Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.P(Cl)(Cl)([Cl:20])=O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([Cl:20])=[N:7][C:6]=2[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Nc2ccccc21
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of amide 9 (1.39 g, 5.70 mmol), phosphorus oxychloride (1.6 mL, 17.1 mmol) and N-dimethylaniline (2.9 mL, 22.8 mmol) in benzene (10 mL) was heated at reflux for 2 hours. The reaction mixture was then cooled to room temperature and excess of phosphorus oxychloride, N-dimethylaniline and benzene were removed at reduced pressure. The resulting residue was dissolved in dioxane (20 mL) and 2 M Na2CO3 (30 mL 0.06 mol) and then heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and dioxane was removed at reduced pressure and the resulting aqueous solution was extracted with EtOAc (30 mL). The organic phase was washed with water, brine, dried (Na2SO4), filtered and solvent evaporated. The resulting crude residue was purified by column chromatography (10% ethyl acetate in hexanes) to afford title compound 10 (869 mg, 58%) as an orange solid. LRMS (ESI): (calc) 262.01. (found) 263.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:16].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=2[C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1C(=O)NCCCn1ccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
4-Chlorobenzenesulphonyl chloride (1.56 g) was added in portions over 2 minutes to a solution of 2-amino-N-(3-imidazol-1-ylpropyl)benzamide (1.8 g) in water (50 ml) at 80° C. on a steam bath. The mixture was stirred at 80°-90° C. for 3 hours, cooled to room temperature and brought to pH 7 with saturated aqueous sodium bicarbonate solution. The crude product which had precipitated was extracted into dichloromethane (2×100 ml); the resulting solution was dried over magnesium sulphate and evaporated to give a solid. The solid was recrystallised from ethanol to give 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide (1.4 g), in the form of a white solid, m.p. 174°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[H-].[Na+].[CH3:20]I.O>C(COC)OC>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:20])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CI
Reactant: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
8-fluoro 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (1.38 g; 6mmol) was added to a suspension of NaH (475 mg; 20 mmol) in glyme (15 ml). The mixture was refluxed for 1.5 hours and cooled quickly to room temperature. Methyl iodide (15 ml) was added and the mixture refluxed for 4 hours, then allowed to cool to room temperature. After addition of water, the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed three times with water, dried over MgSO4 and concentrated under vacuum. Recrystallization from hexane afforded 737 mg (56% yield) of the subtitle compound. Melting point 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])(=[O:14])=[O:13])=[C:8]([CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:26]O>>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:21][CH3:26])=[O:20])(=[O:13])=[O:14])=[C:8]([CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: COc1cccc2c(C)c(S(=O)(=O)Nc3cccc(C(=O)O)c3)sc12
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3c(OC)cccc3c2C)c1
Yield: 71 %

Procedure:
The product was prepared from 3-{[(7-methoxy-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (6.8 mg, 0.018 mmol) (Example 42) and MeOH (50 μL, 1.23 mmol) according to the General Procedure 8, described in Example 119. The title compound was obtained in 71% yield (5.0 mg). 1H NMR (500 MHz, CDCl3:DMSO-d6 6:1) δ ppm 2.23 (s, 3 H) 3.56 (s, 3 H) 3.68 (s, 3 H) 6.60 (dd, J=7.54, 1.10 Hz, 1 H) 6.98 (dd, J=8.13, 7.73 Hz, 1H) 7.05 (dd, J=8.17, 1.10 Hz, 1 H) 7.09 (dd, J=8.17, 7.54 Hz, 1 H) 7.14 (ddd, J=8.13, 2.32, 1.09 Hz, 1 H) 7.38 (ddd, J=7.73, 1.63, 1.09 Hz, 1 H) 7.57 (dd, J=2.32, 1.63 Hz, 1 H) 10.18 (s, 1 H). MS (ESI+) m/z 392 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: CCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCCNCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 120 h

