Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]([O:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([O:27]C)=[O:26])=[C:23]2[C:18]([C@H:19]3[CH2:29][C@H:20]3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:12])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:1]([C@H:3]([O:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][C:15]1[C:24]([C:25]([OH:27])=[O:26])=[C:23]2[C:18]([C@H:19]3[CH2:29][C@H:20]3[CH2:21][O:22]2)=[CH:17][CH:16]=1)(=[O:12])=[O:13])[CH3:2]
Reactant: CC[C@H](OC1CCNC1)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CC[C@H](OC1CCNC1)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OC[C@@H]1C[C@H]21
Yield: 64.5 %

Procedure:
A mixture of methyl (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 213, 0.217 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 mL) and water (1 mL) was irradiated in the microwave at 130° C. for 40 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid, evaporated in vacuo and azeotroped with a mixture of toluene and ethanol. The residue was triturated with 15% methanol in DCM, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20%. The resultant gum was triturated with ether and ethyl acetate and filtered to give (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.136 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:21]C1C(=O)CCN(C(OC(C)(C)C)=O)C1>>[CH3:21][CH:8]1[CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1=[O:1]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC(C)C1=O
Yield: 100 %

Procedure:
The title compound was prepared by a similar method to that of 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (see WO2006029154, example 1a, p 34) from Tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate, yielding 100% of title compound which was taken on for pyrimidone formation without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[NH:21][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(CCCCc3c[nH]c4ccc(C(=O)O)cc34)CC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc(O)cc4)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 4 g of 3-[4-(4-p-methoxyphenylpiperazino)butyl]indole-5-carboxylic acid, 3.2 g of pyridine hydrochloride and 80 ml of pyridine is boiled for 3 hours. It is cooled, evaporated and worked up in a conventional manner, and 3-[4-(4-p-hydroxyphenylpiperazino)butyl]indole-5-carboxylic acid is obtained.
Reaction SMILES: O[CH2:2][C:3]1[O:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1.[Cl:21]CCl.N1C=CC=CC=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[Cl:21][CH2:2][C:3]1[O:7][N:6]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(CO)n2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2noc(CCl)n2)CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
1,1-Dimethylethyl 4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (7.4 g, 26 mmol) was taken into dichloromethane (100 mL) followed by addition of pyridine (5.3 mL, 65 mmol) and the solution was cooled to 0° C. Thionyl chloride (2.3 mL, 31.2 mmol) was added by syringe and the mixture was allowed to warm to room temperature and stirred an additional 12 hours. The mixture was then concentrated in vacuo and the residue partitioned with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed once with 0.1M aqueous hydrochloric acid then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration, concentration and purification of the residue by silica gel flash chromatography using 3:1 hexanes:ethyl acetate provided 1,1-dimethylethyl 4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]piperazine-1-carboxylate (4.82 g, 61% yield) as a slightly yellow crystalline solid. 1H-NMR (400 MHz, CDCl3): 4.53 (s, 2H), 3.51 (tr, 4H), 3.43 (tr, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1.[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[O:36][C:35](=[O:37])[CH:34]=[C:33]([OH:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC>>[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[O:36][C:35](=[O:37])[C:34]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[N:8]=3)=[C:33]([OH:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)c(OC)c1
Reactant: Cc1cnc2nc(C=O)nn2c1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(C)cn4n3)C(=O)O2)c(OC)c1

Procedure:
The title compound was prepared analogously to Example B(97) where 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dione of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.36–1.72 (m, 8H), 1.93–2.02 (m, 2H), 2.35 (s, 3H), 2.42–2.58 (m, 2H), 2.76 (d, J=16 Hz, 1H), 3.34 (s, 6H), 3.69 (s, 2H), 3.73 (s, 2H), 6.46 (dd, J=8, 2.5 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.70 (d, J=2.5 Hz, 1H), 8.85–8.87 (m, 1H), 10.8 (s, 1H). Anal. Calcd. For C27H32N4O5: 0.1H2O: C, 63.51; H, 6.71; N, 10.97. Found: C, 63.50; H, 6.70; N, 10.87. MS (ESI): 493 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([NH2:15])[C:3]=1[NH2:18]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1

Procedure:
A reaction tube was charged with a suspension of 1 (270 mg, 0.9 mmol) and Lindlar catalyst (192 mg, 10 mol %) in methanol (5 mL), and was then placed on a Parr shaker. The was reaction pressurized with H2 (60 psi) and maintained for 1 h. The reaction was filtered through Celite and the remained solids were washed with methanol. The combined organics were concentrated to give 2 as a brown semi-solid which was carried forward without further purification LCMS m/z 273.3 (MH+), tR=1.56 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Br)cc1
Temperature: 60 °C
Yield: 85.2 %

