Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C(=O)=O.[Li]CCCC.[C:20]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C1CCCC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.9 %

Procedure:
A solution of 1-bromo-2-(trifluoromethyl)benzene (0.5 g, 2.222 mmol) in anhydrous THF (10 mL) was cooled to −78° C. (dry ice WA bath) under argon atmosphere. BuLi (2.5 M in hexanes, 1.068 mL, 2.67 mmol) was added in drops with efficient stirring. The reaction mixture was stirred at −78° C. for 40 min. A solution of cyclopentanone (0.243 g, 2.89 mmol) in anhydrous THF (1.5 mL) was added slowly (in drops) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, gradually brought to room temperature, and stirred for 1 h. The reaction mixture was cooled by an ice bath, quenched with water, and acidified to pH 4-5 by addition of concentrated HCl. The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water (2 times), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as an oil (250 mg). LCMS m/z=213.1 [M−H2O+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[C:26](O)(=[O:28])[CH3:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([C:26](=[O:28])[CH3:27])[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)Nc1sc3ccccc3c1C(N1CCNCC1)=N2
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
8-Fluoro-12-(piperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (260 mg) was dissolved in toluene (5 ml) and anhydrous acetic acid (230 mg) and triethylamine (375 mg) were added. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and extracted with chloroform, washed with water and dried over anhydrous magnesium sulfate. After natural filtration, the solvent was evaporated under reduced pressure and the residue was recrystallized from methanol to give 8-fluoro-12-(4-acetylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1/4 hydrate (97 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]2[CH2:32][CH2:31][CH2:30][C:29]=2B(O)O)=[CH:17][CH:16]=1>>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([C:29]2[CH2:30][CH2:31][CH2:32][C:28]=2[C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[O:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:37][CH:36]=2)[CH:3]=[CH:4][C:5]=1[F:13])[CH3:11]
Reactant: OB(O)C1=C(c2cc(Cl)ccc2OCc2ccc(F)cc2)CCC1
Reactant: CCOC(=O)c1cc(Br)ccc1F
Product: CCOC(=O)c1cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)ccc1F
Yield: 23 %

Procedure:
Prepared according to general procedure C(iii) using ethyl 5-bromo-2-fluorobenzoate and 2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopentene-1-boronic acid to give the product as a colourless solid 43 mg 23%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](F)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35]>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][C:22]=1[C:34]#[N:35]
Reactant: Oc1ccncc1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(Oc4ccncc4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 100 °C
Yield: 54.5 %

Procedure:
A mixture of sodium hydride (128 mg, 3.2 mmol) and 4-hydroxypyridine (750 mg, 7.89 mmol) in 5 mL of N, N′-dimethylformamide is heated at 100° C. for 1 hour. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.51 mmol) is added and the reaction mixture is heated at 130° C. for 2 hours. An additional 21 mg of sodium hydride is added and the reaction mixture is heated at 130° C. for an additional 30 minutes. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by heating with methanol and dichloromethane to provide 130 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(pyridin-4-yloxy)-3-quinolinecarbonitrile, mp 267-269° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.S([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C)(=O)=O>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(I)cn2)CC1
Reaction time: 1 h

Procedure:
NaH (60% suspension, 1.13 g, 28.4 mmol) was added portion wise to a solution of 4-iodopyrazole (5 g, 25.7 mmol) in anhydrous DMF (30 mL) at 0° C.; and it was stirred for 1 h. Finally, tert-butyl 4-mesylpiperidine-1-carboxylate (CAS: 141699-59-4) (6.5 g, 32.7 mmol) was added to the reaction mixture and it was stirred at 100° C. for 16 h. It was, then, cooled and quenched with saturated solution of NH4Cl (100 mL). Extraction was carried out using EtOAc (50 mL×2); the combined organic layers were washed with water (100 mL); brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude product, which was further purified by silica gel column chromatography (20% EtOAc in hexanes) to give title compound Va-1-I (4 g, 41%). LCMS: m/z 378.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Nc1cc(Cl)c(Br)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1cc(Cl)c(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A mixture of (2-amino-5-bromo-4-chlorophenyl)methanol (6 g, 25.5 mmol) and manganese(IV) oxide (15.5 g, 0.178 mol) in dichloromethane (100 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title compound as a light yellow solid (5 g, 81%). MS (ES+) C7H5BrClNO requires: 233, 235, found: 234, 236 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[S:9]([O-:12])([O-:11])=[O:10].[K+:13].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:9]([O-:12])(=[O:11])=[O:10])[N:3]=1.[K+:13]
Reactant: O=S([O-])[O-]
Reactant: Clc1cccc(Cl)n1
Agent: [K+]
Product: O=S(=O)([O-])c1cccc(Cl)n1
Yield: 15.8 %

