Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3([CH3:27])[CH2:26][CH2:25]3)[C:5]2=[CH:4][CH:3]=1.[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32].[CH2:37](Br)[CH:38]=[CH2:39].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:39]([N:12]1[C:13](=[O:23])[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:28])[CH:11]1[C:24]1([CH3:27])[CH2:25][CH2:26]1)[CH:38]=[CH2:37].[CH3:29][O:30][CH:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:32]
Reactant: C=CCBr
Reactant: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Br)ccc32)C1C1(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methyl cyclopropyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (200 mg, 0.34 mmol) and allyl bromide (1.2 g, 10 mmol) in DMF (15 mL) was added Cs2CO3 (4 g, 12.1 mmol). The mixture was stirred at room temperature for 2 h, then poured into water (100 mL), extracted with ethyl acetate for 3 times. The organic layer was washed with water, dried over Na2SO4, concentrated to give crude product as a light yellow solid (210 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN1C(=O)CCC1.CCOC(C)=O>[N:17]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][N:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Clc1cccc(-c2n[nH]c3nccnc23)n1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1cc(-c2n[nH]c3nccnc23)nc(N2CCNCC2)c1
Temperature: 150 °C
Yield: 11 %

Procedure:
A mixture of 3-(6-chloro-2-pyridyl)-1H-pyrazolo[3,4-b]pyrazine (150 mg, 0.6476 mmol) and piperazine (167.4 mg, 1.943 mmol) in NMP (1.5 mL) was heated in microwave at 150° C. for a total of 1.5 h. Mixture cooled to ambient, diluted with EtOAc and washed with sat. NaHCO3 solution (1×), water (2×), brine (1×), dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by ISCO companion (24 g SiO2, 0.5 to 10% MeOH (containing 10% ammonium hydroxide), pure fractions combined and concentrated in vacuo. Product re-dissolved in MeCN/H2O and freeze-dried to leave title compound as a yellow solid (20 mg, 11%). 1H NMR (DMSO-d6) δ2.82 (t, 4H), 3.56 (t, 4H), 6.85 (d, 1H), 7.69 (t, 1H), 7.77 (d, 1H), 8.65 (d, 1H) and 8.73 (d, 1H). ES+281.9.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2([C:8]#[N:9])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 4-trifluoromethylbenzyl cyanide (0.92 g, 5.0 mmol) and bis(2-bromoethyl)ether (2.3 mL, 18 mmol) in DMF (10 mL) at room temperature was treated portion wise with sodium hydride (60% in mineral oil, 0.6 g, 15 mmol) over a period of 10 mins followed by stirring at the same temperature for 1 h. The mixture was then stirred at 70° C. for 16 h. Then cooled to room temperature and the reaction mixture was quenched with slow addition of methanol. Water (100 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water and brine and dried over sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography using a gradient of 5% EtOAc in hexanes to 30% EtOAc in hexanes to give the title compound (1.11 g, yield: 87%). 1H NMR (CDCl3 300 MHz): δppm 7.75 (d, 2H), 7.65 (d, 2H), 4.20-4.09 (m, 2H), 4.00-3.85 (m, 2H), 2.27-2.05 (m, 4H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([C:22]#[C:23][C:24]2[S:25][C:26]([C:29](O)=[O:30])=[CH:27][N:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOC(C)=O>[C:16]1([C:22]#[C:23][C:24]2[S:25][C:26]([C:29]([N:2]3[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]3)=[O:30])=[CH:27][N:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)c2cnc(C#Cc3ccccc3)s2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
Example 75 was prepared via the process of Scheme 1, step 3, Method—B, supra, as follows: 2-Phenylethynyl-thiazole-5-carboxylic acid (0.100 g, 0.436 mmol) in tetrahydrofuran (1.7 mL) [Intermediate 1] was stirred, and N,N′-carbonyldiimidazole (0.079 g, 0.49 mmol) (Fluka Chemie AG) was added in one portion at room temperature. The mixture was stirred for 60 minutes and then 4-piperidone monohydrochloride (0.241 g, 1.78 mmol) (3B Pharmachem (Wuhan) International Co., LTD (Libertyville, Ill., USA)) was added, followed by the addition of triethylamine (192 uL, 1.38 mmol). The mixture was stirred for about 2 hours and was worked up by diluting with 25 mL of EtOAc and washing with 2×10 mL of 1.7% aq. HCl, 1×10 mL of water, 3×10 mL of 1.0 M K2CO3, and 1×10 mL of brine; dried (Na2SO4), and concentrated to give the title compound, 1-(2-phenylethynyl-thiazole-5-carbonyl)-piperidin-4-one (55 mg; 41%), as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.63-7.59 (m, 2H), 7.47-7.32 (m, 3H), 4.03 (t, J=6.3 Hz, 4H), 2.59 (t, J=6.3 Hz, 4H). LC/MS (Method 1), RT=1.05 min. Calculated [M+H]+=311; Observed [M+H]+=311.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[C:25]([Cu])#[N:26].[NH4+].[OH-].Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2ccn(Cc3ccccc3)c(=O)c2c1O
