Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C:19]2([CH2:21][CH2:20]2)[C@H:18]2[C@@H:11]([O:12][Si:13]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:14][Si:15]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:16][CH2:17]2)[C@@H:10]1[F:34])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:34][C@H:10]1[C@@H:11]2[O:12][Si:13]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[O:14][Si:15]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[O:16][CH2:17][C@H:18]2[C:19]2([CH2:21][CH2:20]2)[C@@H:9]1[OH:8]
Reactant: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@@H](OCc1ccccc1)C21CC1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)[Si]1(C(C)C)OC[C@@H]2[C@@H](O[Si](C(C)C)(C(C)C)O1)[C@H](F)[C@@H](O)C21CC1
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
A solution of compound 26 (1.38 g, 2.6 mmol) in anhydrous CH2Cl2 was treated with boron trichloride (7.1 ml, 1M solution in CH2Cl2, 8.1 mmol) at −78° C. during 15 minute. After stirred at the same temperature for another 15 min, additional portion of boron trichloride (5.1 mL of 1M solution in CH2Cl2) was added. The reaction was quenched with MeOH at −78° C. after 15 min and concentrated under reduced pressure. The residue was purified by column chromatography on the silica gel (EtOAc:Hexane=1;10 to 1:3) to give 27 (0.84 g, 78%). [α]24D−53.55° (c 0.5, MeOH); 1H NMR (500 MHz, CDCl3) δ 4.65 (dt, J=8.0 & 15.0 Hz, 1H), 4.49-4.45 (m, 1H), 4.26-4.21 (m, 1H), 3.99 (dd, J=4.5 & 12.0 Hz, 1H), 3.89 (dd, J=6.0 & 11.5 Hz, 1H), 2.66 (s, 1H), 0.93-1.08 (m, 28H), 0.72 (m, 1H), 0.68-0.43 (m, 2H), 0.28 (m, 1H); 19F NMR (500 MHz, CDCl3) δ −195.8 (m); 13C NMR (125 MHz, CDCl3) δ 7.8, 12.5, 12.7, 13.3, 13.4, 16.9, 16.98, 17.07, 17.08, 17.4, 17.5, 27.5 29.8, 49.1, 63.7, 73.7, 74.7, 102.3 (d, J=192.7 Hz); HR-MS Calcd. For (C20H39FO4Si2+H)+ 418.2592. found 418.2592.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([CH2:20][OH:21])[CH2:13]2.C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C.ClCCl>[Br:1][C:2]1[C:10]2[C:9]([N:19]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([CH2:20][OH:21])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: OCC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: OCC1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Yield: 91.5 %

Procedure:
5-Bromo-4-chloro-thieno[2,3-d]pyrimidine (1.0 g, 4.0 mmol) in acetonitrile (25 mL) was treated with 8-azabicyclo[3.2.1]octan-3-ylmethanol (705 mg, 16 mmol) and potassium carbonate (2.208 g, 16 mmol) at reflux for 4 h. The reaction was then concentrated in vacuum to a gum and partitioned between ethyl acetate (100 mL) and water (50 mL). The ethyl acetate was separated, dried over sodium sulphate and concentrated in vacuum to give a yellow gum. The gum was columned on silica in a gradient of 2-8% methanol in dichloromethane on a 100 g column. The main first fraction was collected and concentrated in vacuum to a gum. The gum was triturated with diethyl ether (20 mL) and crystallized on standing for a few minutes. The diethyl ether was decanted off and the crystals dried in vacuum to yield 3 [8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl]methanol (1.297 g, 3.66 mmol, 91%). 1H NMR (CDCl3) δ: 1.42 (2H, dd, J=12 Hz, J′=4 Hz), 1.67 (2H, d, J=4 Hz), 1.82 (1H, br s), 1.98 (3H, br m), 2.48 (2H, quintet, J=4 Hz), 3.64 (2H, d, J=4 Hz), 4.7 (2H, br s), 7.32 (1H, s), 8.45 (1H, s).
Reaction SMILES: [Li+].[OH-].FC1C=C(C=CC=1F)C([O:9][CH2:10][C@@H:11]([N:15]([CH3:26])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)[CH:12]([CH3:14])[CH3:13])=O.C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[C:16]([N:15]([C@@H:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][OH:9])[CH3:26])=[O:25]
Reactant: CC(C)[C@@H](COC(=O)c1ccc(F)c(F)c1)N(C)C(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@@H](CO)N(C)C(=O)c1ccc(F)c(F)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
LiOH (25.7 mL, 12.83 mmol) was added to (S)-2-(3,4-difluoro-N-methylbenzamido)-3-methylbutyl 3,4-difluorobenzoate (Compound C2.2) (4 g, 8.56 mmol) in MeOH (40 mL). The resultant mixture was stirred at rt over night. Additional LiOH (10.27 mL, 10.27 mmol) was added and the stirring continued for 2 h. The mixture was neutralized by the addition of acetic acid. The solvent was removed and DCM (50 mL) was added. The organic phase was washed with NaHCO3 (saturated, 1×50 mol, 2×30 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (2.18 g, 99%). The obtained crude product was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:2].[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=3)=[O:25])=[CH:23][C:18]=2[NH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:12]4[CH2:11][CH2:10][N:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[CH2:1][CH3:2])[CH2:14][CH2:13]4)=[O:35])=[CH:29][CH:28]=3)=[O:25])=[CH:23][C:18]=2[NH:17][CH:16]=1
Reactant: O=C(O)Cc1ccc(NC(=O)c2ccc3nc[nH]c3c2)cc1
Reactant: CCc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1N1CCN(C(=O)Cc2ccc(NC(=O)c3ccc4nc[nH]c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(2-ethylphenyl)piperazine (0.19 g; 1.0 mmol), 4-(5-benzimidazolylcarbonylamino)phenylacetic acid (0.329 g; 1.10 mmol), HOBT (0.14 g; 1.0 mmol), and EDC (0.230 g; 1.20 mmol) in DMF (30 mL) was added DIEA (0.23 mL; 1.3 mmol). The reaction was stirred at ambient temperature for 18 h and the solvent was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic phase was separated and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 93:7:0.35 CH2Cl2 :MeOH:NH4OH as eluant. Evaporation of the product-containing fractions under reduced pressure gave the title compound as an amorphous solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=3)[CH2:4]2)=[O:27])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccc([N+](=O)[O-])cc2C1)c1cccc(Cl)c1