Procedure:
To a solution of the aldehyde 6 (132 mg) in 3 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (300 mg), n-pentylamine (0.217 mL), and sodium triacetoxyborohydride (260 mg). After five days, the reaction was poured into EtOAc and washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the amine 7 as a brown oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O)C([O-])=O>>[C:15]([O:14][C:12]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7])=[O:8])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1CCCCN1
Product: CC(C)(C)OC(=O)N1CCCCC1=O

Procedure:
In another process, described in J. Org. Chem. Vol. 48, pp. 2424 to 2426 (1983), δ-valerolactam is reacted with tert-butyl oxydiformate in a first stage to form N-tert-butoxycarbonylvalerolactam, which is then broken down in a second stage with 1.1 equivalents of sodium methylate to form methyl 5-(O-tert.-butylurethano)valerate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].O>CN(C=O)C>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[O:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)o1
Reactant: COC(CCBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2oc(C)nc2C)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
5-(2,4-Dimethyl-oxazol-5-yl)-1H-pyrimidine-2,4-dione (Prep62, 480 mg, 2.32 mmol) and K2CO3 (320 mg, 2.32 mmol) were suspended in dry DMF (6 ml) and stirred at room temperature for 1 h. A solution of 3-bromo-1,1dimethoxy-propane (467 mg, 2.55 mmol) in dry DMF (2 mL) was added dropwise and the mixture stirred at room temperature for 72 hours. Water (80 mL) was added and the product extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 377 mg of the final compound that was used without any other purification in the next step (53% yield).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH:49](O)[CH3:50].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH:15]1([NH:14][C:12](=[O:13])[C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([O:1][CH:49]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=4)[CH3:50])=[CH:23][CH:22]=3)[CH:10]=2)[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: CC(O)c1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OC(C)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 14.6 %

Procedure:
To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (150 mg, 0.484 mmol) in DCM (20 mL) was added polymer supported triphenyl phosphine (937 mg, 1.45 mmol) and the 1-pyridin-2-ylethanol (45 mg, 0.363 mmol). Diethyl azodicarboxylate (126 mg, 0.726 mmol) was then added dropwise. The reaction was stirred for 17 h at room temperature and was then filtered and the filtrates were evaporated. The crude residue was purified by flash silica chromatography using ethyl acetate in iso-hexane (5-100%) as the eluent to give the title compound as a colourless oil (22 mg, 11%); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.68 (m, 2H), 1.64 (d, 3H), 2.22 (s, 3H), 2.83 (m, 1H), 5.60 (q, 1H), 7.02 (d, 2H), 7.31 (d, 2H), 7.43 (d, 1H), 7.62 (d, 1H), 7.80 (m, 2H), 7.90 (d, 2H), 8.35 (d, 1H), 8.58 (d, 1H), 9.75 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH:23]([CH3:24])[CH3:25])[C:20]([NH:30][CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 100 °C
Yield: 97.7 %

Procedure:
A mixture of 890 mg (2.52 mmole) of (3S, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-isopropyldihydrofuran-2(3H)-one (prepared as described in Preparation 1) and 2.5 ml (25.3 mmole) of butylamine was heated at 100° C. for 4 hours. At the end of this time, an excess of the butylamine was removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure column chromatography through silica gel (using a 20:1 by volume mixture of methylene chloride and methanol as the eluent), followed by recrystallization from diisopropyl ether, to afford 1.05 g (yield 98%) of the title compound as white crystals, melting at 115°-118° C. [α]D20 =-34.9° (c=1, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](O)(=O)[CH3:26].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-fluorophenyl)-5-(piperidin-4-yl)-3-(4-pyridyl)-pyrrole (U.S. Pat. No. 5,792,77, 1000 mg, 3.11 mmol; hereinafter referred to as Compound A) and acetic acid (0.18 ml, 3.11 mmol) in anhydrous 1,2-dichloroethane (50 ml) under nitrogen at room temperature, acetaldehyde (0.21 ml, 3.73 mmol) and sodium triacetoxyborohydride (989 mg, 4.67 mmol) were added slowly. The resulting mixture was allowed to stir for 2 hours. The crude product was purified by flash silica gel column (MeOH-CH2Cl2, 8:92 v/v containing 1% NH4OH). After drying, 930 mg of 2-(4-fluorophenyl)-5-(N-ethylpiperidin-4-yl)-3-(4-pyridyl)pyrrole (Compound B) was obtained as the free base.
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:31])[NH:26]OC(=O)C)=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[CH:10][N:9]=1)=[NH:7])(=[O:3])[CH3:2].C(O)C>C(O)(=O)C.[Pd]>[C:1]([OH:4])(=[O:3])[CH3:2].[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[O:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]([NH2:7])=[NH:5])=[N:9][CH:10]=3)=[CH:18][CH:17]=2)=[CH:24][CH:23]=1)(=[NH:26])[NH2:31]
Reactant: CC(=O)ONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC(C)=O)nc3)o2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)nc3)o2)cc1
Reaction time: 4 h
Yield: 68 %