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-1-iodo-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (180 mg, 0.41 mmol) and CuCN (74 mg, 0.83 mmol) in 5 mL of DMF was refluxed for 8 min. The reaction mixture was cooled to r.t. and poured into a stirring mixture of 1% NH4OH solution and CH2Cl2. 4 M HCl was then added with vigorous stirring until no more solid was present. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-15% CH2Cl2/EtOAc+1% AcOH) to give 81 mg of the title compound as a pale yellow solid. MS: (−) m/z 334.00 (M−1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1([C:29]([OH:31])=O)[CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.[N:41]1([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:46][CH2:45][CH:44]([N:47]2[C@H:51]3[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]3[NH:49][C:48]2=[O:56])[CH2:43][CH2:42]1>CC(N(C)C)=O>[CH3:25][C:26]1([C:29]([N:60]2[CH2:61][CH2:62][CH:57]([N:41]3[CH2:42][CH2:43][CH:44]([N:47]4[C@H:51]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]5[NH:49][C:48]4=[O:56])[CH2:45][CH2:46]3)[CH2:58][CH2:59]2)=[O:31])[CH2:28][CH2:27]1
Reactant: CC1(C(=O)O)CC1
Reactant: O=C1N[C@H]2CCCC[C@@H]2N1C1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC1(C(=O)N2CCC(N3CCC(N4C(=O)N[C@H]5CCCC[C@@H]54)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
HBTU (284 mg, 0.75 mmol) was added to a solution of 1-methylcyclopropanecarboxylic acid (75 mg, 0.75 mmol), N,N-diisopropylethyl amine (194 mg, 1.50 mmol) and (3aS,7aS)-1-(1,4′-bipiperidin-4-yl)hexahydro-1H-benzo[d]imidazol-2(3H)-one (153.22 mg, 0.50 mmol) in DMA (10 mL) and stirred at room temperature for overnight. Concentrated in vacuo, diluted in dichloromethane (50 ml) and washed with sat. NaHCO3 (10 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by high pH Prep LCMS to give the titled compound (40 mg, 20.6%). 1H NMR (400 MHz, CHLOROFORM-D): δ ppm 0.51-0.59 (m, 2H) 0.86-0.94 (m, 2H) 1.30 (s, 3H) 1.33-1.45 (m, 6H) 1.68 (s, 1H) 1.74-1.84 (m, 7H) 1.96 (d, J=10.16 Hz, 1H) 2.21-2.32 (m, 3H) 2.48 (t, J=11.13 Hz, 1H) 2.76 (s, 1H) 2.92-3.03 (m, 4H) 3.71-3.81 (m, 1H) 4.49 (s, 3H). MS (M+1): 389.2
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)C(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)C(O)C(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of 2-hydroxy-3-methylbutanoic acid (120 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one (230 mg, 70%). LC/MS: m/z 421.3 (M+H)+ at 2.43 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.79 (d, J=7.2 Hz, 1H), 4.11 (dd, J=7.0, 5.9 Hz, 1H), 3.87 (m, 8H), 2.52 (s, 3H), 1.91 (m, 1H), 0.88 (dd, J=22.8, 6.7 Hz, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:37][CH3:38])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(Cl)c(Cl)c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(6-(3,4-dichlorobenzylamino)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.11 g) as starting compound, acetaldehyde (0.13 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 0.75 g of 4-amino-5-chloro-N-((1-(6-(N-(3,4-dichlorobenzyl)-N-ethylamino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:18][C:19]5[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[NH4+].C(Cl)CCl.C1C=CC2N(O)N=[N:43]C=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:18][C:19]5[CH:25]=[C:24]([C:26]([NH2:43])=[O:27])[CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid (44-0.8 mg, 0.11 mmol), ammonium chloride (11.8 mg, 0.22 mmol), EDC (32.6 mg, 0.17 mmol) and HOBt (23.0 mg, 0.17 mmol) in DMF 3.0 mL was added DIPEA (0.03 ml 0.17 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=6:1) to give 2-(4-adamantan-1-yl phenoxymethyl)-3H benzoimidazole-5-carboxylic acid amide as a white solid (16.8 mg, 37.5% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:29][N:30]1[C:42]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[C:34]([S:43](Cl)(=[O:45])=[O:44])[CH:35]=2>C(Cl)(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:43]([C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]([CH3:29])[C:42]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]4=3)(=[O:44])=[O:45])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Reactant: Cn1c2c(c3cc(S(=O)(=O)Cl)ccc31)CCCC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3c(c2)c2c(n3C)CCCC2)CC1

