Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:19][C:20]([OH:22])=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(OC(=O)C)(=O)C>[C:28]([O:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:20](=[O:22])[CH2:19][N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:11]=2)[CH2:37]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)CN(CC(=O)O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.9 %

Procedure:
A mixture of [carboxymethyl-(4-phenoxyphenyl)amino]acetic acid 19 (0.5 g, 1.66 mmol) in acetic anhydride (10 mL) was heated to reflux with stirring for 45 minutes. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate. Solid sodium bicarbonate was added and the mixture stirred until effervescence had ceased. The aqueous mixture was extracted with ethyl acetate (×2) and the organic fractions combined, washed with saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and evaporated to dryness. The residue was co-evaporated with toluene, dissolved in THF (10 mL) and added to (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (0.39 g, 2.09 mmol). The reaction mixture was stirred for 3 days and then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid (×2), brine, dried (Na2SO4) and evaporated to dryness. The crude product was crystallized from ethyl acetate to give the title compound as a cream powder (0.35 g, 45%). 1HNMR (300 MHz) (CDCl3) δ 1.45 (6H, s), 1.55 (3H, s), 1.8-2.4 (2H, m), 3.4-3.9 (5H, m), 4.05-4.75 (4H, m), 6.48 (2H, m), 6.90-7.07 (5H, m) and 7.28 (2H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:19]([O-:22])(=O)=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=1.[Na+].P(Cl)(Cl)([Cl:26])=O.CN(C)C(=O)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:19]([Cl:26])(=[O:22])=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(S(=O)(=O)[O-])ccc1N=Nc1ccc(O)c(C#N)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)Cl)ccc1N=Nc1ccc(O)c(C#N)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
12.5 g (0.037 mol) of the sodium benzenesulfonate obtained in Step (a) above was stirred in 74 ml of acetonitrile, to which were added dropwise 14 ml of phosphorus oxychloride and then 14 mol of N,N-dimethylacetamide, and the mixture was heated at 50° C. with stirring for 1.5 hours. After cooling, the reaction mixture was added to 300 ml of ice water and the crystals thus-precipitated were collected by filtration. Yield: 11.9 g (96%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[C:27]([CH3:28])=[CH:26][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:29])[CH:7]=1)\[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36](Br)[CH2:37][CH3:38]>C(#N)C.O>[CH3:29][C:8]1[CH:7]=[C:6](/[C:3](=[N:2]/[O:1][CH2:36][CH2:37][CH3:38])/[CH2:4][CH3:5])[C:27]([CH3:28])=[CH:26][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCBr
Reactant: CC/C(=N\O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCO/N=C(\CC)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 0.12 g (0.3 mmol) of (E)-methyl 2-(2-((4-((E)-1-(hydroxyimino)propyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 4 and 0.2 g (0.61 mmol) of cesium carbonate in 10 mL of acetonitrile (CH3CN) was added propyl bromide (0.05 mL, 0.55 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum and the concentrate was purified by silica gel chromatography to afford 0.1 g of (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)propyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate as a white oil (yield: 77%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:6][CH2:7][CH3:8])[CH3:2].Cl[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:37][CH:38]=1)([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCC(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1ccc(OCCN2CCCCCC2)cc1
Product: CCCC(Cc1ccc(OCCN2CCCCCC2)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (3.5 g, 11.7 mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (3.9 g, 12.8 mmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH3:35].Cl>ClCCl>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:6]=[N:7][C:2]([NH:1][S:36]([CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
To a mixture of [4-(6-amino pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.10 g, 0.285 mmol) and triethyl amine (0.037 g, 0.371 mmol) in 10 mL of dichloromethane at 0° C. was added n-propylsulphonyl chloride (0.044 g, 0.313 mmol). The reaction mixture was stirred at room temperature for 4 hours and then dilute hydrochloric acid solution was added (20 mL). The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, the concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (46.3 mg, 35.5% yield). 1H NMR (400 MHz, CDCl3) δ 7.75, 7.63-7.66, 7.56-7.59, 7.37, 7.25, 6.99, 4.04-4.07, 3.85-3.89, 3.71-3.78, 3.35, 1.96-2.00, 1.1.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[O:19]=[C:12]1[NH:11][C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13]1
Reactant: [H][H]
Reactant: O=C(O)[C@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC[C@H](C(=O)O)N1
Yield: 71.3 %

