Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=3)[C@H:12]2[N:22]=[N+:23]=[N-:24])=O)=CC=1)([O-])=O.C[O-].[Na+]>CO.C(Cl)Cl>[N:22]([C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:19][C@@H:11]1[OH:10])=[N+:23]=[N-:24]
Reactant: COc1ccc2c(c1)[C@@H](N=[N+]=[N-])[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@H](N=[N+]=[N-])[C@@H](O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Step AC (4): To a solution of (1R,2S)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-yl 4-nitrobenzoate (248 mg) from Step AC (3) in methanol (2.8 mL) and DCM (2.4 mL) was added sodium methoxide (114 mg), and the reaction mixture was stirred at rt for 30 min. the solvents were removed in vacuo, and water was added. The aqueous layer was separated, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by preparative TLC eluting with 30% EtOAc/70% hexanes to give (1R,2S)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-ol compound as a white solid (100 mg). 1H NMR (400 MHz, CDCl3) δ 7.15 (1H, d), 6.91 (1H, d), 6.87 (1H, dd), 4.72 (1H, d), 4.57 (1H, t), 3.80 (3H, s), 3.09 (1H, dd), and 2.84 (1H, dd). The ee of this product was 86% by chiral HPLC (chircel OJ-H column, 4.6×250 mm, 5 μm; mobile phase: 5% ethanol in CO2; flow rate: 2.0 mL/min). Retention time of the title compound: 10.04 min; Retention time of the other enantiomer: 7.38 min.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].C1(O)C=CC(O)=CC=1.[S:15]1[C:19]2[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1.CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[S:15]1[C:19]2[CH:20]=[C:21]([NH:24][CH2:6][CH:2]([CH3:1])[C:3]([OH:5])=[O:4])[CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc2ncsc2c1
Agent: Oc1ccc(O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(CNc1ccc2ncsc2c1)C(=O)O
Temperature: 100 °C
Yield: 27.4 %

Procedure:
2-Methyl-acrylic acid (0.63 g, 0.00732 mol) and Benzene-1,4-diol (0.029 g, 0.000266 mol) were added to a stirred solution of Benzothiazol-6-ylamine (1 g, 0.00665 mol) in toluene (6 mL) under nitrogen atmosphere. The resulting reaction mass was heated at 70° C. for 72 hours and further at 100° C. for 48 hours. The reaction was monitored by TLC (5% methanol in chloroform). The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (0.75% methanol in chloroform) afforded 0.43 g of the product (26.87% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH2:26])[CH2:19][CH2:18][CH2:17][C:16]2=1>>[Br:12][C:13]1[CH:14]=[C:15]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]1[CH:20]([NH:26][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[CH2:19][CH2:18][CH2:17][C:16]2=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1c(F)cccc1F

Procedure:
N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2,6-difluorobenzamide was prepared from 2,6-difluorobenzoylchloride and 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid: 1H-NMR (CDCl3): δ 8.80 (s, 1H), 7.60 (m, 1H), 7.35 (m, 1H), 7.23 (overlapped dd and d, 2H), 6.94 (t, 2H), 6.37 (d, 1H), 5.35 (m, 1H), 2.7 (m, 2H), 2.26 (m, 1H), 1.95 (m, 3H); MS m/z 404 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26]Cl)=[CH:21][CH:20]=[CH:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH2:26][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:21][CH:20]=[CH:19]2
Reactant: ClCc1cccc2cc(Cl)ccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc2cc(Cl)ccc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 6-chloro-1-chloromethyl-naphthalene (Lit. 14) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 334.0 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:24]I>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH3:24])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1ccn(C)c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=338.1, 340.0 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and methyl iodide.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].N12CCCN=C1CCCC[CH2:28]2.CI>>[CH3:28][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)[CH3:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Solvent: CI
Product: COC(=O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.7 %

