Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:42]2[CH2:43][CH2:44][CH:39]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:40][CH2:41]2)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Reactant: C1CCN(C2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCC(N4CCCC4)CC3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.2 mmol), 4-pyrrolidin-1-yl-piperidine (1.2 eq.), HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, dried and concentrated. The residue was triturated with ethyl ether to give the titled compound.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[CH2:6][O:7][C:8](=[O:30])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([C:21](C)(C)[O:22][SiH2]C(C)(C)C)[O:19][CH:20]=2)[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[CH2:6][O:7][C:8](=[O:30])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[O:19][CH:20]=2)[CH:14]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(Nc1cnn(Cc2coc(CO)n2)c1)OCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of {1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-1H-pyrazol-4-yl}-carbamic acid 2-chloro-benzyl ester (313 mg, 0.65 mmol) in dry THF (5.0 mL) was treated at 0° C. with TBAF (1.0 mL of a 1M solution in THF, 1.00 mmol). The reaction mixture was stirred at 0° C. for 30 min. Sat. aq. NH4Cl (10 mL) was added, the layers separated and the aq. layer extracted with EA (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (EA) gave the title compound as a pale yellow oil. TLC: rf (EA)=0.28. LC-MS-conditions 02: tR=0.84 min; [M+H]+=363.22.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(N(CC)CC)C.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][N:11]([C:36](=[O:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1cccc(C23CCCC2CNCC3)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccccc1)N1CCC2(c3cccc(O)c3)CCCC2C1
Temperature: 70 °C

Procedure:
A solution of 2.17 g. of 4a-(3-hydroxyphenyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine prepared as described in Example 23 in 50 ml. of N,N-dimethylformamide containing 3.95 g. of triethylamine was stirred at room temperature while 3.87 g. of phenylacetyl chloride was added dropwise over 15 minutes. Following complete addition, the reaction mixture was heated at 70° C. for two hours, and then poured into 200 ml. of water. The aqueous reaction mixture was extracted several times with diethyl ether, and the ethereal extracts were combined, washed with saturated aqueous sodium chloride solution and with water, and dried. Removal of the solvent by evaporation under reduced pressure afforded 4a-(3-hydroxyphenyl)-2-(2-phenylacetyl)-2,3,4,4a,-5,6,7,7a-octahydro-1H-2-pyrindine. Such product was dissolved in 50 ml. of tetrahydrofuran and stirred while a solution of 4.0 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran was added dropwise over thirty minutes. The reaction mixture was then heated at reflux for four hours, and then cooled to about 25° C. While the reaction mixture was stirred, 25 ml. of ethyl acetate was added, followed by the addition of a saturated aqueous solution of ammonium tartrate. The reaction mixture was then filtered and the filtrate was concentrated by evaporation of the solvent under reduced pressure. The product thus formed was dissolved in diethyl ether and washed with water and dried. Removal of the solvent then provided 4a-(3-hydroxyphenyl)-2-(2-phenylethyl)- 2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine as an oil. The oil was dissolved in 150 ml. of diethyl ether and stirred while a fifty percent solution of 48% hydrobromic acid in ethanol was added. The hydrobromide salt of the above-named product crystallized and was collected by filtration, affording, after recrystallization from ethyl acetate, 1.3 g. of 4-a-(3-hydroxyphenyl)-2-(2-phenylethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindinium bromide. M. P. 135-137° C.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:5][N:4]([C:6]([C@@H:8]2[CH2:12][C@H:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[C:23]([F:26])([F:25])[F:24])(=[O:15])=[O:14])[CH2:10][C@H:9]2[C:27]([OH:29])=O)=[O:7])[CH2:3]1.[CH2:31]1[C:33]([NH2:36])([C:34]#[N:35])[CH2:32]1.Cl>>[C:34]([C:33]1([NH:36][C:27]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[C:23]([F:24])([F:26])[F:25])(=[O:15])=[O:14])[CH2:12][C@H:8]2[C:6]([N:4]2[CH2:5][C:2]([F:30])([F:1])[CH2:3]2)=[O:7])=[O:29])[CH2:31][CH2:32]1)#[N:35]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)C[C@H]1C(=O)N1CC(F)(F)C1
