Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:17])([O:4][C:5]([NH:7][CH:8]([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[C:9]([OH:11])=O)=[O:6])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:49]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=1[O:62][CH3:63])[CH:50]=[CH2:51]>CN(C)C=O>[C:2]([O:4][C:5](=[O:6])[NH:7][CH:8]([C:9](=[O:11])[N:52]([CH2:49][CH:50]=[CH2:51])[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=1[O:62][CH3:63])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])([CH3:1])([CH3:3])[CH3:17]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCNCc1ccc(OC)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(Cc1ccc(OC)cc1OC)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C=C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3,3-dimethyl-4-pentenoic acid (322 mg, 1.32 mmol; Synthesis see Bartlett, Paul A.; Barstow, James F. Journal of Organic Chemistry (1982), 47(20), 3933-41) was dissolved in dimethylformamide (6 ml) and activated with the coupling reagent TATU (469 mg, 1.46 mmol) and Hünig's base (376 mg, 2.91 mmol) for 2 min. Allyl-(2,4-dimethoxy-benzyl)-amine (274 mg, 1.32 mmol) dissolved in dimethylformamide (2 ml) was added and the mixture was stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, 1 M KHSO4 solution and brine. After drying with magnesiumsulfate the organic layer was concentrated and purified by flash chromatography (heptane/ethyl acetate=2:1) to yield 510 mg (89%) of {1-[allyl-(2,4-dimethoxy-benzyl)-carbamoyl]-2,2-dimethyl-but-3-enyl}-carbamic acid tert-butyl ester; MS: m/e=433.6 (MH+), 450.6 (M+NH4+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH2:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:19]([O:21][CH3:22])=[O:20]
Reactant: Cc1cccc(C)c1NN
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)NNc1c(C)cccc1C

Procedure:
18 g of 2,6-dimethylphenyl-hydrazine and 14 g of triethylamine were dissolved in 150 ml of ethyl ether. Keeping the temperature at 0° C., 12.5 g of methyl chloroformate were added dropwise to the solution. Precipitation of the chlorohydrate of triethylamine was observed.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=[O:3])[CH3:2].[CH2:30]([C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)[CH2:31][CH3:32]>CC#N>[C:1]([O:4][C@@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2[N:34]1[CH:35]=[CH:36][N:37]=[C:33]1[CH2:30][CH2:31][CH3:32])(=[O:3])[CH3:2]
Reactant: CCCc1ncc[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (1.12 g, 2.5 mmol) and 2-propylimidazole (2.20 g, 20 mmol) was dissolved in CH3CN (30 mL) and stirred at 65° C. under N2 for 2 h (reaction complete, TLC). After removal of volatiles, the residue was dissolved in CH2Cl2 (200 mL) and washed (H2O, 3×50 mL). The aqueous phase was extracted with CH2Cl2, and the combined organic phase was dried (Na2SO4) and evaporated to dryness. The residue was chromatographed (MeOH/CH2Cl2, 1:95) to give 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine (977 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][CH2:28][C:29]([CH3:41])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[CH3:30])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](=[O:23])[N:10]([CH2:24][C:25]([NH:27][CH2:28][C:29]([CH3:41])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:38])([F:39])[F:40])[CH3:30])=[O:26])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCC(C)(C)c2ccccc2C(F)(F)F)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCCC(=O)O)c1=O)c1ccccc1C(F)(F)F

Procedure:
The compound from Example 365 (22 mg, 37 μmol) is stirred overnight at RT with 1 ml of a 4 M hydrogen chloride solution in dioxan. The solvent is then removed on the rotary evaporator. The residue is taken up in DMSO and purified by preparative HPLC (Method 20). 14 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[CH2:5][O:6]C(=O)C1C=CC=CC=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:26][CH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[CH:5]=[O:6]
Reactant: Cc1cc(C)cc(COC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C=O)cc(CBr)c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A mixture of benzoic acid 3,5-dimethyl-benzyl ester (24 g, 0.1M) and NBS (39.16 g, 0.22M) in carbon tetrachloride (200 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in ether, washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give 21 g of crude 3-bromomethyl-5-methyl-benzaldehyde.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[O:19]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:20]1=2.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>COCCOC.O.CO>[O:19]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=4)[NH:4][N:3]=3)[CH:26]=[CH:27][C:20]1=2
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1ccc2[nH]nc(-c3ccc4c(c3)CCO4)c2c1
Temperature: 45 °C
Yield: 54.7 %

