Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COCCO.Cl>O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:20]([Cl:26])[CH:21]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: Nc1ncnc(Cl)c1C=O
Agent: Cl
Solvent: COCCO
Solvent: O
Product: Nc1ncnc(Nc2ccc(OCc3ccccc3)c(Cl)c2)c1C=O
Temperature: 25 °C

Procedure:
In a 3-necked round bottom flask equipped with a thermal couple, an overhead stirrer and a condenser was added 4-amino-6-chloro-pyrimidine-5-carbaldehyde Cpd 1a (3.23 g, 19.0 mmol), 4-benzyloxy-3-chloro-phenylamine Cpd 1b (4.24 g, 18.1 mmol), 2-methoxyethanol (27 ml) and water (3 ml). The mixture was stirred at room temperature and a 6N HCl solution (0.30 ml, 0.10 eq.) was added. The mixture was heated to 80° C. for 1-2 hours until the starting materials were consumed. The mixture was cooled to room temperature and 6 N NaOH solution (3.3 ml) and water (8 ml) were added. The mixture was cooled to room temperature again and the solid was collected by vacuum filtration. The reaction flask was rinsed by 1:1 EtOH:water (2×10 ml) and the rinses were used to wash the filter cake. The filter cake was further washed by 1:1 EtOH:water (2×10 ml), suction dried, dried in an vacuum oven at 60° C. under house vacuum to afford the title Compound 1c free base as a light yellow solid (6.06 g). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.14 (s, 1H), 8.11 (s, 1H), 7.90 (bs, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.48-7.32 (m, 5H), 7.21 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 3.24 (bs, 2H); mp 206° C. (by DSC).
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1.O>C1COCC1>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([F:43])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1F)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a cooled (−60° C.) solution of 800 mg 19d in 10 mL THF was added 2.04 mmol n-butyllithium. After stirring at −60° C. for 30 min 877 mg N-fluorobenzenesulfonimide was added. The mixture was allowed to reach room temperature and was stirred for another 2 h. Water was added and the mixture was extracted with 2×ethyl acetate. The combined organic phases were dried and concentrated. The crude product by column chromatography over silica to afford an oil, which was crystallized from heptane/diisopropyl ethyl ether to give compound 340 mg of 27a as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.0145 ml acetylchloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 85 mg yellow solid (98%). MS (ISP) 543.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[S:24]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:29][C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Reactant: OCc1ccsc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(OCc4ccsc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a suspension of methyl 3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (240 mg), 3-thiophenemethanol (68 mg) and triphenylphosphine (218 mg) in dry dichloromethane were added to diethyl azodicarboxylate (139 mg) under ice-cooling. After 2 hr, the reaction mixture was stirred at room temperature. After 6 hr, to a suspension of 3-thiophenemethanol (34 mg) and triphenylphosphine (109 mg) in dry dichloromethane was added diethyl azodicarboxylate (69 mg) under ice-cooling. After 20 hr, the reaction mixture was subjected to flash silica gel chromatography (silica gel 60 ml, eluent: chloroform). The eluate was recrystallized from ethyl acetate to give the objective compound (143 mg) as colorless crystals.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:16]=[N:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[Cl:17][C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:9]2[CH:16]=[N:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:21]=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: N#Cc1ccncc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccncc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.8 %

