Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:10][C:11](OC1C=CC([N+]([O-])=O)=CC=1)=[O:12].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH2:50][NH2:51])[CH:45]=[CH:46][C:47]=1[O:48][CH3:49].[H-].[Na+].I[CH3:55]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:31])[F:32])=[C:25]([O:33][CH2:34][CH:35]2[CH2:36][CH2:37]2)[CH:24]=1)[O:10][C:11](=[O:12])[N:51]([CH2:50][C:44]1[CH:45]=[CH:46][C:47]([O:48][CH3:49])=[C:42]([O:41][CH3:40])[CH:43]=1)[CH3:55]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (for reference procedure see Example 3, Step 1) (300 mg, 0.513 mmol) in dry THF (5 ml), (3,4-dimethoxyphenyl)methanamine (0.077 ml, 0.513 mmol) was added. The mixture was stirred at RT for 2 hours and then cooled to 0° C. NaH (60% w/w dispersion in mineral oil, 61.5 mg, 1.538 mmol) was added portion wise followed by iodomethane (0.080 ml, 1.281 mmol). The cold bath was removed and the reaction was stirred at RT for 5 hours. The mixture was cooled to 0° C., quenched with water and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, the solvent was evaporated, and the crude was purified by flash chromatography on silica gel column (DCM/MeOH 100/2). The desired product was obtained as a white solid (96 mg, 0.153 mmol, 29.9% yield, MS/ESI+ 626.89 [MH]+[αD]=−12.01, c=0.616, DCM).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])S(C2C=CC=CC=2)(=O)=O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C1C=C(NC(N[C@@H]2CCCC[C@H]2N(C)C)=S)C=C(C(F)(F)F)C=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:25][C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH:34]([C:35]([O:37][CH3:38])=[O:36])[C:33]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC(c1cncc(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Agent: CN(C)[C@@H]1CCCC[C@H]1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Tert-butyl {[5-(benzyloxy)pyridin-3-yl](phenylsulfonyl)methyl}carbamate (2.2 g, 4.84 mmol) was suspended in a toluene (16.5 mL) water (13 mL) mixture. At 0° C. tert-butyl methyl malonate (1.0 mL, 5.8 mmol), cesium carbonate (1.58 g, 4.84 mmol) and 1-[3,5-bis(trifluoromethy)phenyl]-3-[(1R,2R)-(−)-2-(dimethylamino)cyclohexyl]thiourea (200 mg, 0.48 mmol) was added and the mixture was stirred for 48 hours at 0° C. After storage at 5° C. for 72 hours the mixture was diluted with water and ethyl acetate, the phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0% to 60%) to yield 1.54 g of enantiomerically enriched tert-butyl methyl 2-{(1S)-[5-(benzyloxy)pyridin-3-yl][(tert-butoxycarbonyl)amino]methyl}propanedioate.
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]=O)([O:3][CH2:4][CH3:5])=[O:2].C1CCN2C(=NCCC2)CC1>CO>[S:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:13]=[C:6]1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1sccc1C=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccsc2s1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 2-(carboethoxymethylthio)-3-formylthiophene (from step c) in MeOH (200 mL) was added DBU (0.6 mL, 4.0 mmole) at 0° C. After 1 hr the mixture was warmed to RT and concentrated. The residue was taken up in EtOAc, washed with 10% HCl, H2O (3×), dried (MgSO4), and concentrated. Flash chromatography on silica gel (50% toluene/hexanes) gave the title compound (3.84 g, 45% over 4 steps) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.26 (d, J=5.2 Hz, 1H), methyl ester 3.92 (s, 3H), ethyl ester 4.38 (q, J=7.1 Hz, 2H)) and 1.41 (t, J=2.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I-].[Na+].CN(C)C(N(C)C)=N.Br[CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C.COCCOC>[Cl:8][C:5]1[N:4]([CH2:21][C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[C:3](=[O:9])[C:2]([F:1])=[CH:7][N:6]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: CN(C)C(=N)N(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: N#Cc1ccccc1Cn1c(Cl)ncc(F)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Example 30B was also prepared from 5-fluoro-2-chloro-3H-pyrimidin-4-one as follows. To a solution of 5-fluoro-2-chloro-3H-pyrimidin-4-one (100.00 g, 0.67 mol) in 1:1 DMF/DME (440 mL) under a nitrogen atmosphere was added sodium iodide (10 g, 67 mmol) and the resulting slurry cooled to 0° C. While maintaining the internal temperature to ≦12° C., 1,1,3,3-tetramethylguanidine (94 mL, 0.74 mol) was added dropwise over 45 minutes to form a homogeneous solution. The ice bath was removed and a solution of 2-(bromomethyl)benzonitrile (145 g, 0.74 mol) in 1:1 