Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH:44]([CH:56]=O)[CH2:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)=[CH:38][CH:37]=1)#[N:35].O>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][CH:44](/[CH:56]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][C:46]2[CH:47]=[CH:48][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:54][CH:55]=2)=[CH:40][CH:41]=1)#[N:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C=O)CCc2ccc(C#N)cc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5.9 ml (9.45 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 1820 mg (4.05 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 50 ml of anhydrous THF at 0° C. Then, at this temperature, 1085 mg (3.38 mmol) of methyl 4-[4-(4-cyanophenyl)-2-formylbutyl]benzoate, dissolved in 40 ml of THF, are added slowly. After warming to room temperature, the reaction solution is stirred for 12 hours and then, after addition of some water, concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→2:1). 1150 mg (2.79 mmol, 83% of theory) of a colorless solid are obtained.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH3:27])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:28]>C1COCC1.O.C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[C:8]2[CH3:28])(=[O:17])=[O:18])=[CH:20][C:21]=1[O:26][CH3:27]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(OC)c2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 M Lithium hydroxide (119 μl) is added dropwise to a cooled (0° C.) solution of [1-(4-fluoro-3-methoxy-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.044 g, 0.119 mmol) in THF/water (4 ml of a 1:1 mixture). After stirring at room temperature for 4 hours, the reaction mixture is diluted with DCM. The resulting mixture is passed through a phase separation cartridge and the aqueous portion is acidified to pH 1-3 with 1M HCl. This portion is extracted with DCM and the organic extracts are combined and concentrated in vacuo to yield the titled compound as a pale yellow solid. (MH+379)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].Cl.[CH3:24][O:25][C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=1>>[CH3:24][O:25][C:26](=[O:38])[C@@H:27]([NH:37][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:13]=1[NH:12][S:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:11])=[O:10])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.54 min. MS (ESI+): mass calcd. for C23H17BrF3IN2O5S, 697.26; m/z found, 697/699 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.37 (s, 1H), 8.11 (d, J=1.4, 1H), 7.55-7.44 (m, 1H), 7.40 (dd, J=8.3, 1.4, 1H), 7.27-7.26 (m, 1H), 7.09-7.04 (m, 2H), 7.02-6.96 (m, 3H), 6.63 (d, J=6.8, 1H), 4.98 (q, J=5.6, 1H), 3.81 (s, 3H), 3.27-3.13 (m, 2H).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([C:21](=[O:25])[CH:22](Br)[CH3:23])[C:11]=2[CH:26]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:27][NH2:28]>C(O)C>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([C:21](=[O:25])[CH:22]([NH:28][CH3:27])[CH3:23])[C:11]=2[CH:26]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Nc1ccc2c(c1)N(C(=O)C(C)Br)c1ccccc1C=C2
Reactant: CN
Solvent: CCO
Product: CCOC(=O)Nc1ccc2c(c1)N(C(=O)C(C)NC)c1ccccc1C=C2
Temperature: 4 °C