Procedure:
To a solution of 1 g (0.0034 Mol) of 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxoethylamine and 1.1 g (0.011 Mol) of triethylamine in 30 ml of chloroform are added dropwise, at ambient temperature and with stirring, 0.96 g (0.0034 Mol) of 9-methyl-1,2,3,4-tetrahydro-carbazol-6-sulphonic acid chloride dissolved in 10 ml of chloroform. After 12 hours' stirring the mixture is evaporated down in vacuo and the residue obtained is chromatographed over a silica gel column (eluant: ethyl acetate/methanol=9:1). The eluate having an Rf value of 0.3 is collected and evaporated down in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15](Cl)[N:14]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][N:25]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:21])[CH2:12][C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([O:23][CH3:22])[CH:29]=2)[N:14]=1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2cc(=O)[nH]c(CC(=O)N3CCc4c(F)cccc43)n2)ccn1
Yield: 60.7 %

Procedure:
The product is prepared by following the procedure described in example 12b using 100 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-chloro-3H-pyrimidin-4-one and 160 mg of 2-methoxypyridine-4-boronic acid pinacol ester. 75 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methoxypyridin-4-yl)-3H-pyrimidin-4-one are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([OH:31])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:19]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([O:31][C:16]1[CH:15]=[C:14]([Cl:13])[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:17]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: N#Cc1ccc(CCOc2cc(O)cc(Cl)c2)cc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(CCOc2cc(Cl)cc(OS(=O)(=O)c3ccc(F)cc3Cl)c2)cc1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
2-Chloro-4-fluorobenzenesulfonyl chloride (1.16 g; 5.0 mmol) was added to a cold solution (ice:water temperature) of 3-chloro-5-[2-(4-cyanophenyl)ethoxy]phenol (0.689 g; 2.5 mmol; from step (ii) above) in pyridine (8 mL). The temperature was allowed to rise (slowly) to ambient overnight. The mixture was re-cooled (ice:water temperature) and ice was added to the reaction flask. After stirring for 4 hours, the pyridine was removed in vacuo. CH2Cl2 was then added and the organic layer was washed with aqueous KHSO4 and water. Drying (MgSO4), evaporation of the solvent and purification by flash chromatography (SiO2; CH2Cl2) afforded 0.84 g (72%) of the sub-title compound.
Reaction SMILES: Cl.[CH2:2]([O:18][CH2:19][CH:20]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1.[C:56](Cl)(=[O:58])[CH3:57]>O>[CH2:2]([O:18][CH2:19][CH:20]([CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:21][CH2:22][CH2:23][CH2:24][NH:25][C:56](=[O:58])[CH3:57])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCCNC(C)=O
Reaction time: 1 h
Yield: 79 %

Procedure:
1,3-Di-O-(n-hexadecyl)-2-O-(3-aminopropyl)-glycerol hydrochloride (1.0 g., 1.6 mmoles) was added to a mixture of potassium carbonate (830 mg., 6.0 mmoles) and benzene (75 ml.). Acetyl chloride (150 mg., 1.9 mmoles) was then added and the resulting mixture stirred for one hour at reflux. Additional acetyl chloride (150 mg., 1.9 moles) was added and the reaction mixture stirred for another hour at reflux. TLC analysis showed that the reaction was essentially complete. The reaction mixture was cooled, water (75 ml.) added, and the resulting mixture extracted with ether (3×100 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated in vacuo to yield the named compound [800 mg., 79% yield, m.p. 53°-54° C., ir (CHCl3) 3400 and 1670 cm-1, n.m.r. (CDCl3) δ1.97 (s, 3, --NHCOCH3)].