DMF/DME (600 mL) was added all at once and the reaction mixture heated to 70° C. for 18 h. In-process assay (by HPLC analysis) showed complete consumption of the starting material. The reaction mixture was cooled to 30° C. and then MTBE (1.14 L) and DI water (2.29 L) were added to form a slurry which was stirred at ambient temperature for 1 h. The crude product was collected by filtration and washed with MTBE (1.14 L). The phases of the filtrate were separated and the organic layer was combined with the filter-cake and concentrated to a thick slurry which was subsequently reslurried with DME (1.00 L). Insoluble impurities were removed by vacuum filtration and washed with DME (500 mL). The filtrate was concentrated to a wet residue which was reslurried with 2-propanol (365 mL) and the solid product collected by vacuum filtration. After removal of residual IPA, the product was reslurried in ethyl acetate (6 vol) at 70° C. and heptane (6 vol) was added slowly while maintaining the internal temperature at 68-70° C. At the end of the addition of heptane, insoluble materials were still visible. The mixture was stirred for an additional 10 min after which insoluble impurities were removed by hot vacuum filtration. The filtrate was slowly cooled to room temperature and then cooled further to about 0° C. by means of a salt-ice bath. The crystallized product was collected by vacuum filtration and then reslurried in ethanol (6 vol) at 50° C., cooled to 40° C., and the product collected by vacuum filtration to give 80.62 g (45%, 95.6% AUC by HPLC) of 2-(2-chloro-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.P(Br)(Br)[Br:14]>CN(C=O)C>[Br:14][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: O=c1c(Cl)c[nH]c2ccccc12
Solvent: CN(C)C=O
Product: Clc1cnc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.07 h

Procedure:
To a cooled suspension of 3-chloroquinolin-4(1H)-one (A275-1) (5.15 g, 28.7 mmol) in DMF (43.4 mL) at 0° C. was added phosphorous tribromide (2.77 mL, 29.5 mmol) dropwise over 3 min and then the mixture became orange homogenous mixture. After 4 min, yellow precipitates were formed and the yellow heterogeneous mixture was further stirred at 0° C. for 15 min. After 15 min, the cooling bath was removed and the yellow heterogeneous mixture was stirred at room temperature. After 15 h, the mixture was poured into ice water (300 mL) and stirred at 0° C. for 20 min. The mixture was then neutralized by the addition of 2 M NaOH solution (50 mL) until pH was >9 (pH paper). The resulting precipitate was collected by filtration, washed the solid with water (400 mL), and dried under high vacuum to give 4-bromo-3-chloroquinoline (A275-2) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (1H, s), 8.20 (1H, dd, J=8.2, 1.6 Hz), 8.12 (1H, dd, J=8.3, 0.9 Hz), 7.81-7.93 (2H, m); LCMS (ESI) m/z 242.0 [M+H (79Br)]+ and 243.9 [M+H (81Br)]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][NH2:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH2:15]([O:17][C:18](Cl)=[O:19])[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:15]([O:17][C:18](=[O:19])[NH:14][CH2:13][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([F:1])[CH:3]=1)[CH3:16]
Reactant: NCCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCc1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
2-(3-Fluoro-4-trifluoromethyl-phenyl)-ethylamine (I-47b: 2.46 g, 11.88 mmol) was reacted with ethylchloroformate (1.54 g, 14.26 mmol), 2N Na2CO3 solution (24.0 mL) and chloroform (24 mL). The resulting mixture was stirred for 30 minutes at 0° C. to afford 3.0 g of the crude product.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14](=O)[CH3:15])[CH3:12]>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:11]([CH3:12])[C:13]2([CH2:17][CH3:18])[CH2:14][CH3:15]
Reactant: CCC(CC)C(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: CCC1(CC)c2cc(Br)ccc2NC1C
Yield: 63.8 %

Procedure:
This compound was prepared according to the procedure for Example 1 using 4-bromo-phenyl hydrazine hydrochloride (5.9 g, 26.3 mmol) and 3-ethyl-2-pentanone (3.0 g, 26.3 mmol). The subtitled compound (4.5 g) was obtained in 65% yield as a yellowish oil: 1H-NMR (CDCl3) δ 0.81(t, J=7.4 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H), 1.18 (d, J=6.5 Hz, 3H), 1.42 (dq, J=14.0, 7.4Hz, 1H), 1.66 (dq, J=14.0, 7.4Hz, 3H), 3.73 (q, J=6.5 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 7.02 (d, J=2Hz, 1H)7.09 (dd, J=8.2, 2.0 Hz, 1H); 13C-NMR (CDCl3) δ 10.46, 10.66, 17.70 (q), 26.5, 29.67 (t), 52.25 (s), 64.80 (d), 111.64 (s), 112.41, 129.07, 131.58 (d), 139.57, 151.04 (s); MS (EI) m/z 268, 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=4[F:24])[CH:19]=[O:20])=[CH:12][N:11]3[CH:25]=2)=[CH:4][CH:3]=1.[CH3:26][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.C(OCCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[CH3:26])[CH:21]=[CH:22][C:23]=4[F:24])=[CH:12][N:11]3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: CC(O)c1ccc(F)c(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Temperature: 0 °C

Procedure:
470 mg of 3-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-4-fluorobenzaldehyde are placed in a round-bottomed flask and dissolved in 90 ml of diethyl ether and 45 ml of tetrahydrofuran. The solution is cooled to 0° C. with an ice bath and 4 ml of a 1M solution of methylmagnesium bromide in dibutyl ether are added dropwise thereto. The mixture is stirred in the ice bath for 1 h 30 and 22 ml of a saturated aqueous ammonium chloride solution are added. The organic phase is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture. 401 mg of compound are obtained.
Reaction SMILES: C[O:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][NH:10][C:9]2=[S:13])=[CH:5][C:4]=1[F:17].B(Br)(Br)Br.[CH3:22]O>C(Cl)Cl>[OH:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13][CH3:22])=[CH:5][C:4]=1[F:17]
Reactant: COc1c(F)cc(Cn2cc[nH]c2=S)cc1F
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1nccn1Cc1cc(F)c(O)c(F)c1

Procedure:
A solution of 1-(4'-methoxy-3',5'-difluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione (0.0046 mol) in 40 ml methylene chloride is treated with a solution of BBr3 (0.014 mol) in 10 ml methylene chloride. After four hours methanol is cautiously added, the mixture is stirred for an additional eighteen hours and the solvents are evaporated. The residue is dissolved in water, washed with ethyl acetate, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extracts are dried (MgSO4) and filtered and the solvent evaporated to yield 1-(4'-hydroxy-3'5'-difluorobenzyl)-2-(methylthio)imidazole. This compound then is substituted for 1-(4'-hydroxy-3',5'-difluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione in the process of Example 1 to yield 1-(4'-acetoxy-3',5'-difluorobenzyl)-2-(methylthio)imidazole.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[CH:23]=[CH:22][N:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[C:24]=4[CH:23]=[CH:22][N:21]=[CH:20]5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc2cnccc12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5cnccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with isoquinoline-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 5-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]isoquinoline.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([CH:18]=[O:19])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:23]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18]([OH:23])=[O:19])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)c1c(C=O)c2cnc(Cl)cc2n1Cc1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)c1c(C(=O)O)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (Compound 14, 146 mg, 0.47 mmol) in t-BuOH (15 ml) and 2-methyl-2-butene (10 ml) was added a solution of NaH2PO4 (1.41 g, 11.8 mmol) and NaClO2 (80%, 1.05 g, 9.3 mmol) in H2O (10 ml). The mixture was stirred at room temperature for 16 h and was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes, then 0→30% MeOH—CH2Cl2) to yield the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2](CC)([CH2:5][OH:6])[CH2:3][OH:4].[C:9](=O)(OCC)[O:10]CC.[CH3:17][CH2:18]O>C[O-].[Na+]>[CH2:17]([N:1]1[CH:2]([CH2:3][OH:4])[CH2:5][O:6][C:9]1=[O:10])[CH3:18]
Reactant: CCOC(=O)OCC
Reactant: CCC(N)(CO)CO
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Product: CCN1C(=O)OCC1CO

Procedure:
Sodium methoxide (2.2 g, Aldrich) was added to a solution of 2-amino-2-ethyl-1,3-propanediol (100.0 g, Aldrich) and diethyl carbonate (169.0 g, Aldrich) This solution was refluxed in a Dean Stark apparatus until no more EtOH was collected. The reaction mixture was cooled, added acetone (200 ml) and allowed to stand overnite at room temperature. The resulting suspension was filtered to give 81.0 g of the desired product as a beige solid. 1H NMR consistent with the proposed structure.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([O:10][C:11]1[C:16]([C:17]2[NH:18][C:19](=[O:33])[C:20]3[C:21](=[C:23]([CH2:31][CH3:32])[N:24]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[N:25]=3)[N:22]=2)=[CH:15][C:14]([C:34]#[CH:35])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9]>CC(C)=O.CO.S([O-])([O-])(=O)=O.[Hg+2]>[C:34]([C:14]1[CH:15]=[C:16]([C:17]2[NH:18][C:19](=[O:33])[C:20]3[C:21](=[C:23]([CH2:31][CH3:32])[N:24]([CH2:26][CH2:27][N:28]([CH3:29])[CH3:30])[N:25]=3)[N:22]=2)[C:11]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[N:12][CH:13]=1)(=[O:2])[CH3:35]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1cnc(OCCCC)c(-c2nc3c(CC)n(CCN(C)C)nc3c(=O)[nH]2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCN(C)C)nc2c(=O)[nH]1

Procedure:
1 N Sulfuric acid (1 mL) was added to a stirred solution of 5-(2-butoxy-5-ethynyl-3-pyridinyl)-2-[2-(dimethylamino)ethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 46) (280 mg, 0.69 mmol) in acetone (8 mL) at room temperature. Mercury sulfate (40 mg, 0.14 mmol) was added and the mixture heated at reflux for 5 h. The reaction mixture was cooled, diluted with methanol (10 mL), filtered and the filtrate washed with further methanol. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (100 mL). The aqueous was washed with a further 100 mL of ethyl acetate and the combined organics dried (MgSO4) and concentrated. Purification by flash column chromatography (elution with 95% dichloromethane/methanol) gave the product as a cream coloured solid (140 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=1)=[O:5].[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[O:5])=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc(NC(=O)c2ccccc2N)c1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 1B except starting with 2-amino-N-(3-cyanophenyl)benzamide and 4-t-butylbenzoyl chloride, the title compound was obtained as a white solid (92%); MP: 194-6° C.; IR(KBr): 757, 1584, 1647, 2969, 3256 cm−1; NMR(300 MHz, CDCl3): 1.40 (s, 9H); 6.90 (t, 1H, J=7.2 Hz); 7.31 (m, 1H); 7.49-7.55 (m, 3H); 7.60 (d, 2H, J=7.5 Hz); 7.95 (d, 3H, J=8.4 Hz); 8.36 (s, 1H); 8.46 (d, 1H, J=8.4 Hz); 9.19 (s, 1H); 11.42 (s, 1H); MS(FD): 397.1.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18](=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:18](=[S:19])[NH:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: S=C=S
Solvent: c1ccncc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of (2e)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (1.90 g, 8.04 mmol) and carbon disulfide (0.58 ml, 9.64 mmol) in pyridine (30 ml) was stirred at 60° C. for 3 hours. After cooling to room temperature, the solid formed was filtered and dried to yield the desired product (1.90 g, 84.9%). LCMS calculated for: C11H14N6OS (M+H) 280.1; found: 280.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C=O)c23)c(C)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
To a solution of 9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (249 mg, 0.622 mmol) in tetrahydrofuran (3 mL) was added trimethyl(trifluoromethyl)silane (0.276 mL, 1.87 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.124 mL, 0.124 mmol) at 0° C. After the mixture was stirred at 0° C. for 15 min, to the reaction mixture was added trimethyl(trifluoromethyl)silane (0.276 mL, 1.87 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.124 mL, 0.124 mmol) at 0° C. After the mixture was stirred at 0° C. for 15 min, to the mixture was added 1N hydrochloric acid (3 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 10 min. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (241 mg, 0.512 mmol, 82%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:8]2[CH2:9][O:10][CH2:11][CH:4]1[CH2:5][NH:6][CH2:7]2.Br[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:2][N:3]1[CH:8]2[CH2:9][O:10][CH2:11][CH:4]1[CH2:5][N:6]([C:13]1[CH:18]=[N:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN1C2CNCC1COC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 112h (800 mg, 5.6 mmol) and 5-bromo-2-nitropyridine (1.37g, 6.86 mmol) in DMSO (50 ml) was added Cs2CO3 (5g) and t-BuNH4I (cat.). The reaction mixture was stirred at 120° C. overnight. Then it was cooled to room temperature, and extracted with EtOAc (300 ml). The organic layer was washed with water (3×100 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to get crude product, which was purified through a silica gel column eluting with DCM:MeOH=100:1 to 50:1 to give 112i as a yellow solid (850 mg, 72%) MS: [M+H]+: 265