Procedure:
3-Carbethoxyamino-5-(α-bromopropionyl)-5H-dibenz[b,f]-azepine (10 g) is mixed with 15 ml of approximately 35% aqueous methylamine solution and 75 ml of ethanol and heated in a laboratory autoclave for 12 hours at 90° to 95° C. After cooling to 4° C., the formed precipitate is filtered off with suction, mixed with 50 ml of acetone and then, again filtered off with suction and dried. 3-Carbethoxyamino-5-(α-methylaminopropionyl)-5H-dibenz[b,f]azepine (7 g) is obtained, which can be purified by being dissolved in dilute hydrochloric acid and precipitated with concentrated ammonia solution. The purified compounds melts at 217° to 219° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH:15]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH:15]2[O:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1COc2ccccc2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
12.20 g (64 mmol) of p-toluenesulphonyl chloride are added at room temperature and while stirring to a solution of 10.81 g (60 mmol) of 2-(2-hydroxyethyl)benzo-1,4-dioxan in 35 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 15.50 g (77.2%) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan, which melts at 82°-84°, are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)ccc1C)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)ccc1C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a mixture of 2-(5-fluoro-2-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethylester (3.78 g, 10.6 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (2 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with saturated aqueous sodium bicarbonate solution (2×mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.70 g, 19%) as a white solid: LC/MS m/e calcd for C21H24FNO2 (M+H)+: 342.4, observed: 342.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:14][S:15](C)=O>[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([CH2:9][CH2:10][O:11][CH2:12][CH3:13])=[N:4][C:5]([S:15][CH3:14])=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: CCOCCc1nc(Cl)ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOCCc1nc(SC)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3,6-Dichloro-2-(2-ethoxyethyl)-pyridine (1.18 g, 5.00 mmol) was dissolved in 25 mL DMSO, treated with NaSCH3 (0.53 g, 7.5 mmol), and stirred at room temperature overnight. The mixture was diluted with brine, then extracted with, EtOAc. The combined EtOAc extracts were combined, dried over Na2SO4, and concentrated in vacuo to yield 3-chloro-2-(ethoxyethyl)-6-(methylthio)pyridine (0.91 g, 76%) as a yellow oil, used without further purification.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1>CN(C)C=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)=[N:31][CH:32]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Tetrahydrofuran (10 mL) and 5 N aqueous sodium hydroxide solution (448 μL, 2.24 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (600 mg, 2.24 mmol) described in Manufacturing Example 5-1-1, which was irradiated by ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. 2-Chloromethyl-5-fluoro-pyridine (359 mg, 2.46 mol) described in Manufacturing Example 41-2 and N,N-dimethylformamide (10 mL) were added to the resulting white solid and stirred for 1 hour at 60° C. After being cooled to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (650 mg, 77%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C@@H:30]([NH:32][C:33]1[N:38]=[C:37]([N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH:36]=[CH:35][N:34]=1)[CH3:31])=O)C1C=CC=CC=1.Br.CC(O)=O>C(Cl)Cl.O>[C:19]1([NH:18][C:17]([N:14]2[CH2:15][CH2:16][NH:11][C@H:12]([C@@H:30]([NH:32][C:33]3[N:38]=[C:37]([N:39]4[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[CH:40]4)[CH:36]=[CH:35][N:34]=3)[CH3:31])[CH2:13]2)=[O:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a solution of (S,S)-2-[1-(1-(benzyloxycarbonyl)-4-(N-naphth-1-yl-carbamoyl)piperazin-2-yl)ethylamino]-4-[benzi midazol-1-yl]pyrimidine (24 mg) dissolved in 2 mL of CH2Cl2 and cooled to 0° C. was added 1 mL of 30% HBr/AcOH. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for an additional 2 hours while warming to room temperature. The mixture was diluted with 5 mL of water and extracted with 2×5 mL of CH2Cl2. The aqueous layer was basified to pH 11 using 5N NaOH and extracted with 5×5 mL of ethyl acetate while maintaining a pH of 11. The combined organic phases were washed with 10 nL of brine, dried with Na2SO4, and concentrated to provide 9.6 mg the title compound. Mass spectrum (ESI) 493.3 (M+1).
Reaction SMILES: [OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10]>CO>[OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:14])[CH3:15])[NH:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
In the presence of 20 mg of Nishimura catalyst (Rh(III)- and Pt(VI)-oxide monohydrate, Degussa) 100 mg (0.165 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in the form of a solution in 8 ml of methanol are hydrogenated under low pressure at RT. Removal of the catalyst by filtration through ®Celite and concentration of the filtrate by evaporation yields the title compound: FAB-MS (M+H)+ =612.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:11][CH2:10]2)=[O:6]>O1CCOCC1>[C:19]1([S:16]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
1M LiOH aqueous solution (2.4 ml, 2.40 mmol) was added to a solution of 11 (0.38 g, 1.20 mmol) in dioxane (15 mL). The reaction mixture was stirred at 40° C. overnight and then was concentrated under reduced pressure. The residue was dissolved in water and concentrated HCl was added up to acidic pH to give the precipitation, which was dried by vacuum to afford 16 (0.34 g). 1H NMR (500 MHz, CD3OD): δ 2.97 (t, J=8.6 Hz, 2H), 3.99 (t, J=8.6 Hz, 2H), 7.51-7.54 (m, 2H), 7.61-7.64 (m, 2H), 7.74 (s, 1H), 7.84-7.88 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[Cl:14][CH2:15][CH2:16][CH2:17]Br.CC(C)=O>O>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:7]1[C:6]([O:12][CH3:13])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[C:9]([OH:10])[CH:8]=1
Reactant: ClCCCBr
Reactant: COc1cc(C(C)=O)c(O)cc1O
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)c(O)cc1OCCCCl
Yield: 70.3 %

Procedure:
A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K2O3 (1.4 g, 10.0 mmol), 3chlorobromopropane (1.6 g, 10.0 mmol) and acetone (25 mL) was stirred and refluxed under N2 for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H2O, brine) dried (MgSO4) and concentrated to yield 1.4 g of an off-white solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99°-101° C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:29]3[C:28]([CH3:30])=[C:27]([CH3:31])[N:26]=[C:25](OC4C=CC=CC=4)[C:24]=3[N:23]=[C:22]2[CH2:39][CH2:40][CH3:41])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:29]3[C:28]([CH3:30])=[C:27]([CH3:31])[N:26]=[C:25]([NH2:5])[C:24]=3[N:23]=[C:22]2[CH2:39][CH2:40][CH3:41])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
Ammonium acetate (20.2 g, 0.262 mol) and 1-[5-(4-chlorobenzenesulfonyl)pentyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (2.20 g, 4.18 mmol) were stirred at 160° C. in a sealed tube for 18 hours. The solution was allowed to cool to room temperature and partitioned between chloroform (50 mL) and water (25 mL). The aqueous solution was adjusted to pH 11 with the addition of 1 M sodium hydroxide and two solid sodium hydroxide pellets. The aqueous solution was then extracted with chloroform (4×50 mL). The combined organic solutions were washed with 1 M sodium hydroxide (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product as a tan foam. The crude product was purified by column chromatography on silica gel (eluting with 94:5:1 dichloromethane:methanol:triethylamine) to provide a product that was impure as determined by HPLC analysis. A second purification by column chromatography on silica gel (eluting with 96:3:1 dichloromethane:methanol:triethylamine) also resulted in impure material. The solid was recrystallized from acetonitrile, and the crystals were isolated by filtration, washed with cold acetonitrile and ethyl acetate, dried under high vacuum to provide 0.53 g of 1-[5-(4-chlorobenzenesulfonyl)pentyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as white needles, mp 147.0–149.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25]>CO>[CH3:27][O:26][C:24](/[C:23](/[NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)=[CH:22]/[C:28]([O:30][CH3:31])=[O:29])=[O:25]
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: CCCOc1ccc(N/C(=C\C(=O)OC)C(=O)OC)cc1C1=NC(=O)C2=NN=NC2=N1
Yield: 46.6 %