Procedure:
The title compound was prepared as described in Example 411, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.750 g, 2.45 mmol), in ethylene glycol dimethyl ether (50 mL), 2,3-dihydrobenzo[b]furan-5-boronic acid (0.480 g, 2.9 mmol), [1,1′-bis(diphenylphosphino-ferrocene] complex with dichloromethane (1:1) (0.200 g, 0.20 mmol) and potassium phosphate (5.2 g, 24 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45° C. for 5 h. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven to afford the title compound (0.350 g, 64% yield over 2 steps): ES-MS (m/z) 262 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][O:23]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][O:23][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCOS(C)(=O)=O
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCOc1ccccc1
Yield: 25 %

Procedure:
Combine (S)-4-benzyl-2-(2-methanesulfonyloxyethyl)piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 7.08 mmol), sodium iodide (0.106 g, 0.708 mmol), and phenol (3.33 g, 35.4 mmol) in dimethyl formamide (40 mL) and stir at 100° C. for 20 hours. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with a step gradient (100% dichloromethane to 5% 2N ammonia-methanol in dichloromethane) to obtain (S)-4-benzyl-2-(2-phenoxyethyl)piperazine-1-carboxylic acid tert-butyl ester (0.703 g, 25%): mass spectrum (APCI): m/z=397.2 (M+1).
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:7][C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:12][C:8]1[S:7][C:6]([CH2:5][OH:4])=[C:10]([CH3:11])[CH:9]=1
Reactant: CC(=O)OCc1sc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Br)sc1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
A mixture of 62.4 (3.58 mmol) and K2CO3 (0.99 g, 7.16 mmol) in MeOH (18 mL) was stirred for 5 hours at room temperature. The mixture was filtered (DCM) and concentrated, and the crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 62.5 (0.61 g, 82%) as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 1H), 4.68 (s, 2H), 2.18 (s, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>CN1CCCC1=O.[OH-].[Na+]>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nccn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol) in N-methylpyrrolidone (1.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.151 mL, 1.00 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→75/25), and precipitated from diisopropyl ether to give the title compound (195 mg, 98%) as a white powder.
Reaction SMILES: CN(C)CCNC.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=1.[I:23]I>C1COCC1.CCOCC>[I:23][C:21]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:22]=1
Reactant: II
Reactant: COc1ccc(C=O)cn1
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(I)c(C=O)cn1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To a stirred solution of N,N,N′-trimethylethylenediamine (1.9 mL, 15 mmol) in anhydrous THF (65 mL) under argon at −70° C. was slowly added 1.6M n-BuLi in hexanes (9.0 mL, 14 mmol). After stirring at −70° C. for 15 minutes, 6-methoxy-nicotinaldehyde (1.3 g, 9.8 mmol) was added dropwise. After the addition was complete, stirring was continued at −70° C. for another 15 minutes. Then 1.6M n-BuLi in hexanes (10 mL, 16 mmol) was added dropwise and stirring continued at −45° C. for 4 h. The solution was cooled to −70° C. and then a solution of iodine (3.0 g, 12 mmol) and anhydrous THF (25 mL) was added dropwise. When the addition was complete, stirring was continued at −70° C. for 30 minutes and then at RT for 3 h. The crude product was taken up in ether (40 mL) and washed successively with saturated ammonium chloride (2×40 mL) and 5% sodium thiosulfate (2×20 mL). The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:1) as eluent gave 0.41 g (15% yield) of 4-iodo-6-methoxynicotinaldehyde.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[NH:24]1[CH2:28][CH2:27][C@H:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:8]1[C:7]([N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([Cl:17])[CH:9]=1)(=[O:20])[CH3:19]
Reactant: CS(=O)(=O)N[C@H]1CCNC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NS(C)(=O)=O)C1
Temperature: 65 °C
Yield: 40.2 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.17 g, 0.25 mmol, from Example 47, Step 2), N-[(3S)-pyrrolidin-3-yl]methanesulfonamide hydrochloride (0.062 g, 0.31 mmol), palladium acetate (1.1 mg, 0.0049 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.6 mg, 0.0074 mmol), and cesium carbonate (0.31 g, 0.94 mmol) in tetrahydrofuran (4 mL, 50 mmol) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate were washed with brine, dried over MgSO4, evaporated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (37 mg, 41%). LCMS calculated for C16H19ClN3O3S (M+H)+: m/z=368.1; Found: 368.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:9][C:10]=1[F:11])[C:6](O)=[O:7].C(O)(=O)C.[CH:17](N)=[NH:18]>CCO>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)[N:12]=[CH:17][N:18]=1
Reactant: N=CN
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)c(F)cc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
A mixture of 4,5-difluoroanthranilic acid (20.43 g, 118 mmol) and formamidine acetate (13.55 g, 130 mmol) in reagent EtOH was stirred at 120° C. (oil bath) for 3 hr. The reaction was briefly a homogeneous brown solution, and then became an opaque mixture. The reaction was allowed to cool to rt, and the resulting solid was filtered, washed with denatured EtOH (1×10 mL), and allowed to air dry. Powdering with a mortar and pestle provided 4-hydroxy-6,7-difluoroquinazoline as a beige powder (16.9 g, 79%). 16.6 g of this material (91.1 mmol) was taken up in SOCl2 (66 mL), DCE (66 mL), and DMF (7.05 mL, 91 mmol), and was stirred at 110° C. (oil bath) for 1 hr. The resulting homogeneous amber solution was then concentrated under rotary evaporation, and taken up in toluene (2×100 mL) with repeated rotary evaporation to provide the crude title compound as a beige solid. A portion of this material (8.4 g of 17.7 g total) was taken up in DCM (80 mL) and gently shaken with 2M trisodium citrate (1×40 mL) until a homogeneous clear organic layer resulted. This organic layer was immediately applied (without drying) directly onto a silica flash column (79 mm×6″) pre-equilibrated with 1:1 hexanes/EtOAc. Trivial elution with 1:1 hexanes/EtOAc, followed by repeated rotary evaporation from toluene (2×50 mL) of the combined fractions afforded the title compound as a light yellow solid (6.79 g, 78%). 1H-NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.05 (dd, 1H), 7.86 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([CH:9]=1)[CH:7]=[CH:6][S:5]2.S(=O)(=O)(O)O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[C:15](=[O:17])[CH3:16])[CH:7]=[CH:6][S:5]2
Reactant: Clc1cn2ccsc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(Cl)nc2sccn12
Temperature: 140 °C
Reaction time: 4 h