Procedure:
To 2-amino-5-nitroindane hydrochloride (1.5 g, 7.0 mmol) in methylene chloride (50 ml) at 0° C. was added triethylamine (2.1 ml, 15.0 mmol) followed by 3-chlorobenzoyl chloride (1.0 ml, 7.5 mmol). The mixture was dumped immediately into water and the layers separated. The aqueous layer was extracted with methylene chloride (2×20 ml) and the combined extracts washed with water, dried over MgSO4, filtered, and concentrated to an oil which was homogeneous by TLC and used immediately in the next step: M.S. (M+H)+ =317.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:15]([CH2:17]O)=[N:16][C:12]=2[CH:11]=1.C(Cl)(=O)C(Cl)=O.[I-].[Na+].[CH3:35][NH:36][CH3:37]>CN(C)C=O.O1CCCC1.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:15]([CH2:17][N:36]([CH3:37])[CH3:35])=[N:16][C:12]=2[CH:11]=1
Reactant: CNC
Reactant: OCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Yield: 43 %

Procedure:
An eggplant flask (50 mL) equipped with a reflux condenser was charged with 5-(benzoxazol-2-yl)-2-hydroxymethyl-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 13) (0.055 g, 0.16 mmol), oxalyl chloride (0.024 g, 0.19 mmol), and anhydrous dichloromethane (3 mL), and after the addition of anhydrous N,N-dimethylformamide (5 drops) at room temperature, this was refluxed for 3.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. To the yellow residue was added anhydrous tetrahydrofuran (5 mL) and anhydrous sodium iodide (0.036 g, 0.24 mmol), followed by a tetrahydrofuran solution of dimethylamine (2.0 M, 3 mL), and this was refluxed for 14 hours. After being allowed to cool to room temperature, the solvent was distilled off under reduced pressure. The yellow residue (0.70 g) was purified by silica gel column chromatography (silica gel: 2.6 g; MeOH/CHCl3=1/5) to yield the title compound (0.026 g, 43% yield) as a pale yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].[C:16]1([CH2:22][N:23]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C@H:25]3[CH2:32][NH:33][CH2:34][CH2:35][C@@H:24]23)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(C(C)=O)C(C)C>[C:16]1([CH2:22][N:23]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C@H:25]3[CH2:32][N:33]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH:11]=[CH:12][CH:13]=[CH:14][C:7]5=[N:6][C:5]=4[CH3:15])[CH2:34][CH2:35][C@@H:24]23)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Reactant: c1ccc(CN2c3ccccc3[C@H]3CNCC[C@H]32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1nc2ccccn2c(=O)c1CCN1CC[C@@H]2[C@H](C1)c1ccccc1N2Cc1ccccc1
Yield: 50 %

