Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH:8]([OH:10])=[O:9]>C1(C)C=CC=CC=1.C(#N)C>[CH:8]([O-:10])=[O:9].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC[NH+](CC)CC
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.4 %

Procedure:
To a solution of triethylamine (33.05 g, 326.7 mmol) in toluene (150 mL) was added 96 percent formic acid (13.81 g, 300.1 mmol) slowly over 5 min. The two-phase system was stirred overnight (17 hr) at ambient temperature. The toluene was removed by distillation (maximum bath temperature 120° C., overhead temperature kept above 100° C.) over several hr. The remaining oil was transferred to a graduated cylinder and the contents sparged with a flow of nitrogen until no noticeable odor of toluene remained. The pale yellow triethylammonium formate (25.35 g, 172.2 mmol, 57.4 percent yield) was diluted to 172.2 mL with acetonitrile giving a 1.0 molar solution. The contents were stored in a serum-capped storage bottle under nitrogen. This or similarly prepared material was used in the following examples whenever preformed triethylammonium formate was called for.
Reaction SMILES: N1C=CC=CC=1.Cl.[OH:8][CH:9]([C:17]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:28])[NH:22]2)[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH3:12].[C:29]([Cl:34])(=[O:33])[CH:30]([CH3:32])[CH3:31].C(OCC)C>CC(C)=O>[ClH:34].[OH:8][CH:9]([C:17]1[CH:26]=[CH:25][C:24]([O:27][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:28])[NH:22]2)[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH3:12]
Reactant: CC(C)C(=O)Cl
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)C(C)C)c2c1CCC(=O)N2
Temperature: 0 °C

Procedure:
25 ml of pyridine was added to 1 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxy-3,4-dihydrocarbostyril hydrochloride, and 3 ml of isobutyryl chloride was added dropwise to the mixture while cooling with ice-water and stirring followed by stirring for 3 hours. After addition of about 200 ml of diethyl ether, acetone was added to the precipitate formed to obtain a crystalline product. The product thus obtained was recrystallized from acetone to obtain 0.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-isobutyryloxy-3,4-dihydrocarbostyril hydrochloride having a melting point of 239°-240° C. (with coloration and decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9](C)[C:10]2[CH:11]=[C:12]([CH:28]=[CH:29][CH:30]=2)[CH2:13][NH:14][C:15]2[C:24]3[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[O:8])=[CH:5][CH:4]=1.NC1C([F:43])=C(C=CC=1)C#N.COC1C=CC(C(O)=O)=CC=1>>[F:43][C:11]1[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:30][CH:29]=[CH:28][C:12]=1[CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([C:25]([NH2:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][N:16]=1
Reactant: N#Cc1cccc(N)c1F
Reactant: COc1ccc(C(=O)N(C)c2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1
Agent: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2F)cc1

Procedure:
The title compound was prepared according to example 4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid amide, starting from 3-Amino-2-fluoro-benzonitrile and 4-Methoxy-benzoic acid:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])NC(C(O)=O)(C)C)=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.N[CH2:54][CH2:55][OH:56].[NH2:57][C:58]([CH3:63])([CH3:62])[C:59]([NH2:61])=[O:60]>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:57][C:58]([C:59](=[O:60])[NH:61][CH2:54][CH2:55][OH:56])([CH3:63])[CH3:62])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:51])[CH3:52])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCO
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)NCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 2-aminoethanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]I)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][N:16]1[C:21](=[N:22][N+:23]([O-:25])=[O:24])[NH:20][CH2:19][O:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:20]2[CH2:19][O:18][CH2:17][N:16]([CH3:15])[C:21]2=[N:22][N+:23]([O-:25])=[O:24])=[CH:5][N:6]=1
Reactant: Clc1ncc(CI)s1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 2.0 g of 2-chloro-5-iodomethyl-thiazole, 20 ml of dimethylformamide, 2.66 g of potassium carbonate and 1.23 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine is stirred for 16 hours at 50° C., cooled to room temperature and filtered; the filtrate is concentrated to dryness by evaporation. The residue is purified by column chromatography on silica gel using dichloromethane/methanol (9:1), yielding the title compound having a melting point of 132-134° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]#[N:10])=[C:4]([NH:11][C@H:12]([C:14]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:22](=[O:31])[C:21]3[C:16](=[C:17](I)[CH:18]=[C:19]([F:32])[CH:20]=3)[N:15]=2)[CH3:13])[N:3]=1.[CH3:34][N:35]1C(=O)CCC1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]([C:14]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[C:22](=[O:31])[C:21]3[C:16](=[C:17]([C:34]#[N:35])[CH:18]=[C:19]([F:32])[CH:20]=3)[N:15]=2)[CH3:13])[C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=1
Reactant: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2c(I)cc(F)cc2c(=O)n1-c1cccc(F)c1
Reactant: CN1CCCC1=O
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2c(C#N)cc(F)cc2c(=O)n1-c1cccc(F)c1