Procedure:
To a solution of 5.31 g (0.0307 moles) of 4-bromophenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 60° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75° C. for 4 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried, which gave 8.1 g of crude product. The crude product was dissolved in CH2Cl2 and washed with 10% aqueous NaOH, water and dried (Na2SO4). Removal of solvent in vacuo gave 7.5 g (85% yield) of product. Recrystallization from ethanol afforded purified 2-(4-bromophenoxy)-5-nitrobenzonitrile, mp 171°-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)[N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cc(OCCOCCOC)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCOCCOC)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1 g 5-[2-(2-Methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml of DMF and 154 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 5 min at room temperature, 966 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 2 h. Then 50 ml of water were added and the mixture was extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was used in the next reaction step without further purification. Yield: 1.2 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[O:12][C:11](=[O:29])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:30])[CH:36]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.926, m/z=472.2; 1H NMR (CD3OD) 1.31 (s, 3H), 1.41 (s, 1H), 1.58 (d, 3H), 2.30 (m, 2H), 2.34 (m, 1H), 2.43 (m, 1H), 2.61 (d, 2H), 2.81 (s, 3H), 3.21 (m, 1H), 5.62 (m, 1H), 7.08 (m, 2H), 7.29 (d, 2H), 7.41 (m, 2H), 7.79 (d, 2H), 8.09 (m, 1H), 8.19 (s, 1H), 8.68 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([CH2:24]Cl)(=[O:23])=[O:22])[C:15]=2[OH:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[O:26][CH2:24][S:21](=[O:23])(=[O:22])[N:20]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NS(=O)(=O)CCl)c2O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCS(=O)(=O)N3Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.3 %

Procedure:
To a flask containing 7 mL methanol was added 4-(3-chloromethanesulfonylamino-2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (190 mg., 0.471 mmol) and potassium carbonate (195 mg, 1.4 mmol). The suspension was refluxed for two hours under nitrogen and allowed to cool to room temperature. To the reaction mixture was added benzyl bromide (0.083 mL, 0.7 mmol) and potassium carbonate (87 mg., 0.7 mmol), and the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the resulting crude solid was dissolved in ethyl acetate. The solution was washed with 50 mL water and 50 mL brine, and the ethyl acetate was removed in vacuo. The resulting residue was purified by flash chromatography to give 57 mg of 4-(1-Benzyl-2,2-dioxo-2,3-dihydro-1H-benzo[4,2,1]oxathiazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a light purple oil (26%). (M+H)+=460
Reaction SMILES: [I-].[C:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S+:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]2=3)=[CH:10][CH:9]=1)(=[O:4])[CH3:3].[OH-].C[N+](C)(C)C.C(O)(=O)C>CO.C(Cl)(Cl)Cl.C([O-])(=O)C.[Ag+]>[C:2]([O-:5])(=[O:4])[CH3:3].[OH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S+:14]2[C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=3)=[CH:12][CH:13]=1
Reactant: CC(=O)OCCc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: OCCc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 154.8 %

Procedure:
While cooling with ice, 10.0 g of dibenzothiophene-S-oxide synthesized in the above step (1) is added to 30 g of diphosphorus pentoxide/methanesulfonic acid (9/1), and 10 ml of 2-phenylethyl acetate is further added thereto. The reaction solution is stirred at room temperature for 6 hours, and then poured into ice water. The obtained aqueous solution is filtered, and 23 g of potassium iodide is added. The crystals precipitated are recovered by filtration to obtain 11.1 g of 5-[4-(2-acetoxyethyl)phenyl]dibenzothiophenium iodide. The obtained 11.1 g of 5-[4-(2-acetoxyethyl)phenyl]-dibenzothiophenium iodide is dissolved in 200 ml of methanol, and 10.7 g of a 20% aqueous solution of tetramethylammonium hydroxide is added to the reaction solution. After stirring the reaction solution at room temperature for 2 hours, 10 ml of acetic acid is added and the reaction solution is further stirred at room temperature for 30 minutes. Further, 3.9 g of silver acetate is added to the reaction solution and stirred at room temperature for 1 hour. After filtering the reaction solution, the mother liquor is distilled off under reduced pressure. The crystals obtained are dissolved in chloroform, and washed with water three times. After distilling off the chloroform under reduced pressure, the reaction product is recrystallized with ethyl acetate/acetonitrile (10/1), whereby 6.6 g of 5-[4-(2-hydroxyethyl)phenyl]dibenzo-thiophenium acetate is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2].[CH3:20][O:21][C:22]([N:24]=[C:25]=[S:26])=[O:23]>CC(C)=O>[CH3:20][O:21][C:22]([NH:24][C:25](=[S:26])[NH:19][C:6]1[CH:7]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])=[O:23]
Reactant: CC(=O)Nc1ccc(SCc2ccccc2)cc1N
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(SCc2ccccc2)ccc1NC(C)=O
Reaction time: 8 h

Procedure:
1.6 G. of 1-acetamido-2-amino-4-benzylthiobenzene is dissolved in 32 ml. acetone and treated with 2.4 g. methoxycarbonylisothiocyanate. The mixture is left overnight at room temperature, then concentrated and the residue triturated with ether. Pure 1-(3-methoxycarbonyl-2-thioureido)-2-acetamido-5-benzylthiobenzene is obtained by recrystallization from methanol.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([OH:13])(=[O:12])[CH2:10][OH:11].Cl>[OH-].[Na+]>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH:10]([OH:11])[C:9]([OH:13])=[O:12])=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: O=C(O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 137.7 %