Procedure:
A mixture of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.45 g), disclosed in EP-0,196,132, intermediate 5 (2.7 g), sodium carbonate (3.3 g) and potassium iodide (0.1 g) in methyl isobutyl ketone (250 ml) was stirred and refluxed for 18 hours. The reaction mixture was cooled, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /CH3OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN (25 ml). The crystals were filtered off and dried, yielding 2.3 g (50%) of (±)-cis-3-[2-[1,3,4,4a,5,9b-hexahydro-5-(phenylmethyl)-2H-pyrido[4,3-b]indol-2-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (compound 9, mp. 145.1° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[NH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[CH2:19][C:18]1([CH3:29])[CH3:28].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:26]([C:23]1[CH:24]=[C:25]2[C:20]([CH2:19][C:18]([CH3:29])([CH3:28])[C@H:17]2[NH:16][C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])=[CH:21][CH:22]=1)#[N:27]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-nitro-1H-indole-2-carboxylic acid (144 mg, 0.698 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (110 mg, 0.591 mmol), BOP reagent (401 mg, 0.907 mmol), N-methylmorpholine (0.30 mL, 2.73 mmol) in DMF (2 mL) was stirred at rt for 16 hr. To the mixture was added 5% NaHCO3 solution (35 mL) and the resulting mixture was stirred at rt for 15 min. The precipitating title product (250 mg) was collected as a beige solid by suction filtration and dried over Drierite® under vacuum. LCMS (M+H)+=375.25. 1H NMR (500 MHz, DMSO-d6) δ: 8.84 (d, J=9.3 Hz, 1H), 8.69 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J=11.0 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 5.39 (d, J=9.3 Hz, 1H), 2.87 (dd, J=20.9, 16.5 Hz, 2H), 1.22 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.NCCCCN.C([Li])CCC.[O:19]=[C:20]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:22]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:44][O:45][C:46]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:47]=1[CH2:48]Cl.S(=O)(=O)(O)[O-].[K+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[O:19]=[C:20]([NH:35][CH:36]([CH2:48][C:47]1[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:46]=1[O:45][CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:22]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)CNC(=O)CC(C1CCCCC1)C1CCCCC1
Reactant: COc1ccc(OC)c(CCl)c1
Agent: NCCCCN
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CC(NC(=O)CC(C2CCCCC2)C2CCCCC2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The following procedure was carried out under argon. A stirred solution of 4.1 ml (29.2 mmol) of diisopropylamine and 4.3 ml (28.5 mmol) of tetramethylenediamine in 75 ml of tetrahydrofuran was cooled to -75° C. and treated portionwise with 18 ml (28.4 mmol) of 1.6M n-butyllithium in hexane. After stirring for 20 minutes, α-[(1-oxo-3,3-dicyclohexylpropyl)amino]acetic acid, 1,1-dimethylethyl ester (5.0 g; 14.2 mmol) in 30 ml of tetrahydrofuran was added dropwise at -75° C. The color changed from nearly colorless to yellow. Stirring at -75° C. was continued for 1 hour, after which the gelatinous dianion solution was treated portionwise with 2.65 g (14.2 mmol) of 2,5-dimethoxybenzyl chloride in 10 ml of tetrahydrofuran. After stirring at -75° C. for 1 hour, the mixture was allowed to warm gradually to room temperature. The color lightened to pale yellow. After stirring overnight, the mixture was poured with stirring into 100 ml of crushed ice and 100 ml of 10% potassium bisulfate, ethyl acetate (50 ml) was added, the mixture shaken, and the layers separated. Since the aqueous phase was still basic, additional 10% potassium bisulfate was added (2×10 ml), followed by shaking, until the pH was approximately 6. The aqueous layer was then extracted with ethyl acetate (3×50 ml) and the combined organic layers washed with 40 ml each of 5% potassium bisulfate, water, and saturated sodium chloride solution. After drying (magnesium sulfate), the solvents were evaporated to give 7.6 g of a light yellow, mostly solid residue. The latter was ground in a mortar under 40 ml of ether, kept 3 hours at room temperature, cooled for 0.75 hours, and the colorless solid filtered, washed with 20 ml of cold ether, and air-dried (3.4 g; melting point 108°-111° C. s, 103° C.). Following crystallization from 45 ml of isopropyl ether, the product weighed 2.9 g, melting point 114°-116° C.
Reaction SMILES: C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C(C)C.Br[C:20]1[S:21][C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:23][N:24]=1.Br[C:39]1[CH:45]=[CH:44][C:42](N)=[CH:41][CH:40]=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:22]3[S:21][C:20]([C:39]4[CH:45]=[CH:44][CH:42]=[CH:41][CH:40]=4)=[N:24][CH:23]=3)=[O:26])=[CH:30][C:31]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1cnc(Br)s1
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: O=C(NCc1ccn2ccnc2c1)c1cnc(-c2ccccc2)s1