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8](O[Si](C(C)(C)C)(C)C)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:30])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([Cl:30])=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)[C@H](Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 21.0 g (53 mmol) of (1,1-dimethylethyl)-dimethylsilyl (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)-3-phenylpropanoate (3) and five drops of N,N-dimethylformamide in methylene chloride at 0° C. was added 29.3 mL (59 mmol) of a 2.0M solution of oxalyl chloride in methylene chloride over a 30 min period. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 18 hours. The solvent and excess oxalyl chloride were removed by rotary evaporation resulting in a yellow liquid. Purification by vacuum distillation afforded 12.7 g (80%) of (2S)-2-((1,1-dimethylethyl)-dimethylsilyloxy)-3-phenylpropanoyl chloride (4) as a clear liquid: bp 88°-90° C. (0.2 mm Hg); 1H NMR (CDCl3) δ-0.215 (s, 3 H), -0.0339 (s, 3 H), 0.840 (s, 9 H), 2.94-3.01 (m, 1 H), 3.23-3.29 (m, 1 H), 4.52-4.56 (m, 1 H), 7.25-7.35 (m, 5 H); 13C NMR (CDCl3) δ175.7, 135.9, 129.8, 128.4, 127.1, 81.1, 40.8, 25.5, 18.0, -5.40, -5.76.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][CH:29]=O.Cl>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][CH2:29][N:2]([CH3:1])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:8]1
Reactant: O=CCCc1ccc(Cl)cc1Cl
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: CN(CCCc1ccc(Cl)cc1Cl)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Condensation of 15 (550 mg, 1.9 mmol) and 3-(2,4-dichlorophenyl)-propionaldehyde (390 mg, 1.9 mmol) following the procedure described in Example 45, Step 2, followed by conversion to the HCl salt, gave 6-(trans-4-{[3-(2,4-dichlorophenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (446 mg, 50%), as an off-white solid: mp 273-279° C.; IR (KBr): 2949, 1775, 1500, 1474 cm−1; 1H NMR(500 MHz, DMSO-d6): δ 11.49 (s, 1H), 10.01 (s, 1H), 7.61 (d, J=2 Hz, 1H), 7.47-7.41 (m, 2H), 7.17 (s, 1H), 7.00 (s, 2H), 3.34-3.29 (m, 1H), 3.22-3.17 (m, 1H), 3.11-3.03 (m, 1H), 2.79-2.73 (m, 2H), 2.71 (d, J=5 Hz, 3H), 2.59-2.48 (m, 1H), 2.14-2.06 (m, 2H), 2.03-1.97 (m, 2H), 1.94-1.88 (m, 2H), 1.69-1.50 (m, 4H); ESI (m/z): 433 [M+H]+; HPLC: method A, 6.78 minutes (>99%); Anal. Calcd for C23H26Cl2N2O2.HCl: C, 58.80; H, 5.79; N, 5.96. Found: C, 58.62; H, 5.76; N, 5.89.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.CO[C:15](=N)[C:16]([Cl:19])([Cl:18])[Cl:17]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15]([C:16]([Cl:19])([Cl:18])[Cl:17])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (12.0 mmol) Methyl-3,4-diamino-benzoate were dissolved in 50 mL concentrated acetic acid. Then 2.09 mL (1.4 equiv.) methyl-2,2,2-trichloroacetimidate were added slowly and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with 100 mL toluene and the solvent was removed under reduced pressure. The residue was taken up in dichloromethane and washed once with a saturated NaHCO3-solution and once with brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give pure methyl-2-trichloromethyl-1H-benzoimidazole-5-carboxylate as a light brown amorphous solid. Yield: 3.64 g MS (ES+): m/e=293, chloro pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13]O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: OCc1nc(-c2ccc(Cl)cc2)cs1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2csc(CBr)n2)cc1
Temperature: 120 °C
Yield: 16.6 %

Procedure:
To the solution of [4-(4-Chloro-phenyl)-thiazol-2-yl]-methanol (0.80 g, 3.55 mmol) in 10 ml of toluene was added PBr3 (0.51 ml, 5.33 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.17 g, 17%). The corresponding cyano derivative was also prepared by the same general method.