Procedure:
2-Methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (208 mg, 0.54 mmol) is suspended in acetoitrile (5 mL). 1,8-Diazabicyclo[5,4,0]undec-7-ene (0.096 mL, 0.64 mmol) is added and followed by the addition of methyl iodide (0.073 mL, 1.18 mmol). The reaction mixture is stirred at room temperature for 3.5 h. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The combined organics are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica, eluent: DCM, MeOH) to provide 171 mg of the title compound. Yield: 79%; m/z 403 [M+H].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH:15]1[C:11]2=[N:12][CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[C:10]2[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)NCc1ccnc2[nH]ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccnc2[nH]ccc12
Reaction time: 14 h

Procedure:
To a solution of (1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (200 mg, 0.809 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (1.58 mL, 20.6 mmol). After 14 hours, the reaction was concentrated in vacuo to afford the title compound which was used in the without purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]([OH:30])=[O:29]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28]([OH:30])=[O:29])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: NCCN1CCCC1C(=O)O
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCCC3C(=O)O)s2)c(C)[nH]c1=O
Yield: 88 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(2-aminoethyl)-pyrrolidine-2-carboxylic acid as described in Step 5, Example 24 to give the title compound (88% yield). LC/MS: RT 2.04 min; m/e 440 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.Cl.[C:25](O)(=[O:29])[C@H:26]([CH3:28])[OH:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:25](=[O:29])[CH:26]([OH:27])[CH3:28])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCNCC3)sc2n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)C(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-piperazin-1-ylmethyl-thiazolo[5,4-d]pyrimidine with HCl salt (1 g, 2.6 mmol), L-(+)-lactic acid (460 mg, 5.1 mmol), HATU (1.9 g, 5.1 mmol) and N,N-diisopropylethylamine (1.4 mL, 7.8 mmol) in 8 mL of DMF was stirred overnight. The mixture was diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to yield the crude 1-[4-(5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperazin-1-yl]-2-hydroxy-propan-1-one (900 mg).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1)([O-])=O>CO.[Ni]>[ClH:1].[NH2:2][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([NH:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)NC(=O)CNCc1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CC(Cc1cccc(N)c1)NC(=O)CNCc1ccccc1

Procedure:
7.5 gm of chloroacetyl chloride were added dropwise to a mixture of 18 gm of 1-(3'-nitro-phenyl)-2-amino-propane, 14 gm of potassium carbonate and 150 ml of acetonitrile, whereby the temperature of the mixture rose to 45° C, and the resulting mixture was refluxed for two hours. Thereafter, the reaction mixture was allowed to cool, and then it was diluted with ice water, whereupon 1-(3'-nitro-phenyl)-2-(chloroacetyl-amino)-propane (m.p. 118° -120° C, recrystallized from ethyl acetate/petroleum ether) crystallized out. 17 gm of this compound were added to a mixture of 14 gm of benzylamine and 200 ml of acetonitrile, and the mixture was refluxed for two hours. Thereafter, the benzylamine hydrochloride which had precipitated out was removed by suction filtration, the filtrate was acidified with ethereal hydrochloric acid, and the crystalline precipitate formed thereby was recrystallized from 1 N hydrochloric acid, yielding 11.5 gm of 1-(3'-nitro-phenyl)-2-(benzylaminoacetyl-amino)-propane hydrochloride, m.p. 167° -170° C. This hydrochloride was hydrogenated in methanol in the presence of Raney nickel at atmospheric pressure and room temperature, yielding 1-(3'-aminophenyl)-2-(benzylaminoacetyl-amino)-propane hydrochloride which was dissolved in ethanol, and the solution was admixed with the calculated amount of ethereal hydrochloric acid, yielding the dihydrochloride of the formula ##STR28## which had a melting point of 234° -236° C (decomp.).
Reaction SMILES: C(N1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36](O)=[O:37])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.Cl.C(N)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36](=[O:37])[NH:3][CH2:7][CH3:6])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: CCN
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Under ice cooling, 1,1′-carbonyldiimidazole (1.0 g) was added to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (2.0 g) in dimethylformamide (40 ml). After stirring the mixture for 2 hr, ethylamine hydrochloride (0.51 g) was added thereto. Then the resultant mixture was allowed to warm to room temperature and stirred for additional 5 hr. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then the residue was dissolved in hot toluene (10 ml). After allowing to cool to room temperature, the resulting crystals were collected by filtration to give the title compound (1.3 g) as a white powder (yield: 56%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Na].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24].[H-].[Na+].C1(O)C=CC=CC=1>CN(C)C=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:19][C:18]=1[CH3:24]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(Cl)c(C)c2)ccc1[N+](=O)[O-]