Reactant: N#CC1(N)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 117, step 7, using (1R,2R,4S)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid and 1-amino-cyclopropyl cyanic hydrochloride. White solid. MS (EI): 524.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2ccc(Br)cc2c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
To a solution (200 mL) of 1-(5-bromo-2-hydroxyphenyl)ethanone (25.0 g) in N,N-dimethylformamide were added potassium carbonate (24.0 g) and methyl bromoacetate (11.5 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was filtered, 1,8-diazabicyclo[5.4.0]undec-7-ene (23.2 mL) was added to the filtrate, and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and ice water was added. The precipitate was washed with ethanol-water to give the title object compound (16.8 g, 52%) as a pale-red solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=1>CCOCC>[CH3:7][C:8]1[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(CO)cn1
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a suspension of lithium aluminium hydride (7.24 g, 191 mmol) in Et2O (400 ml) at −78° C. was added via cannula over a period of one hour a solution of methyl 6-methylnicotinate (19.62 g, 130 mmol) in Et2O (200 mL). Once addition was completed, the mixture was stirred for a further 3 h. Excess lithium aluminium hydride was quenched by dropwise addition of EtOAc (40 ml). The mixture was then warmed using a water-ice bath, and further quenched with sat NH4Cl (500 mL). The ethereal layer was decanted, and EtOAc was added (500 mL). The mixture was stirred vigorously, and the organic layer was again decanted. The extraction procedure was repeated twice (500 mL EtOAc). The combined organic extracts were dried (MgSO4) and concentrated to yield the desired product (13.6 g, 85%). 1H NMR (300 MHz, CDCl3) δ: 8.39 (1H, s), 7.62 (1H, dd, J=2.1, 8.1 Hz), 7.14 (1H, d, J=7.8 Hz), 4.68 (2H, s), 2.54 (3H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])=[O:3]>C(O)C.[Pt]>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:13])=[O:3]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pt]
Solvent: CCO
Product: CC(=O)c1cccc(N)c1O
Reaction time: 2.5 h

Procedure:
A solution of 2-hydroxy-3-nitroacetophenone [4.0 g; prepared by the method of Allen et al., J. Chem. Soc., (1949), 821] in ethanol (150 ml) was hydrogenated at 25° C. and 50 p.s.i. for 2.5 hours, using a catalyst of platinum on charcoal. The mixture was filtered and the filtrate was evaporated in vacuo to give a black solid, which was purified by chromatography on a column of silica gel, using diethyl ether as eluant. The fastest moving band (yellow) was collected to give 3-amino-2-hydroxyacetophenone (3.0 g), in the form of a bright yellow solid, m.p. 95°-97° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:16]([CH2:14][CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: ClCC(CCl)OCc1ccccc1
Solvent: O
Product: CCN1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 61 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane, 45.1 parts of monoethylamine and 45.1 parts of water were added to an autoclave and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 11.6 parts of 3-benzyloxy-1-ethylazetidine boiling at 73°-74° C. under 2 mm Hg were obtained. The yield was 61%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13]S(C1C=CC=CC=1)(=O)=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[ClH:23].[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][N:32]=[C:31]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:30]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[ClH:23].[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[O:33][N:32]=[C:31]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][CH2:11][C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]=4[CH3:1])[CH2:36][CH2:35]3)[C:30]=2[CH:40]=1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Reactant: COc1ccc2onc(C3CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccc2onc(C3CCN(CCCc4c(C)[nH]c5ccccc45)CC3)c2c1

