2 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (0-35% EtOAc/chloroform, linear gradient) to afford 234 mg (10% yield) of the titled compound as a pale yellow solid. The solid was recrystallized from EtOH to afford an analytical sample. LC-MS (M+H)+ 453.3. 1H NMR (500 MHz, chloroform-d) δ ppm 7.50 (d, J=1.53 Hz, 1 H) 7.44 (d, J=2.14 Hz, 1 H) 7.27-7.34 (m, 1 H) 7.21-7.26 (m, 1 H) 7.16 (t, J=7.17 Hz, 1 H) 7.04-7.13 (m, 2 H) 7.01 (d, J=1.53 Hz, 1 H) 6.76 (dd, J=8.39, 2.29 Hz, 1 H) 6.60 (s, 1 H) 4.38-4.48 (m, 2 H) 4.22 (dd, J=14.50, 9.92 Hz, 1 H) 3.74 (s, 3H) 2.00-2.27 (m, 4H) 1.79-1.94 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[NH2:22][N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:22][N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: Nn1cccc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)cc(C)cc1C)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 40 h

Procedure:
Monoimine (1, 3.0 g, 10.7 mmol) and 1-aminopyrrole (1.0 g, 12.18 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 40 hours the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 1.85 g (50%) of mixed diimine 15.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH:8](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][CH:4]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2/[CH:19]=[CH:18]/[CH:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)Cc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(C#N)cc1
Yield: 92.2 %

Procedure:
A solution of 1.75 g (4.64 mmol) of ethyl E-6-(4-cyanobenzyl)-8-(2-hydroxyphenyl)oct-7-enoate from Example 112A in 50 ml of dry acetonitrile is mixed with 1579 mg (6.95 mmol) of 4-(tert-butyl)benzyl bromide and 961 mg (6.95 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→4:1). 2.24 g (4.28 mmol, 92% yield) of a solid are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].F[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1[C:31]([N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=[O:32]>>[Br:1][C:2]1[C:3]([C:8](=[O:9])[N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])=[N:4][N:5]([C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=2[C:31]([N:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Br
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Yield: 51.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-bromo-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (646 mg, 2.04 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 1D, 1.07 g, 3.27 mmol) were converted to the title compound (660 mg, 48%). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 8.24-8.19 (m, 1H), 8.14-8.10 (m, 1H), 7.45-7.39 (m, 1H), 7.25-7.09 (m, 3.5H), 6.88 (d, J=7.3 Hz, 0.5H), 4.78 (d, J=8.8 Hz, 1H), 4.49-4.36 (m, 3H), 3.71-2.69 (m, 8H), 2.32 (s, 2H), 2.28 (s, 1H), 1.54-1.27 (m, 8.5H), 1.11 (d, J=7.7 Hz, 2H), 0.92 (q, J=7.2 Hz, 3.5H), 0.79 (t, J=8.0 Hz, 3H); MS(ESI+) m/z 625.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[OH:22]>C(OCC)C.N1C=CC=CC=1>[C:1]([O:22][C:15]1[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
A solution of decanoyl chloride (Pfaltz and Bauer, 5.6 ml) and 2,4,5-trichlorophenol (5.6 g) in diethyl ether (1 L) and pyridine (120 ml) is stirred for 4 hours. The reaction mixture is filtered and dried in vacuo. The 2,4,5-trichlorophenyl n-decanoate is purified on a silica-gel column (Woelm), using toluene as the eluent. Fractions are monitored by TLC, using short-wave UV for detection. Appropriate fractions are pooled and dried in vacuo to give 10.4 g of 2,4,5-trichlorophenyl n-decanoate.