Procedure:
32.4 g (0.30 mol) of o-cresol are dissolved in 150 ml of 2N sodium hydroxide solution under a nitrogen atmosphere. After cooling to +5° C., 4.8 g (0.12 mol) of sodium hydroxide and 13.3 ml (0.12 mol) of 50% aqueous glycolic acid are added, and the reaction mixture is stirred at room temperature for 4 hours. A further 0.12 mol of sodium hydroxide and glycolic acid (a total of 0.36 mol) is added twice after 4 hours each time. The reaction mixture is then stirred for another 12 hours, neutralised with concentrated hydrochloric acid and washed twice with 75 ml of petroleum ether. The aqueous phase is then acidified with concentrated hydrochloric acid and extracted several times with ether. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator, giving 30.1 g (55%) of 4-hydroxy-3-methylmandelic acid, melting point 115°-120° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:31]=[CH:30][C:17]2[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[NH:20][C:16]=2[CH:15]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:31]=[CH:30][C:17]3[NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)=[N:20][C:16]=3[CH:15]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: COc1cccc(Nc2nc3ccc(N)cc3[nH]2)c1
Product: COc1cccc(Nc2nc3cc(NC(=O)c4ccc(N(C)C)cc4)ccc3[nH]2)c1

Procedure:
Compound 429 was prepared from 4-dimethylaminobenzoate and 5-amino-2-(3-methoxyphenylamino)benzimidazole by standard conditions. [M+H]+ calcd for C23H23N5O2: 402.19; found: 401.96.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[N:24]#[C:25]Br.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[NH2:24][C:25]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:23])=[C:10]([Cl:22])[C:11]3[N:12]([CH:19]=[CH:20][N:21]=3)[CH:13]=2)=[N:17][N:18]=1
Reactant: N#CBr
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nnc(-c2cn3ccnc3c(Cl)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (100 mg, 0.25 mmol) was suspended in dioxane (2 mL). Cyanogen bromide (27 mg, 0.253 mmol) was added, followed by a solution of sodium bicarbonate (21 mg, 0.25 mmol) in H2O (1.2 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield the desired product (97 mg, 91%) as a white solid. MS ESI (+) m/z 423, 425 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CH3OD) δ 8.98 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.33 (d, 1H), 7.17 (d, 1H), 6.78 (t, 1H). 19F (376 MHz, CD3OD) −128.6 (t).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:17])[C:7]=1[N+:18]([O-])=O.[H][H]>[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:14])=[O:15])=[C:8]([OH:17])[C:7]=1[NH2:18]
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCO2)c([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1c(N2CCCO2)cc(Cl)c(S(N)(=O)=O)c1O
Yield: 128.9 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, (N-tetrahydroisoxazyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (0.76 g, 2.35 mmol) was reduced with hydrogen and 10% Pd/C (0.76) to form the desired product (0.89 g, crude). LC-MS m/z 293(M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[N:16]1([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:27][CH2:26]1
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 79.6 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (200 mg, 0.703 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)piperidine (168 mg, 1.00 mmol) to afford the desired product (233 mg, 80%) as a yellow solid: ESI MS m/z 416 [C21H26BrN3O+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([C:14]#[C:15]/[CH:16]=[CH:17]\[C:18]#[C:19][Si](C)(C)C)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO>[C:10]([Si:7]([C:14]#[C:15]/[CH:16]=[CH:17]\[C:18]#[CH:19])([CH3:9])[CH3:8])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)C#C/C=C\C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C/C=C\C#C[Si](C)(C)C(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Solid potassium carbonate (5.36 g, 38.9 mmol, 1.10 equiv) was added to a solution of (Z)-1-(tert-butyldimethylsilyl)-6-trimethylsilyl-3-hexen-1,5-diyne (9.26 g, 35.3 mmol, 1 equiv) in methanol (100 mL) at 23° C. and the resulting suspension was stirred at 23° C. for 1 h. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (200 mL) and hexanes (200 mL). The aqueous layer was separated and extracted further with hexanes (200 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (hexanes) to furnish tert-butyl[(Z)-3-hexene-1,5-diynyl]dimethylsilane (18) as a brown oil (6.35 g, 95%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][C:3]=1[CH3:14].[F:15][C:16]1[CH:17]=[CH:18][C:19](B2OC(C)(C)C(C)(C)O2)=[C:20]2[C:24]=1[C@H:23]([O:25][C:26]1[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=1)[CH2:22][CH2:21]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:14][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:19]1[CH:18]=[CH:17][C:16]([F:15])=[C:24]2[C:20]=1[CH2:21][CH2:22][C@H:23]2[O:25][C:26]1[CH:39]=[CH:38][C:29]2[C@H:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nnn[nH]2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn[nH]6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-bromo-3,5-dimethylphenyl)-1H-tetrazole and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.05 min; Mass spectrum (ESI+): m/z=515 [M+H]+.