Procedure:
In the same manner as in Example 1, 2,6-dichloropyridine and potassium sulfite were reacted to obtain 540 mg (15.8%) of potassium 2-chloropyridine-6-sulfonate. Purification was conducted by recrystallization from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1csc(-c2ccccc2O)n1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1nc(C(=O)O)cs1
Temperature: 25 °C

Procedure:
To a solution of 2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (900 mg) dissolved in dry pyridine (15 ml) was added dropwise acetic anhydride (0.461 ml) under ice-cooling. The mixture was allowed to warm up to room temperature and to react for additional 1.5 hours. Then the solvent was removed and the residue was treated with water, acidified with 2N--HCl and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give the desired compound,
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])[C:6]=2[N:7]=1.[CH3:31][NH:32][CH2:33][CH3:34].C(N(C(C)C)C(C)C)C.[F-].[Cs+]>CS(C)=O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:5]2[C:4]([NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)=[N:3][C:2]([N:32]([CH2:33][CH3:34])[CH3:31])=[N:7][C:6]=2[C:8]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])=[N:9]1)[CH3:15]
Reactant: CCOCCn1nc(C(=O)NS(C)(=O)=O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Reactant: CCNC
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1nc(C(=O)NS(C)(=O)=O)c2nc(N(C)CC)nc(Nc3cc(C)ccn3)c21
Temperature: 110 °C
Yield: 57.7 %

Procedure:
The chloro compound of Step 9 (110 mg, 0.24 mmol), NI-methyl-ethylamine (79 mg, 1.2 mmol), N-ethyldiisopropylamine (210 μL, 1.20 mmol) and caesium fluoride (37 mg, 0.24 mmol) were dissolved in dimethyl sulphoxide (1 mL) and the reaction mixture heated to 110° C. for 5 hours in a ReactiVial™. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL) and the organic phase separated and washed with water (2×10 mL). The organic phase was then dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 99:1 to 97:3. The purified material was evaporated and dried to yield a pale yellow solid (66 mg). The PXRD pattern for the solid is shown as FIG. 14.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([Se:23][C:24]#[C:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[CH:16][C:17]=3[C:18]([CH3:22])([CH3:21])[CH2:19][CH:20]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([Se:23][C:24]#[C:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[CH:16][C:17]=3[C:18]([CH3:22])([CH3:21])[CH2:19][CH:20]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3cc([Se]C#Cc4ccc(C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 1 g, by reacting 0.28 g (0.5 mmol) of methyl 4-[5-(4-tert-butylphenyl)-8,8-dimethyl-7,8-dihydro-2-naphthylselanylethynyl]benzoate with 0.28 g (6.6 mmol) of lithium hydroxide monohydrate, a cream-colored powder is obtained (0.08 g; yield=30%; m.p.=231° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[NH:8][S:7]1(=[O:15])=[O:14].Cl.[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1>CN(C)C=O.C(N(CC)CC)C>[Cl:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[NH:8][S:7]3(=[O:15])=[O:14])[CH2:28][CH2:29]2)[CH:21]=[N:20][CH:19]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: CC1CC(=O)N(CCCCBr)S(=O)(=O)N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CC(=O)N(CCCCN2CCN(c3cncc(Cl)n3)CC2)S(=O)(=O)N1