Procedure:
2-(5-Amino-2-propoxyphenyl)-8-azapurin-6-one (1.43 g), dimethyl acetylenedicarboxylate (0.85 g) and dry methanol (20 ml) were stirred and heated together at reflux for 5 hours. The resulting mixture was then cooled in an ice-bath for 30 minutes and the resulting yellow crystalline precipitate was filtered off and recrystallised from ethanol to give (Z)-2-[5-{1,2-bis(methoxycarbonyl)vinylamino}-2-propoxyphenyl]-8-azapurin-6-one (1.0 g), m.p. 199°-200° C. (with decomposition).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>>[N:10]1([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: OCc1ccccc1O
Product: Oc1ccccc1Cn1cncn1
Temperature: 160 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
The mixture of 2-hydroxymethylphenol (25.3 g) and 1H-1,2,4-triazole (15.5 g) was agitated at about 160° C. for 1 hour. After left to stand for cooling, the mixture was solidified into crystal, which was then recrystallized from ethanol and collected to give the title compound (27 g; 76 %).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5](Br)[C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[S:23])=[CH:20][CH:19]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:24]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=3)[S:23][C:5]=2[CH2:4][C:3]([O:2][CH3:1])=[O:16])=[CH:8][CH:9]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: COC(=O)CC(Br)C(=O)c1ccc(Cl)cc1
Product: COC(=O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1

Procedure:
By a process analogous to Example 2, methyl-3-bromo-3-(4-chlorobenzoyl)propionate and 4-hydroxy-thiobenzamide are reacted to give methyl 4-(4-chlorophenyl)-2-(4-hydroxyphenyl)thiazole-5-acetate. This compound is hydrolysed using 2 N sodium hydroxide to give the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2].[SH2:26].B(F)(F)F.CCOCC>ClCCl.C(Cl)(Cl)Cl>[CH3:2][CH2:1][S:3][C@@:4]1([SH:26])[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3
Reactant: S
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCS[C@@]1(S)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: -40 °C
Reaction time: 3.75 h

Procedure:
A solution of 2.0 g of 17-ethylthio-9-fluoro-11β-hydroxyandrosta-1,4,16-triene-3-one in dry dichloromethane (120 ml) was cooled and stirred in a bath at about -40° C. and a slow stream of hydrogen sulfide gas was passed into the solution while boron trifluoride etherate (1.2 ml) was added. After about 3.5 to 4.0 hours, the mixture was diluted with chloroform, warmed to room temperature and washed successively with a dilute sodium bicarbonate solution and water. The soluiton was dried (anhydrous magnesium sulfate), evaporated and the solid residue crystallized from ethyl acetate to afford 1.4. g of the title compound, melting point 239°-242° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Product: CC(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
The starting material was prepared as follows. An Ullmann reaction using p-fluorophenol and p-bromoacetophenone gave 4'-(4-fluorophenoxy)acetophenone, m.p. 65°-67°C. This was subjected to the Willgerodt reaction using morpholine and sulfur, followed by hydrolysis, to give crude 4-(4-fluorophenoxy)phenylacetic acid, which was esterified and gave ethyl 4-(4-fluorophenoxy)phenylacetate, b.p. 139°-142°C./0.3 mm. This ester was treated conventionally with diethyl carbonate and sodium ethoxide, and then with dimethyl sulfate, to yield the required ethyl 2-[4-(4-fluorophenoxy)phenyl]-2-methylmalonate, b.p. 174°-182°C./0.7 mm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:33](=[O:35])[CH3:34])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: CC(=O)Cl
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.23 mmol) was dissolved in pyridine (2 mL) and the mixture was heated at 50° C. Acetyl chloride (65 uL, 0.92 mmol) was added and the mixture was stirred at this temperature for 1 h. Solvent was removed in vacuum and the residue was purified using reverse phase prep HPLC to afford the title compound as a white solid (55 mg). 1HNMR (500 MHz, DMSO-D6) δ 8.34 (s, 1H), 8.04 (d, J=1.0 Hz, 1H), 7.70-7.58 (m, 5H), 3.69 (m, 2H), 3.45 (m, 2H), 3.34 (m, 2H), 3.16 (m, 2H), 2.17 (s, 3H). LCMS: m/e 478 (M+H)+, ret time 1.07 min (method 3).