Procedure:
To a solution of (S)-2,4-diamino-6-((1-(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (560 mg, 1.0 mmol) in NMP (4 mL) was added cuprous cyanide (2.0 mmol, 180 mg) and tetrakis(triphenylphosphine)Pd(0) (0.10 mmol, 120 mg). The mixture was irradiated in microwave reactor at 150° C. for one hour. Purification by flash chromatography (40 g flash silica, 30% EtOAc/Hexanes to 20% MeOH/EtOAc), followed by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v trifluoroacetic acid) provided (S)-2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO) δ 8.55 (dd, J=2.8, 8.4 Hz, 1H), 8.20 (dd, J=3.2, 8.0 Hz, 1H), 7.88-7.17 (m, 5H), 5.07 (m, 1H), 1.44 (d, J=6.8 Hz, 3H). ES/MS 460.1 (M+H+);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1COC)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])C.[I-:22].[Na+].[CH3:24][Si](C)(C)Cl>C(#N)C>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:24])[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[I:22])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5]
Reactant: [I-]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(C)c2[nH]c3ccccc3c2c1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 1.5 g of 4-methoxymethyl-beta-carboline-3-carboxylic-acid-ethylester, 20 ml of acetonitrile, 3.1 g of sodium iodide and 2.7 ml of trimethylchlorosilane is stirred at 60° C. for 2 h. After cooling, it is poured into ice water and extracted with ethyl acetate. The extracts are washed with saturated sodium thiosulfate solution, dried and concentrated. 1.65 g of 4-iodo-methyl-beta-carboline-3-carboxylic-acid-methylester with a m.p. of 280°-286° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:11])[C:7](Cl)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:12][S-:13].[Na+]>C(O)(C)(C)C.O.CCOCC>[C:1]([C:4]1[CH:5]=[C:6]([Cl:11])[C:7]([S:13][CH3:12])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: O
Product: CSc1ncc(C(C)=O)cc1Cl
Temperature: 25 °C
Yield: 92.6 %

Procedure:
5-Acetyl-2,3-dichloropyridine (24.5 g, 0.129 mol) was slurried in t-butanol (200 mL) and sodium methanethiolate (10 g, 0.143 mol) was added. The mixture was heated under reflux conditions for two hours, cooled to room temperature, and diluted with water (200 mL) and ether (150 mL). This was separated and the aqueous phase extracted with ether (50 mL). The combined organic extracts were washed with water (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulphate, and evaporated to dryness to give the desired product (24.1 g, 94%) as a pale, low melting solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:9][CH2:8][C:3]([C:4]([CH3:5])=[O:6])([CH3:7])[CH2:2][O:1]2)=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(C)COC(c2ccc(N(C)C)cc2)OC1

Procedure:
3,3-bis(Hydroxymethyl)butanone (29.0 g), p-dimethylaminobenzaldehyde (29.8 g), toluene-p-sulphonic acid (250 mg) and toluene (140 ml) were heated under reflux in a Dean and Stark water trap until the theoretical amount of water had separated. The solution was concentrated in vacuo, the crude residue was washed with 8% aqueous sodium bicarbonate solution (100 ml) and crystallised from petroleum ether (b.p. 80°-100°)/ethyl acetate as a crystalline solid m.p.118°-120° (Cis-trans 96:4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(O)C=CC=CC=1.Br.CC(O)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCOC(c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CNCCO2)cc1
Temperature: 75 °C