Procedure:
The title compound is prepared by adding to a stirred solution of 2 g (0.006 mol) of 2-(4-bromobutyl)-5,6-dihydro-5-methyl-2H-1,2,6-thiadiazin-3(4H)-one 1,1-dioxide in 50 mL of dimethylformamide, 4 mL of triethylamine and 1.41 g (0.006 mol) of 1-(6-chloro-2-pyrazinyl)piperazine hydrochloride.
Reaction SMILES: CC1C=[C:6]([N:8]2C=N[N:10]=[N:9]2)C=CC=1CC(O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1>>[N:17]1([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[CH:6]=[N:8][N:9]=[N:10]1
Reactant: Cc1cc(-n2cnnn2)ccc1CC(=O)O
Reactant: Nc1ccc(CC(=O)O)c(C(F)(F)F)c1
Product: O=C(O)Cc1ccc(-n2cnnn2)cc1C(F)(F)F

Procedure:
[4-(1H-tetrazol-1-yl)-2-(trifluoromethyl)phenyl]acetic acid was prepared in a similar fashion to that described for the synthesis of [2-methyl-4-(1H-tetrazol-1-yl)phenyl]acetic acid starting from [4-amino-2-(trifluoromethyl)phenyl]acetic acid. LC-MS (IE, m/z): 273 [M+1]+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[C:13]1([C:19]2[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:24]([C:22]3[S:23][C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:20][CH:21]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(-c2ccccc2)s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccc2)s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-phenylthiophene-2-carboxylic acid (Maybridge) according to methods A and C; yield 62 mg, 0.17 mmol (53%): 1H NMR (300 MHz, methanol-d4) δ 2.08-2.27 (m, 5H), 2.47 (s, 2H), 3.48 (d, J=13 Hz, 2H), 3.55 (s, 2H), 3.81 (d, J=13 Hz, 2H), 4.25 (t, J=3 Hz, 1H), 7.32-7.47 (m, 4H), 7.65-7.71 (m, 2H), 7.83 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 339 (M+H)+; Anal. C20H22N2OS.HCl: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([OH:24])[C@@H:11]([NH:13][C:14](=[O:23])OCC2C=CC=CC=2)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:10]2[O:24][C:14](=[O:23])[NH:13][C@H:11]2[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2OC(=O)N[C@H]2C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of benzyl ((1R,2S)-1-(3-chloro-4-methoxyphenyl)-1-hydroxypropan-2-yl)carbamate (0.24 g, 0.686 mmol) in THF (4.6 mL) was added NaH (0.036 g, 0.892 mmol) at 0° C. The reaction mixture was warmed to RT and stirred overnight. It was then quenched with 1N HCl (1.5 mL). This mixture was diluted with EtOAc and washed with sat. aqueous NaHCO3, water and brine. The organic phase was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with EtOAc to give (4S,5R)-5-(3-chloro-4-methoxyphenyl)-4-methyloxazolidin-2-one (intermediate K, 0.13 g). 1H NMR (500 MHz, CDCl3): δ 7.37 (s, 1H), 7.21 (d, 1H), 6.97 (d, 1H), 5.84 (b, 1H), 5.65 (d, 1H), 4.21 (m, 1H), 3.96 (s, 3H), 0.87 (d, 3H).
Reaction SMILES: C1(C)C(C)=CC=CC=1.C[O-].[K+].CO[C:14](=[O:17])[O:15][CH3:16].[CH:18]1([CH2:24][C:25](=[O:27])[CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C.O>[CH:18]1([CH2:24][C:25](=[O:27])[CH2:26][C:14]([O:15][CH3:16])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)OC
Reactant: CC(=O)CC1CCCCC1
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: COC(=O)CC(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A 500 ml flask was charged with 120 g xylene, 33.8 g of solid potassium methylate (3.2 molar equivalent) and 34.0 g of dimethylcarbonate (2.5 molar equivalent). The slurry was heated to 50° C. and over the course of 4 hours 24.2 g of 1-cyclohexylpropan-2-one (87% GC, 1 molar equivalent) was added. Stirring was continued for 2 hours and then the reaction mixture was cooled to 25° C. 95 g of an acetic acid/water mixture (1:2) was then added carefully. After decantation the aqueous phase was drained and the organic phase concentrated. The crude product was distilled leading to 24.9 g of methyl 4-cyclohexyl-3-oxobutanoate (81% GC, 68% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+].[C:54]([O:58][C:59](=[O:67])[NH:60][CH2:61][C:62]1[O:63][CH:64]=[CH:65][CH:66]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[Pd](Cl)Cl>[C:54]([O:58][C:59](=[O:67])[NH:60][CH2:61][C:62]1[O:63][C:64]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3[NH:18][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[C:3]([Cl:2])[CH:4]=2)=[CH:65][CH:66]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCc1ccco1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 110 °C
Reaction time: 9 h
Yield: 46.4 %