Procedure:
A flask was charged with sodium hydride (3.99 g, 158 mmol) and DMF (50 mL), and 3-hydroxyisonicotinonitrile (15.8 g, 132 mmol) was added. The reaction was stirred for 2 hours at ambient temperature. 2-Chloro-4-nitropyridine (21.9 g, 138 mmol) was added and the reaction was and stirred overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated. The crude product was purified by silica gel chromatography, eluting with DCM, 5% ammoniated methanol in DCM to give the desired product (0.250 g, 0.820% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18](=S)[CH3:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][NH2:28])=O.C(O)CCC>ClCCl.[Hg]=O>[Cl:1][C:2]1[C:3]([N:17]2[C:18]([CH3:19])=[N:28][N:27]=[C:25]2[C:24]2[CH:29]=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(NC(C)=S)c2nc1OC
Reactant: NNC(=O)c1cccc(Cl)c1
Agent: O=[Hg]
Solvent: ClCCl
Solvent: CCCCO
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(C)nnc3-c3cccc(Cl)c3)c2nc1OC
Yield: 35.4 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-thioacetamidoquinoxaline (250 mg, 0.753 mmol), 3-chlorobenzhydrazide (167 mg, 0.978 mmol), mercury(II) oxide (163 mg, 0.753 mmol), powdered 4 Å molecular sieves (175 mg) and n-butanol (7 mL) was heated under reflux for 18 hours. After being cooled, the mixture was filtered through ARBOCEL (trade mark) filter aid and the residue washed with dichloromethane. The filtrate was concentrated under reduced pressure to afford a green solid which was dissolved in dichloromethane, washed twice with 2M aqueous hydrochloric acid solution followed by brine, then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane:methanol (98:2, by volume) to give the title compound (120 mg, 35%) as a pale yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].O=O.[C:6]([OH:9])(=[O:8])[CH3:7]>C(OC(=O)C)(=O)C>[C:6]([O:9][CH2:1][CH:2]([O:9][C:6](=[O:8])[CH3:7])[CH3:3])(=[O:8])[CH3:7]
Reactant: C=CC
Reactant: CC(=O)O
Agent: O=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(C)OC(C)=O
Temperature: 140 °C

Procedure:
1 g of tantalum-V-chloride was dissolved in 400 ml of glacial acetic acid and 50 ml of acetic acid anhydride. After saturation with propylene and the further introduction under pressure of about 10 atmospheres of propylene, 20 atmospheres of oxygen were additionally added and the mixture was heated to about 140° C. After cooling, the batch was distilled. 20 g of propylene glycol diacetate were formed.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](O)=[O:54])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.B#B>C(Cl)Cl.O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CCCCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: B#B
Agent: OCCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: BrCCCCCCCCc1ccccc1

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) as refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° D.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1N)=[O:5])[CH3:2].C(O)(=O)C.N(OC(C)(C)C)=O.[ClH:28]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]=1[Cl:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(CCCOC)c1N
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1cnn(CCCOC)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a mixture of 5-amino-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5.22 g, 23.0 mmol) in dry acetonitrile (46 mL) was added anhydrous cuprous chloride (3.73 g, 37.7 mmol) and acetic acid (2.6 mL, 46.0 mmol). The mixture was cooled to 0° C. in an ice-water bath after which tert-butyl nitrite (4.9 mL, 36.8 mmol) was added over 10 minutes. The solution was allowed to warm to room temperature and stir for 4 h. To the solution was carefully added 6.0N hydrochloric acid (20 mL). The aqueous layer was extracted with methylene chloride (2×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the crude material. The product was purified by column chromatography on silica gel (eluting with ethyl acetate/hexanes, 1:1) to provide 5-chloro-1-(3-methoxypropyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.71 g, 30%) as an orange oil. Mass spectrum: m/z: 247.3 (M+1).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl[CH2:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][O:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])=[C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:19]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(O)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Reactant: O=C(CCl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(OCC(=O)OCc3ccccc3)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.5 %