Procedure:
Methyl 5-fluoro-2-nitrobenzoate was reacted with the sodium salt of 4-chloro-3-methylphenol (prepared from sodium hydride and the phenol) in dimethylformamide at 100° C. for 2.5 hours and the resulting methyl 5(4-chloro-3-methylphenoxy)-2-nitrobenzoate isolated in the usual way; the ester had a melting point of 85°-87° C.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13]([S:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:13]([S:16]([N:18]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)S(N)=O
Reactant: CCOC(=O)CCCCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)CCCCC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A yellow solution of ethyl 6-oxohexanoate (44.80 mmol) in DCM (92 ml) was treated with 2-methylpropane-2-sulfinamide (5.431 g; 44.80 mmol) and with anh. CuSO4 (14.302 g; 89.61 mmol). The resulting beige heterogeneous mixture was further stirred at rt, under nitrogen, for 24 h. The resulting heterogeneous mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained orange filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 6-((tert-butylsulfinyl)imino)hexanoate as a yellow/orange oil. LC-MS (conditions B): tR=0.81 min.; [M+H]+: 262.07 g/mol.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]1([CH3:29])[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[C:26](O)=[O:27])=[CH:17][CH:16]=1>>[F:13][C:10]([F:12])([F:11])[C:9]([NH:8][CH2:7][C@H:2]1[N:3]([C:26]([C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([CH3:29])=[CH:16][CH:17]=2)=[O:27])[CH2:4][C@H:5]2[C@@H:1]1[CH2:6]2)=[O:14]
Reactant: Cc1ccc(-c2sccc2C(=O)O)cc1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Product: Cc1ccc(-c2sccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)cc1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-p-tolyl-thiophene-3-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]3[N:19]=[C:20]([CH3:22])[CH:21]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>N#N.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=3)[N:15]3[N:19]=[C:20]([CH3:22])[CH:21]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C)cc3)cc(Cl)n2n1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C)cc3)cc(-c3cccc(CO)c3)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A suspension of 4-tert-butyl-N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)benzamide (1K, 40 mg, 1.0 equivalent), 3-(hydroxymethyl)phenylboronic acid (1.9 equivalents), Pd(PPh3)4 (0.10 equivalent), and Na2CO3 (4.0 equivalents) in N2-saturated 5:1 DMF/H2O (0.05 M with respect to 1K) was stirred at 100° C. overnight. After cooling, the mixture was diluted with brine and extracted with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography (SiO2, gradient of 40 to 50% EtOAc/hexanes). The product was then recrystallized from CH2Cl2-hexanes to give the titled compound (62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9H) 2.50 (s, 3H) 4.83 (d, J=6.1 Hz, 2H) 6.29 (s, 1H) 7.44-7.71 (m, 5H) 7.88 (d, J=8.3 Hz, 2H) 8.03 (s, 1H) 8.15 (s, 1H) 8.59 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH2:15]C(O)=O)(=[O:14])=[O:13])=[C:7]([Cl:19])[CH:6]=1)[CH3:2].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([Cl:19])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:9]([Cl:11])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(S(=O)(=O)CC(=O)O)c(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)c(S(C)(=O)=O)c(Cl)c1