Procedure:
The title compound was prepared as described in Example 51A, substituting phenyl boronic acid for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiazole-5-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.34 (t, J=5.8 Hz, 1H), 8.56-8.48 (m, 2H), 8.05-7.95 (m, 2H), 7.90 (d, J=0.8 Hz, 1H), 7.60-7.49 (m, 4H), 7.45 (s, 1H), 6.87 (dd, J=7.0, 1.6 Hz, 1H), 4.52 (d, J=5.7 Hz, 2H); MS (ESI(+)) m/e 335 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][CH2:4]1)(=[O:18])=[O:17]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Yield: 80.9 %

Procedure:
To a solution of 4-hydroxypiperidine (5.10 g, 50 moles) and triethylamine (20.9 ml, 150 moles) in methylene chloride (150 ml) was added methanesulfonyl chloride (8.54 ml, 110 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was solidified with ethyl acetate-n-hexane to obtain 11.45 g of the desired product (88.3%, pale yellow solid).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])=[CH:4][CH:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:11][C:10]=2[F:18])=[CH:4][CH:3]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccc(Cl)nc2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4ccc(Cl)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((6-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:27])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([CH:38]=O)[CH:36]=[CH:37][C:29]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.ClCCl>[O:28]1[C:29]2[CH:37]=[CH:36][C:35]([CH2:38][N:19]3[CH2:20][CH2:21][C:16]([CH2:15][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:27])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18]3)=[CH:34][C:30]=2[O:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To 2 mL of dichloromethane solution containing 80 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 40 mg of 2,3-dihydrobenzo(b)(1,4)dioxin-6-carbaldehyde and 14 μL of acetic acid were added at room temperature, 78 mg of sodium triacetoxyborohydride was added under ice-cooling, and stirred at room temperature for 1 hour. To the reaction mixture, water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=15:1], to give 0.10 g of ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[N:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(Cl)(=O)C>C1C=CC=CC=1.C(O)C>[CH2:9]([N:8]1[C:7]2=[N:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]2[N:25]=[C:23]1[CH3:24])[CH3:10]
Reactant: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCn1c(C)nc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 15 °C

Procedure:
2-Chloro-3-ethylamino-5,6-diphenylpyrazine, (3.10 g, 0.01 moles) is dissolved in benzene (50 ml) and then triethylamine (1.29 g, 0.013 moles) and acetyl chloride (1.00 g, 0.013 moles) are added. The solution is refluxed 41/2 hours, cooled to 15° C and filtrate. The filtrate is diluted with ethanol (3 ml), warmed briefly at 50° C and then all volatile materials evaporated. The resultant brown oil is treated with liquid ammonia (17 g) in ethanol (60 ml) in a bomb at 165° C for 12 hours. The solution is diluted with water (200 ml), cooled and the yellow precipitate filtered off. The solid is triturated with boiling 50% aqueous methanol, filtered, and the filtrate chilled. The product is collected by filtration. Yield 0.45 g (14%). It is recrystallized from benzene-heptane, m.p. 178.5°-180° C.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=O)C>Cl>[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(c2ccc(S(N)(=O)=O)cc2)CC1
Agent: Cl
Product: NS(=O)(=O)c1ccc(C2CCNCC2)cc1

Procedure:
A mixture of the product of part (ii) above (17.0 g) and 5N aqueous hydrochloric acid (150 ml) was heated under reflux for 3 hours. The resulting solution was evaporated and the residue was dissolved in the minimum volume of water. The solution was made basic (to a pH of about 8-9) by the addition of solid sodium bicarbonate. The solid was filtered off, washed with a little water and crystallised from ethanol/methanol (2:1) to give the title compound, (7.70 g), m.p. 229°-230°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].O1CCCC1.[H-].[Na+].C(O)(=O)C.O[CH2:30][NH:31][C:32](=[O:34])[CH3:33]>O.C(Cl)Cl.C(OCC)(=O)C.C(Cl)Cl>[Cl:7][C:6]1[N:5]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[C:3]([C:16]#[N:17])[C:2]=1[Cl:1]
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Reactant: CC(=O)NCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)NCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A slurry of 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (15.3 g, 0.05 mol) and tetrahydrofuran (80 mL) is cooled to 10° C. and treated portionwise over 20 minutes with sodium hydride (2.2 g, 60% in oil, 0.055 mol). After stirring for 15 minutes this solution is added dropwise to a 50° C. solution of N-(hydroxymethyl)acetamide acetate (ester) (9.18 g, 0.07 mol) and tetrahydrofuran (20 mL). The reaction mixture is refluxed for two hours, cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. Flash chromatography of the solid on silica gel packed in methylene chloride using ethyl acetate/methylene chloride solutions as eluents gives a solid. Recrystallization of the solid from ethyl acetate gives the title product as off white crystals (5.35 g, mp 162°-162.5° C.) which is identified by IR and NMR spectral analyses.