Procedure:
A mixture of 2-(4-Nitrophenyl)-4-tosylmorpholine (185) (430 mg, 1.19 mmol), phenol (670 mg, 7.12 mmol) and 33% HBr/AcOH (2.2 mL) was heated in a sealed tube (microwave tube, conventional heating) at 75° C. for twenty hours. The cooled mixture was concentrated and the residue loaded onto a 10 g SCX cartridge in methanol. The cartridge was washed with methanol (200 mL), then eluted with 1% methanolic methylamine (100 mL). The methylamine eluent was evaporated to give the title compound (I86) (204 mg, 83%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.27-8.18 (m, 2H), 7.57-7.51 (m, 2H), 4.63 (dd, J=10.3, 2.5 Hz, 1H), 4.13-4.04 (m, 1H), 3.82 (td, J=11.3, 3.1 Hz, 1H), 3.13 (dd, J=12.3, 2.5 Hz, 1H), 3.06-2.92 (m, 2H), 2.74 (dd, J=12.3, 10.3 Hz, 1H). LCMS Method C: rt 1.49, 1.58 min; m/z 209.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([C:13](=[O:24])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH3:15])[CH:3]=1.[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][CH2:28]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][O:11][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Br:1])=[CH:3][C:4]=1[C:13](=[O:24])[N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:15]
Reactant: C[Si](C)(C)CCO
Reactant: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1CC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of DCM (10 mL) containing 2-{4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid (427 mg, 1.0 mmol) and 2-trimethylsilylethanol (183 mg, 1.5 mmol), were added DMAP (18.9 mg, 0.15 mmol) and DCC (320 mg, 1.5 mmol). The mixture was stirred at rt for 24 hrs, concentrated, and then directly purified via silica gel column chromatography eluting with ethyl acetate in hexane (20%) to yield {4-bromo-5-chloro-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-acetic acid 2-trimethylsilanyl-ethyl ester (520 mg). MS: (M-CH2CH2)+487.9/486.0; tR=3.34 min (method 1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Nc1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 5-bromo-pyridin-3-ylamine (example B.44) (156 mg, 0.9 mmol) according to general procedure II. Obtained as a light brown solid (40 mg, 9%). MS (ISN) 506.1 [(M+OAc)−]; mp 216-217° C.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:15]=[CH:14][C:13]2[CH:9]3[CH2:10][NH:11][CH2:12][CH:8]3[CH2:7][C:6]=2[C:5]=1[O:16]C.[C:18]([NH-])(=O)[CH2:19][CH3:20].B(Br)(Br)[Br:24]>>[BrH:24].[CH2:18]([N:11]1[CH2:12][CH:8]2[CH2:7][C:6]3[C:5]([OH:16])=[C:4]([OH:3])[CH:15]=[CH:14][C:13]=3[CH:9]2[CH2:10]1)[CH2:19][CH3:20]
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CC1CNCC21
Reactant: CCC([NH-])=O
Agent: Cl
Product: Br
Product: CCCN1CC2Cc3c(ccc(O)c3O)C2C1
Yield: 92 %

Procedure:
The compound of Example 6 (4.00 g.) was converted in 92% yield to the N-propionyl amide by the method of Example 10. This was reduced to the amine in 65% yield by the method in Example 11 and this was demethylated with BBr3 by the method of Example 7 in 80% yield to give the desired product, m.p. 192°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27](=[S:36])[NH:26][CH:25]=2)([CH3:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][S:36][C:27]1[N:28]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:24]([C:21]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)([CH3:23])[CH3:22])=[CH:25][N:26]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Product: COc1ccc(C(C)(C)c2cnc(SCc3c(F)cccc3Cl)n2-c2ccc(F)cc2)cc1OC