Procedure:
Under nitrogen atmosphere, to a solution of (R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester (1.61 g) in methanol/tetrahydrofuran (4/1, 20 ml) was added 10 wt % palladium on carbon (161 mg) at room temperature, and the mixture was stirred for 24 hours under one atmosphere of hydrogen. Under nitrogen atmosphere, palladium on carbon in this reaction solution was filtered off through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added diisopropyl ether and n-hexane, and the mixture was stirred. A solid was collected from this suspension by filtration, and dried under reduced pressure to give the titled compound (565 mg).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])[CH:5]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:20])=[O:2])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(Br)cc2F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(Br)cc2F)c1

Procedure:
A solution of 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid methyl ester (5.5 g, 16.22 mmol) in dioxane was treated with a solution of lithium hydroxide (1.86 g, 81.1 mmol) in water at room temperature overnight, followed by acidification with concentrated HCl and diluted with water. The precipitate was collected by filtration, washed with water, and dried to give 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid, 5.2 g (99%). LC-MS (ES) calculated for C14H10BrFO3, 323; found m/z 324 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:50])[CH2:44][C@H:45]1[CH2:49][CH2:48][CH2:47][O:46]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:50])[CH2:44][C@H:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@H]2CCCO2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 19.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(R)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.2 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([OH:14])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[OH:6].CO[C:18](=O)[C@@H:19](O)[C@@H](C1C=CC=CC=1Cl)O>>[CH3:1][O:2][C:3]([C@@H:4]1[C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[O:6][CH:18]([CH3:19])[O:14]1)=[O:15]
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1F
Reactant: COC(=O)[C@@H](O)[C@H](O)c1ccccc1Cl
Product: COC(=O)[C@H]1OC(C)O[C@@H]1c1ccccc1F
Yield: 70 %

Procedure:
The substantially same method as described in Example 60 was conducted, except that (2S,3R)-methyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (Preparation example 81) was used instead of ((2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate, to obtain the title compound (3.1 g, 70˜95%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Reactant: NC1CCCCC1
Product: CCOC(=O)c1ccc(Nc2nc(NC3CCCCC3)nc3[nH]cnc23)cc1