Procedure:
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride (0.913 g, 1.68 mmol) (from Step E, Example 1) is dissolved in DMF (20 ml) and the solution is degassed under nitrogen. The above solution is added over 10 hours to a heated (110° C.) degassed suspension of tricyclohexyl phosphine (0.475 g, 1.7 mmol), palladium dichloride (15.2 mg, 0.086 mmol), potassium acetate (0.35 g, 3.6 mmol), tetra n-butyl ammonium bromide (0.552 g, 2.15 mmol), and Furan-2-ylmethyl-carbamic acid tert-butyl ester (2.9 g, 15 mmol) in DMF (5 ml). Heating is continued for 9 hours after the end of addition. The reaction mixture is cooled, diluted with water and extracted with EtOAc. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography on silica with 10-50% EtOAc:hexanes gradient elution yields 0.450 g (0.78 mmol, 46%) of the clean desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:69])/[C:30](=[N:56]\[O:57][C:58]3([C:62]([O:64]C(C)(C)C)=[O:63])[CH2:61][CH2:60][CH2:59]3)/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)[C:26](=[O:70])[N:17]2[C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])[CH3:9].C1(OC)C=CC=CC=1>CS(C)=O>[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:69])/[C:30](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:56]\[O:57][C:58]3([C:62]([OH:64])=[O:63])[CH2:59][CH2:60][CH2:61]3)[C:26](=[O:70])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OC3(C(=O)OC(C)(C)C)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: CS(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3(C(=O)O)CCC3)c3csc(N)n3)[C@H]2SC1
Yield: 53 %

Procedure:
Trifluoroacetic acid (100 ml) was added to a mixture of the product of Stage (a) (12.5 g) and anisole (5 ml) at 0°. The mixture was treated substantially as described in Example 1 (b) to give the title compound (4 g), λmax (pH 6 buffer) 246 nm (E1 cm1% 264), λinf 295 nm (E1 cm1% 118), [α]D20 +27.3° (c 1.0, DMSO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][Si](C)(C)C)[C:9]#N)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.BrC[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][C:28]([CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:11])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To 2-(4-fluorophenyl)-2-[(trimethylsilyl)oxy]acetonitrile (0.500 g, 2.24 mmol) in degassed THF (11 ml) at −78° C. was added LHMDS 1M in THF (2.4 ml). To the previous reaction mixture a solution of methyl 4-(bromomethyl)benzoate (0.513 g, 2.25 mmol) in THF (2 ml) was then added. After a period of 1 h at r.t., tetrabutylammonium fluoride solution 1 M in THF (2.23 ml) was added to the reaction mixture and stirred for 10 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 30% giving 0.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[OH-].[Na+:26]>CO>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[Na+:26]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 105.4 %

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (1.7 g, 0.0047 mole) is dissolved in methanol (25 ml) and sodium hydroxide (4.7 ml of 1N NaOH in methanol, 0.0047 mole) is added rapidly. The solvent is then removed in vacuo to give 1.9 g of product that decomposes at 217° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.CCOC(C)=O>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)=[O:27])[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)N2CCN(CC(=O)O)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Dissolve {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester (45) (100 mg, 0.25 mmol) in MeOH (2.0 mL) at rt and add 2M aqu NaOH (260 μL, 0.52 mmol). Stir the reaction mixture for 1 h under reflux. Add dropwise 1M aqu. HCl (550 μL, 0.55 mmol), extract the mixture with EtOAc (3 times) and remove solvent obtain {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid (46) (88 mg, 95%) as a brown sticky solid. No further purification. 1H NMR (400 MHz, CDCl3/CD3OD 9+1): 2.54 (br.t, 2H); 2.78 (t, 2H, J=7.5 Hz); 2.83-3.10 (br.m, 2H); 3.24 (s, 2H); 3.43-3.62 (br.m, 2H); 3.68 (s, 3H); 3.73 (s, 6H); 3.74-3.85 (br.m, 4H); 6.34 (s, 2H).