Procedure:
A solution of 1-[5-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (intermediate E, 29 mg, 0.056 mmol) and potassium tert-butoxide (0.062 mL, 1M, 0.062 mmol) in tetrahydrofuran (0.5 mL) was stirred at ambient temperature for 10 minutes. Benzyl 2-chloroacetate (0.010 mL, 0.067 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. Ethyl acetate and aqueous HCl solution was added until the pH was about 7. The organic layer was eluted through a short pad of silica gel column and the crude material was purified by HPLC and prep TLC to afford the title compound (1.3 mg, 3.5% yield). MS (ESI) [m/e, (M+H)+]=667.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.74-7.70 (m, 12H), 6.15-6.31 (m, 1H), 3.94-5.36 (m, 8H), 2.56-3.71 (m, 6H), 2.09-2.35 (m, 3H), 0.65-1.70 (m, 14H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[NH4+:11].[OH-]>N.CO>[NH2:11][CH2:10][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:9]
Reactant: [NH4+]
Reactant: Brc1cccc([C@H]2CO2)c1
Agent: N
Agent: [OH-]
Solvent: CO
Product: NC[C@@H](O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(S)-2-(3-Bromophenyl)oxirane was dissolved in 7N NH3/MeOH solution (5 mL) and aqueous NH4OH (25%, 5 mL) was added to the reaction mixture which was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure to give (S)-2-amino-1-(3-bromophenyl)ethanol (0.801 g) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([C:22]1[S:26][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])=[CH:24][CH:23]=1)=[O:21])[NH2:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([C:22]3[S:26][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])=[CH:24][CH:23]=3)=[O:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (24 mg, 0.083 mmol) in isopropanol (2.0 mL) was heated with tert-butyl 3-{[5-(hydrazinocarbonyl)thiophene-2-carbonyl]amino}propionate (18 mg, 0.057 mmol) prepared in Reference Synthetic Example 7 and 6 mg of p-toluenesulfonic acid monohydrate at 100° C. for 8 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, methanol and chloroform and dried to give 28 mg of the desired product (yield 85%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:35][CH:36]1[CH2:39][NH:38][CH2:37]1.C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH:36]([F:35])[CH2:37]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: FC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(F)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-fluoro-azetidine hydrochloride in DMF. [α]D20=+19.7° (c=0.17, CHCl3), ES-MS m/e (%): 445 (M+H+, 100).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1
Reactant: OCCCCCCCCCl
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(OCCCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of diethyl azodicarboxylate (7.3 g; 42 mmol) and tetrahydrofuran (15 ml) was added dropwise at 0° C. to a solution of 4-hydroxybenzonitrile (4.2 g; 35 mmol), 8-chloro-1-octanol (6.9 g; 42 mmol), triphenylphosphine (11.0 g; 42 mmol) and tetrahydrofuran (70 ml) and stirred at room temperature overnight. The reaction mixture was added to water (200 ml) and extracted with ethyl acetate (3×100 ml), dried over magnesium sulphate and filtered. The solvent was then removed in vacuo. The residue was purified by column flash chromatography on silica gel using toluene/ethyl acetate (97:3) as eluent, to give 8.8 g (94%) of p-[(8-chlorooctyl)oxy]benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[CH:35].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:35]#[C:34][C:36]3[CH:37]=[CH:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (230 mg; 0.43 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (229.7 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 140 mg. HPLC-MS: m/z: 641.5 (M+H)+; Rt: 2.89 min
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:50]([NH:49][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[CH:47]=[CH:46][C:45]=1[F:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)Nc1nc(N)ccc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 2 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.56 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.42 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 0.6 g of anhydrous potassium carbonate and 1.5 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 20 minutes and allowed to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, supplemented with 2 ml of ethanol, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 0.48 g of the title compound as a pale yellow powder.
Reaction SMILES: C([O:8][C:9]1[C:14]2[C:15]([CH3:45])=[C:16]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:41]([O:43][CH3:44])=[O:42])[CH:38]([CH3:40])[CH3:39])(=[O:35])=[O:34])=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[O:19])[O:17][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:46][CH3:47])C1C=CC=CC=1.C1COCC1>CO.[Pd]>[CH2:46]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([NH:36][C@H:37]([C:41]([O:43][CH3:44])=[O:42])[CH:38]([CH3:40])[CH3:39])(=[O:34])=[O:35])=[CH:31][CH:32]=4)=[CH:25][CH:26]=3)=[O:19])=[C:15]([CH3:45])[C:14]=2[C:9]=1[OH:8])[CH3:47]
Reactant: CCc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c2c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c2c1O
Reaction time: 4 h
Yield: 129.9 %

Procedure:
To 0.1 g (0.15 mmol) of methyl N-{[4′-({[4-(benzyloxy)-5-ethyl-3-methyl-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valinate from Example 89, dissolved in 20 mL of methanol and 10 mL of THF was added 0.2 g of 10% palladium on active carbon and the mixture was hydrogenated in a Parr hydrogenator at 40 psi for 4 hours. The reaction mixture was then filtered through celite and the celite pad was washed with with methanol. The filtrate was concentrated in vacuo to provide 0.11 g of methyl N-[(4′-{[(5-ethyl-4-hydroxy-3-methyl-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valinate. Yield ˜100%, m.p. 75-80° C. MS: 565.2 (M+H)+.