Procedure:
The procedure is carried out as in stage 2 of Example 1, using 238 mg of the product obtained in stage 1 of Example 1 and 0.86 ml of cyclohexylamine in place of trans-1,4-diaminocyclohexane. 121 mg of the expected product are thus obtained.
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a suspension of (3S,4S)-4-methyl-piperidin-3-ol hydrochloride (intermediate 26; 0.04 g, 0.3 mmol) in dichloromethane (1 ml) was added triethylamine (0.04 ml, 0.3 mmol) and acetic acid (0.03 ml, 0.5 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.08 g, 0.3 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.07 g, 0.4 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=468.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:10]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1csc(C2OCCO2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (14.2 g) in tetrahydrofuran (400 mL) was slowly added a 1.6M n-butyllithium hexane solution (62 mL) at −78° C. The reaction mixture was stirred for 30 min, diethyl oxalate (16.5 g) was added, and the mixture was further stirred for 2 hr. The reaction mixture was warmed to room temperature, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (12.2 g, yield 52%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 258 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:34]([NH2:36])=[O:35])[CH3:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:34]([NH2:36])=[O:35])[CH3:9]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.23 g of 3-[(1R)-1-(2-bromophenyl)ethoxy]-5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide in 21 ml THF is cooled to 0° C. At 0° C. 0.76 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[Br:14][C:11]1[CH:10]=[N:9][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][CH:12]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
Potassium carbonate (0.34 g) was added to a solution of 2-chloro-5-bromo-pyrimidine (0.5 g) in DMF (20 ml). The reaction mixture was stirred at rt for 15 min. Morpholine (0.2 g) was added and the reaction mixture was stirred at rt for 2 h. The excess DMF was removed by evaporation and the residue was partitioned between H2O/EtOAc (30:30 ml) The EtOAc layer was dried (MgSO4) and evaporated to dryness to give the sub-title compound as a cream solid (0.2 g). LCMS electrospray(+ve) 246 (MH+).
Reaction SMILES: [C:1]1([S:7][C:8]2(SC3C=CC=CC=3)[C:16]3[S:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:13][C:12]=3[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:21]([NH:20][C:18]([NH:17][C:14]1[S:15][C:16]2[C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH2:10][CH2:11][C:12]=2[N:13]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)(Sc1ccccc1)CCC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2c(s1)C(Sc1ccccc1)=CCC2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-[7,7-di(phenylsulfanyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl]-N′-ethylurea (700 mg, 1.59 mmol) in THF (14.0 mL) was added DBU (0.36 mL, 2.38 mmol). The reaction mixture was stirred at about 20° C. for about 30 min. The reaction was concentrated in vacuo. The residual yellow oil was taken up in CH2Cl2, washed with AcOH/H2O 1/10 and dried over MgSO4. The organic solvent was removed in vacuo and the residual oil (1.0 g) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[OH:21][C:16]1[CH:17]=[C:18]2[O:19][CH2:20][C:3]3[C:4](=[N:5][C:6]4[C:11]([C:2]=3[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=3)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[C:13]2=[CH:14][CH:15]=1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2c3c(nc4ccc(O)cc24)-c2ccc(O)cc2OC3)c1
Yield: 87 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 3-methoxyphenylboronic acid according to method M. Yellow powder; Yield: 87%; mp 155-158° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 3.82 (s, 3H), 4.99 (d, J=14.2 Hz, 1H), 5.04 (d, J=14.2 Hz, 1H), 6.35 (d, J=2.3 Hz, 1H), 6.60 (dd, J=8.6, 2.3 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 6.90 (m, 1H), 6.92 (d, J=1.6 Hz, 1H), 7.12 (m, 1H), 7.24 (dd, J=9.1, 2.7 Hz, 1H), 7.52 (dd, J=8.2, 7.9 Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 8.15 (d, J=8.6 Hz, 1H), 9.80 (s, 1H), 9.96 (s, 1H); MS (ESI) m/z 370 ([M−H]−), 372 ([M+H]+); HRMS (ESI+) calcd for C23H17NO4372.1230 ([M+H]+). Found: 372.1223.
Reaction SMILES: [OH:1]O.[CH2:3]([S:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)=[O:8])[CH3:4]>C(O)(=O)C>[CH2:3]([S:5]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)=[O:8])=[O:1])[CH3:4]
Reactant: CCSCC(=O)c1ccc(-c2ccccc2F)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CCS(=O)CC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.8 ml of 30% hydrogen peroxide were added dropwise, while stirring, to a suspension of 16.3 gm (59.5 millimols) of ethyl-[2-(2'-fluoro-4-biphenylyl)-2-oxo-ethyl]-sulfide in 170 ml of glacial acetic acid at 15° C. A clear solution was obtained which was stirred for 1 hour at room temperature. The reaction product was precipitated with water and recrystallized from isopropanol. Yield: 11.6 gm (67% of theory); m.p. 91-93° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([CH3:45])[C:26]1[N:43]([CH3:44])[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[N:27]=1>>[CH3:24][N:25]([CH3:45])[C:26]1[N:43]([CH3:44])[C:29]2=[N:30][CH:31]=[C:32]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:33]=[C:28]2[N:27]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN(C)c1nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2n1C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)nc(N(C)C)n5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and dimethyl-[3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-amine (Stage 70.1.1) to give the title compound as a white solid. (HPLC: tR 2.21 min (Method A); M+H=468 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.17-8.06 (m, 3H), 7.96-7.90 (m, 1H), 7.72-7.67 (m, 1H), 7.56-7.52 (m, 1H), 3.91 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 3.06 (s, 6H), 1.97 (s, 3H))
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[C:12]([O:16][C:17]([NH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C:20]1([C:23]([NH:1][N:2]2[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]2[C:8]([O:10][CH3:11])=[O:9])=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1c(Cl)ccn1N
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(Cl)ccn1NC(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a stirred solution of methyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (1.50 g, 8.59 mmol) in DCM (50 mL) was added 1-((tert-butoxycarbonyl)amino) cyclopropanecarboxylic acid (2.59 g, 12.9 mmol), HOBT (1.58 g, 10.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.47 g, 12.9 mmol) and DIPEA (3.00 mL, 17.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give methyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropanecarboxamido)-3-chloro-1H-pyrrole-2-carboxylate (950 mg, 30.9%) as a white solid. LCMS Condition B-16: retention time 0.87 min, [M+1]=358.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.06 (m, 2H), 1.30-1.38 (m, 2H), 1.41 (s, 9H), 3.74 (s, 3H), 6.27 (s, 1H), 6.99 (d, J=2.4 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 11.08 (s, 1H).