Procedure:
In a manner similar to that described for Example 1, the title compound was prepared from 2-chloro-6-fluorobenzyl bromide and 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione. 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 7.17-7.10 (m, 2H), 6.92-6.88 (m, 1H), 6.75-6.71 (m, 2H), 6.65 (d, 1H), 6.52 (d, 1H), 6.47 (dd, 1H), 6.34 (m, 2H), 4.24 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.49 (s, 6H); MS (EI) m/z 515 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([F:19])[C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.C(N(CC)CC)C.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([F:19])[C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D9 (0.36 mmol, 0.1 g) was dissolved in dichloromethane (10 ml) and triethylamine (3 eq., 1.08 mmol, 80 microliters), tetrahydro-4H-pyran-4-one (4.5 eq., 1.62 mmol, 162 mg), sodium triacetoxyborohydride (4.5 eq., 1.62 mmol, 345 mg) were added at room temperature and the mixture was stirred at room temperature for 2 hours. Additional tetrahydro-4H-pyran-4-one (2 eq., 0.72 mmol, 72 microliters) and sodium triacetoxyborohydride (2 eq., 0.72 mmol, 0.015 g) were added at room temperature and the mixture was stirred at room temperature for two further hours. The mixture was quenched with water and brought to pH≈10 by sodium hydroxide (aqueous solution). The organic phase was separated from the aqueous phase (by hydrophobic filters) and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-chloro-4-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 15 mg, 11%, M++H=354 and 356, which was converted to the hydrochloride salt using 1M HCl in diethyl ether.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCCl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](NS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (47 mg, 0.108 mmol) and 1,2-dichloroethane (4 ml). To the stirred solution was added methanesulfonyl chloride (10 μl, 0.12 mmol), triethylamine (30 μl, 0.22 mmol) and 4-dimethylaminopyridine (catalytic amount). The solution was stirred for 17 hr then partitioned between aqueous sodium hydroxide (5 ml, 0.2M) and dichloromethane (5 ml). The aqueous phase was extracted with dichloromethane (2×5 ml) and the combined organic layers were washed with brine (8 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was adsorbed onto silica gel and purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 1:3, v/v) to give the title compound (39 mg, 70%) which solidified on standing. δH(CDCl3) 0.17 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.00 (9H, s), 1.53 (2H, m), 1.71 (4H, m), 1.94 (2H, m), 2.85 (1H, m), 2.99 (3H, s), 3.78 (1H, m), 4.83 (1H, d), 6.28 (1H, d), 6.42 (1H, dd), 6.97 (1H, d).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[Cl:20].CN([CH:24]=[O:25])C.[Cl-].[NH4+]>C1COCC1>[Cl:20][C:19]1[C:14]([Cl:13])=[CH:15][N:16]=[CH:17][C:18]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Clc1ccncc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cncc(Cl)c1Cl
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (10.73 ml, 75.9 mmol) in THF (60 ml) at −40° C., was added n-butyllithium (47.45 ml, 75.9 mmol, 1.6M in hexanes) and the solution was stirred for 15 min at −40° C., before cooling to −70° C. A solution of 3,4-dichloropyridine (10.7 g, 72.3 mmol) in THF (30 ml) was added dropwise to maintain the temperature below −65° C. The reaction was stirred at −70° C. for 2 hours before the addition of DMF (6.74 ml, 86.8 mmol). The reaction was then stirred at −40° C. for 1 hours and then allowed to warm to −5° C. before the careful addition of saturated ammonium chloride solution (50 ml) with rapid stirring over 3 min. The mixture was then partitioned between saturated ammonium chloride (150 ml) and dichloromethane (150 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined organic layers were dried over magnesium sulfate, then concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, dichloromethane:ethyl acetate gradient 100:0 to 94:6) afforded the title compound as white waxy solid (8.01 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][C:8](OC)([O:30]C)[CH2:7][C:6]=2[CH:34]=1.Cl.O.[OH-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][C:8](=[O:30])[CH2:7][C:6]=2[CH:34]=1
Reactant: COC1(OC)CCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCC(=O)Cc3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 7-chloro-4,4-dimethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1g) in acetone (10 ml)is added 1N hydrochloric acid (5 ml), and the mixture is stirred at room temperature for 6 hours. Water is added to the reaction solution, and the mixture is neutralized with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-4-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>C1COCC1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:10][N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Agent: [K]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(O)(c1ccc(Cl)cc1)c1ccc(I)cc1
Temperature: 100 °C
Yield: 34 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* (571 mg, 1.60 mmol) and potassium phthalimide (340 mg, 1.84 mmol) in THF (5 mL) and DMSO (2 mL) was heated at 100° C. for 20 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine (×2), dried (MgSO4), filtered and concentrated to give a crude product which was purified by column chromatography (SiO2), eluting with a gradient of ethyl acetate/petrol (2.5% to 100%) then 10% methanol/dichloromethane to give the title compound (273 mg, 34%); LCMS (PS-A2) Rt 3.22 min [M+H]+ 504.