Procedure:
Continuing with Scheme 3, to a solution of 19 (380 mg, 0.90 mmol) in glacial acetic acid (13 mL), and ethanol (25 mL) was added 10% palladium on carbon (120 mg). The mixture was placed on Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through HYFLO® matrix (available from Word Minerals Corporation of Santa Barbara, Calif., United States of America) and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 20, in 68% yield, mp 266–268° C.dec.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].[ClH:19]>CO>[ClH:19].[CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of (R)-tert-butyl 3-(dimethylcarbamoyl)piperidine-1-carboxylate (9 g, 35.15 mmol) in methanol (20 mL) at 0° C. was added hydrogen chloride in methanol (50 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to afford (R)—N,N-dimethylpiperidine-3-carboxamide hydrochloride (7 g, 90%). MS (ES+APCI) [(M-2HCl)+H] 157.1; LCMS retention time: 6.36 min (Method F1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[CH:47]1([C:53]2[C:54]3[CH:55]=[CH:56][C:57]([C:77]([O:79][CH3:80])=[O:78])=[CH:58][C:59]=3[N:60]3[C:67]=2[C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[O:64][CH2:63][CH:62]([CH2:72][CH2:73][C:74](O)=[O:75])[CH2:61]3)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[C:34]([O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:74](=[O:75])[CH2:73][CH2:72][CH:62]2[CH2:61][N:60]3[C:59]4[CH:58]=[C:57]([C:77]([O:79][CH3:80])=[O:78])[CH:56]=[CH:55][C:54]=4[C:53]([CH:47]4[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)=[C:67]3[C:66]3[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=3[O:64][CH2:63]2)[CH2:27][CH2:26]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)O)COc1ccccc1-3
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Temperature: 50 °C