Procedure:
A mixture of 4.0 g of 2-methyl-3-(3-phenylsulfonylpropyl)indole, 3.0 g of 5-methoxy-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 8.0 g of potassium carbonate and 70 ml of 2-butanone was heated under reflux, with stirring, and refluxed under nitrogen for 16 hours. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The insoluble material was collected and washed with diluted sodium hydroxide to give a solid. The ethylacetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give an additional solid. Treatment of the combined solids with a saturated hydrogen chloride-toluene solution gave the salt. The salt was triturated with acetone and recrystallized from ethanol-ether to give an ethanolate, mp 163°-165° (foaming). Recrystallization of the alcoholate from acetonitrile and subsequent drying of the sample at 100° and ca 1 mm gave 1.60 g (33%) of product, mp 130°-132°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>O1CCCC1>[N:1]1([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)n1ccnc1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a suspension of imidazole (12.2 g, 175 mmol) in tetrahydrofuran (250 ml) was added ethyl chlorooxoacetate (10 mL, 90 mmol) in tetrahydrofuran (250 ml) at 0° C., and the mixture was stirred for 1 hour and then filtered off and washed with cold tetrahydarofuran (100 mL). The solvent was evaporated off under the reduced pressure to obtain 14.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[C:25]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:26]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: COc1ccc(C(=O)O)cc1-c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 4-methoxy-3-phenylbenzoic acid (129 mg, 0.57mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:2) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-4-methoxy-3-phenylbenzamide (45 mg). NMR; δH CDCl3 7.90, (1H, dd), 7.82-7.79,(4H, m), 7.58,(1H, dd), 7.53-7.33,(5H, m), 7.27-7.25,(1H, m), 7.05,(1H, d), 6.25,(1H, t), 3.87,(3H, s), 3.34,(2H, m), 2.22,(3H, s), 1.08,(1H, m), 0.57,(2H, m), 0.29,(2H, m). LCMS: retention time 3.78 min, MH+491.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:1][CH:2]1[O:6][C@H:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1ccc([C@@H]2CCC(=O)O2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1ccc([C@@H]2CCC(O)O2)cc1
Temperature: -30 °C
Yield: 64 %

Procedure:
N-[4-[(2S)-Tetrahydro-5-oxo-2-furanyl]-phenyl]methanesulfonamide (IIb) from Preparation 3 (9.823 g, 38.5 mmol) was dissolved in a CH2Cl2/toluene (100 ml/41 ml) at 23° C., then cooled to −30° C. The mixture was a slurry. DIBAL-H (59 ml, 1.5 M in toluene) was added slowly to the mixture (1 ml/min). After addition was complete, the solution was stirred until less than 1% of lactone remained by HPLC assay. When the reaction was complete, excess DIBAL-H was pre-quenched with EtOAc (15 ml). This mixture was then added to a pre-cooled (0° C.) aqueous solution of disodium citrate (1.0 M, 200 ml). The reaction mixture was not allowed to warm during this addition period. Ethyl acetate (200 ml) was added, and the resulting two-phase mixture was stirred for at least 5 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine (2×150 ml). The solvent was removed under reduced pressure. The crude solids were crystallized from ethyl acetate (6 mL/g). A white solid was obtained (8.04 g), having 3% diol by area. Recrystallization from ethyl acetate provided 6.4 g of the title product as a white, powdery solid (64% yield, 93 area %, GT 99% ee). Melting point=129-130° C. 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.21 (d, J=8.1 Hz, 2H), 5.65 (m, 0.5H), 5.53 (m, 0.5H), 5.14 (t, J=6.9 Hz, 0.5H), 4.93 (t, J=7.6 Hz, 0.5H), 2.92 (s, 3H), 2.49 (m, 1H), 2.25 (m, 1H), 1.98 (m, 1H), 1.92 (m, 1H); 13C NMR (100 MHz, CD3OD) δ C 142.9, 141.2, 140.6, 138.6, 138.5; CH 128.4, 127.9, 121.7, 121.6, 99.9, 99.5, 83.2, 80.3, 74.4, 74.3; CH2 35.5, 35.1, 34.4, 34.2, 33.9; CH3 39.1, 39.0. MS (EI) m/z calcd for C11H15NO4S 257.07 (M+).