Procedure:
3,5-Dichloro-4-[(carboxymethyl)sulfonyl]benzoic acid ethyl ester (3.1 g) was mixed with toluene (100 mL) and pyridine (1.0 mL) and the mixture was refluxed for 30 min and then evaporated to dryness (yield 2.6 g). 1H-NMR (400 MHz, DMSO-d6) d=1.34 (t, J=7.0 Hz, 3H), 3.51 (s, 3H), 4.37 (q, J=7.0 Hz, 2H), 8.05 (s, 2H).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:27])[N:16]([CH2:17][CH2:18][C:19](=[S:21])[NH2:20])[C:15](=[O:22])[C:14]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:13]12>>[C:15]1(=[O:22])[N:16]([CH2:17][CH2:18][C:19]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:20]=2)[C:12](=[O:27])[C:13]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:14]12
Reactant: NC(=S)CCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2CC1Br
Product: O=C1c2ccccc2C(=O)N1CCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 3-phthalimidopropanethioamide
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Si:14]([O:21][C@H:22]1[CH2:26][CH2:25][O:24][C:23]1([OH:28])[CH3:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O>[Si:14]([O:21][C@@H:22]([CH2:26][CH2:25][O:24][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C:23](=[O:28])[CH3:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(O)OCC[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Imidazole (125 mg, 1.84 mmol, 2.2 equiv) and tert-butyl-dimethylsilyl chloride (139 mg, 0.92 mmol, 1.1 equiv) are added to a solution of (3S)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-2-methyl-tetrahydrofurane 13 (194 mg, 0.83 mmol) in dimethyl formamide (800 μl). The mixture is stirred for 24 h at r.t. Purification of the reaction mixture by flash column chromatography (pentane/diethyl ether 20:1) affords (S)-3,5-di-(tert-butyidimethylsilyloxy)pentan-2-one 14 (226 mg, 78%) as a colourless oil. [α]D20=−11.8; [α]54620=−14.1 (c=1.0, CHCl3); 1H-NMR (200 MHz, CDCl3): δ(ppm)=4.16 (dd, 1H); 3.8-3.5 (m, 2H); 2.16 (s, 3H); 1.9-1.7 (m, 2H); 0.92 (s, 9H); 0.88 (s, 2H); 0.06 (s, 6H); 0.04 (s, 3H), 0.03 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[O:24]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:23]([NH:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[Cl:14])=[O:24])=[C:3]([OH:13])[C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 73.7 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (0.88 g, 3.9 mmol) and 2,3-dichlorophenylisocyanate (0.62 mL, 4.6 mmol) in 5 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70 to 50/50, v/v), followed by recrystallization from dichloromethane and hexane, gave the desired product (1.18 g, 74%). mp 241-242° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:13](=O)[O:12][C:10](=O)[C:9]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:8]12)(=[O:3])[CH3:2].CSC1[NH:22][CH2:23][CH2:24][N:25]=1.[OH-].[K+]>O1CCOCC1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:8]2[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10](=[O:12])[N:22]2[CH2:23][CH2:24][N:25]=[C:13]12)(=[O:3])[CH3:2]
Reactant: CSC1=NCCN1
Reactant: CC(=O)OCCn1c(=O)oc(=O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)OCCN1C2=NCCN2C(=O)c2ccccc21

Procedure:
A mixture of 18 g. of N-(2-acetoxyethyl)isatoic anhydride, 8.5 g. of 2-methylmercapto-imidazoline and 2 pellets of potassium hydroxide in 300 ml. of dioxane is heated at reflux for 5 hours, the solvent then evaporated off and water added. The resulting precipitate is recovered by filtering and washed twice with water. The precipitate is dissolved in methylene chloride and extracted 3times with 1N. hydrochloric solution. The combined hydrochloric acid solutions and filtered through celite, sodium carbonate solution is added and the resulting precipitate is recovered by filtering, washed with water, air dried, dissolved in methylene chloride, dried, filtered and the methylene chloride exchanged for diethyl ether. The resulting precipitate is recovered by filtering, washed with cold diethyl ether and dried under reduced pressure at 40° C. to obtain 10-(2'-acetoxyethyl)-2,3-dihydro-imidazo[2,1-b] quinazolin-5(10H)-one, m.p. 124°-126° C.