Procedure:
HATU (1.1 eq) was added to a stirred mixture of tert-butyl piperazine-1-carboxylate (1.1 eq), DIPEA (2.5 eq) and 3-[14-cyclohexyl-11-(methoxycarbonyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]propanoic acid (0.03 M) in DMF under N2 at RT. The reaction was warmed at 50° C. for 10 min. The reaction was allowed to cool to RT before being partitioned between EtOAc and 1N HCl (aq). The organics were washed with 1N HCl (aq), sat. aq. NaHCO3, water and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The material was taken on without further purification (88%). (ES+) m/z 630 (M+H)+; 652 (M+Na)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:6]([CH2:18][OH:19])[CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[CH:6]([CH2:18][O:19][C:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2CO)cc1
Product: COC(=O)c1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 22 (d), from tert-butyl (3RS,4RS,5SR)-1-benzyl-4-(4-bromo-phenyl)-5-hydroxymethyl-piperidin-3-ol [Example 68 (e)] by a palladium catalyzed carbonylation with carbon monoxide in methanol there was obtained methyl (3RS,4RS,5SR)-4-(1-benzyl-3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate, hydrogenolysis of which in the presence of 5% palladium-charcoal at atmospheric pressure in methanol analogously to Example 2 (e) gave methyl 4-(3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate. Subsequent introduction of the BOC group analogously to Example 1 (f) yielded tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate, from which by reaction with triphenylchloromethane analogously to Example 68 (i) there was obtained tert-butyl (3RS,4RS,5SR)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-5-trityloxymethyl-piperidine-1-carboxylate. Subsequent alkylation by means of 2-bromomethyl-naphthalene analogously to Example 1 (g) yielded tert-butyl (3RS,4RS,5SR)-4-(4-methoxycarbonyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, reduction of which with lithium borohydride analogously to Example 22 (e) yielded tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 737 (M+NH4)+. Further alkylation with 2-(benzyloxy)-ethyl iodide [Helv.Chim. Acta Vol.71, (1988), 2039] analogously to Example 1 (g) gave tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which after cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 629 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][NH:28]C.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][NH:28][CH2:27][C:26]([N:25]([CH3:31])[CH3:24])=[O:30])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reactant: CNCC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.21 g, 0.60 mmol) was added to a stirred solution of N1,N1,N2-trimethylglycinamide (Me2N-Gly-Nme) (0.348 g, 1.81 mmol) and DIPEA (0.234 g, 1.81 mmol) in dimethylformamide (1 ml) at 140° C., over a period of 5 minutes. The reaction mixture was stirred for 5 minutes, cooled to room temperature and purified by preparative LCMS (standard acidic system) to give N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.193 g, 74.2%) as a white solid. 1H NMR Spectrum: (DMSO-d6) 2.27 (s, 3H), 2.80 (s, 3H), 2.98 (s, 3H), 3.71 (s, 2H), 3.94 (s, 3H), 7.19 (s, 1H), 7.27 (t, 1H), 7.47-7.52 (m, 2H), 8.30 (s, 1H), 8.43 (s, 1H), 9.85 (s, 1H); Mass Spectrum: (M+H)+ 432. Solid N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.150 g, 0.348 mmol) was added over a period of 1 minute to a stirred solution of anhydrous lithium iodide (0.232 g, 1.74 mmol) in 2,4,6-collidine (0.5 ml) at 130° C., previously stirred for 30 minutes at 130° C. The reaction mixture was allowed to stir for 5 hours, cooled, concentrated and purified by preparative LCMS (standard acidic system) to afford N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazolin-6-yl}methyl)-N1,N1-dimethylglycinamide (0.080 g, 55.2%) as an orange foam; Mass Spectrum: (M+H)+ 418.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Cn2cc(Cl)cnc2=O)c1
Yield: 20.5 %

Procedure:
A solution of 5-chloropyrimidin-2-one (504 mg) and 2-bromo-3'-methoxyacetophenone (880 mg) in triethylamine (1 ml) and ethanol (50 ml) was stirred at ambient temperature for 20 hours. After evaporation of solvents, the residue was triturated with water (50 ml). The resulting solid was crystallised from ethyl acetate to give the title pyrimidinone (220 mg,); m.p. 134°-137°; λmaxEtOH 249.5 nm (ε 12660), 317 nm (ε 4070), λinf 334.5 nm (ε2950), 344.5 nm (ε 1990).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.O>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A solution of methyl [3,5-dihydroxyphenyl]acetate (2.1 g, 11.5 mmol) in acetone (100 mL) was treated with potassium carbonate (2.4 g, 17.4 mmol), potassium iodide (0.38 g, 2.31 mmol) and benzyl bromide (1.5 mL, 12.7 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with water, and was extracted with dichloromethane (×3). Combined organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified on a Biotage™ 40 M column (silica), eluting with 40% ethyl acetate/hexane, to give methyl [3-benzyloxy-5-hydroxyphenyl]acetate (1.0 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.32-7.42 (m, 5H), 6.48 (d, J=1.4 Hz, 1H), 6.38-6.39 (m, 2H), 4.99 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H).