Reaction SMILES: [CH3:1][S:2]([CH:5]1[CH2:10][O:9][C:7](=[O:8])[C@@H:6]1[OH:11])(=[O:4])=[O:3].S(=O)(=O)(O)[OH:13]>>[OH:9][CH2:10][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:6]([OH:11])[C:7]([OH:13])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)C1COC(=O)[C@@H]1O
Product: CS(=O)(=O)C(CO)[C@@H](O)C(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(S)-3-methanesulfonyl hydroxybutyrolactone (1.0 g, 5.6 mmol), D2O (10 ml), and the concentrated sulfuric acid (0.0549 g, 0.56 mmol) were placed in a 25 ml reactor and stirred at 50° C. for 3 hours. The reacting solution was cooled to room temperature and extracted with dichloromethane (10 ml) twice to recover the unreacted (S)-3-methanesulfonyl hydroxybutyrolactone. The presence of the target (S)-4-hydroxy-3-methanesulfonyl hydroxybutyric acid in a pure form in the D2O layer was confirmed by nuclear magnetic resonance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].Cl>C1COCC1>[Cl:1][C:2]1[C:7]([C:16]([OH:18])=[O:17])=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: COc1cc(Cl)nc(Cl)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Cl)c1C(=O)O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 4.0 g (22.5 mmol) 2,6-dichloro-4-methoxy-pyridine in THF (20 ml) was added 10.0 ml (2.47 M in hexane, 24.7 mmol) n-butyllithium at −78° C. After stirring for 1 h at −78° C. excess dry ice was added and the mixture was allowed to warm to RT. Then the mixture was acidified with 6N aqueous hydrochlorid acid to pH 3-4 followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 4:1) provided 3.5 g (15.8 mmol, 70%) 2,6-dichloro-4-methoxy-pyridine-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].O>CN(C)C=O>[CH2:19]([O:6][C:5](=[O:7])[C:4]1[C:8]([F:11])=[CH:9][N:10]=[C:2]([Br:1])[CH:3]=1)[CH3:20]
Reactant: CCI
Reactant: O=C(O)c1cc(Br)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Br)ncc1F
Reaction time: 24 h
Yield: 49.5 %

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinic acid (5.2 g) in N,N-dimethylformamide (100 mL) were added potassium carbonate (9.8 g) and iodoethane (7.4 g) at room temperature, and this mixture was stirred at same temperature for 24 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([N:27](C)[C:28](=O)CCCCC)[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:36])=[CH:6][CH:5]=1)([O-:3])=[O:2].OS(O)(=O)=O>>[CH3:28][NH:27][C:25]1[CH:24]=[CH:23][C:21]2[N:20]([CH:26]=1)[C:19]1[N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11](=[O:36])[C:12]3[C:17]([C:18]=1[N:22]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCCCCC(=O)N(C)c1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: O=S(=O)(O)O
Product: CNc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 27.1 %

Procedure:
A suspension of 87 (0.612 mmol, 0.296 g) in a 6 M aqueous H2SO4 solution (15 ml) was stirred at 85° C. for 5 h. The mixture was cooled to room temperature, the precipitate was filtered off and successively washed with water, saturated NaHCO3 solution, isopropanol and isopropyl ether to give 9-(methylamino)-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (89) (0.064 g, yield=27%, purity (LC)=97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11])[O:23][S:32]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=1)(=[O:34])=[O:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccc(OS(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, step 5, 183 mg, 0.5 mmol) in dichloromethane (8 ml) was treated with triethyl amine (116 ml, 1.15 mmol) and cooled down to 0° C. To the cooled solution, 4-(chlorosulfonyl)benzoic acid (132 mg, 0.6 mmol) was added in three portions (10 min). The reaction mixture was stirred at 0° C. for 15 min. and 2 h at r.t., followed by dilution with dichloromethane (8 ml). The reaction mixture was extracted with 1M aq HCl, the organic phase was washed twice with water and brine, dried over MgSO4, filtered and concentrated. The solid residue was dried under high vacuum to give the title compound (275 mg) as a white solid. MS (m/e)=550.1 [M+H+].
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:43]=[C:42]([F:44])[C:15]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:14]([F:45])[CH:13]=1)(C(C)(C)C)(C)C>CC#N>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:18]([S:17][CH2:16][C:15]3[C:14]([F:45])=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:43][C:42]=3[F:44])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: CC#N
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole in CH3CN (1 mL) was added a 5% solution of aqueous HF in CH3CN (3 mL). The reaction was complete in 1 h and the crude product was extracted with EtOAc (3×75 mL). The combined extracts were washed with H2O and brine, and dried over anhyd Na2SO4, concentrated and purified by flash chromatography (20% MeOH/DCM) to yield the title compound (493 mg, 95%) as a white solid. MS (EI) m/z 563.30 (MH+).