Procedure:
To a solution of 6-chloroimidazo[2,1-b]thiazole (7.93 g, 50 mmol) in acetic anhydride (150 mL) was added 0.2 ml of concentrated sulfuric acid. The mixture was stirred at 140° C. for 4 hours. The mixture was evaporated to dryness and the residue was taken up in water (300 mL), and the pH adjusted to pH ˜10 with aqueous NaOH. The resulting precipitate was filtered, washed with water and vacuum dried, providing the title compound. MS: (ESI(+)) m/e 200.8 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([S:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[C:8]([CH:19]([CH3:21])[CH3:20])[N:7]=[C:6]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](OC)=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[CH2:24]([O:23][CH2:22][C:6]1[N:5]([CH2:4][CH:1]([OH:3])[CH3:2])[C:9]([S:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[C:8]([CH:19]([CH3:21])[CH3:20])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2CC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
In methanol (5 ml)was dissolved 371 mg (0.8 mmol)of 1-acetylmethyl-2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (17v"), followed by addition of 38 mg (1.0 mmol)of sodium borohydride with stirring at room temperature, and the mixture was stirred for 1.5 hours. This reaction mixture was concentrated under reduced pressure, and to the residue were added water and methylene chloride to extract. The organic layer was washed with water and was dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:9), to obtain 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-(2-hydroxypropyl)-4-isopropyl-1H-imidazole (17v'")as oil quantitatively.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>C(Cl)Cl.CCOC(C)=O.O>[N:35]([CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)COCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of (S)-tert-butyl 1-(benzyloxy)-3-hydroxypropan-2-ylcarbamate (1.89 g, 6.4 mmol) in DCM (50 mL) was added MSCl (0.55 mL, 7.04 mmol) and DIEA (1.27 mL, 7.68 mmol). The mixture was stirred at RT for 30 min. The mixture was diluted with DCM (300 mL), washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in DMF (20 mL). To this DMF solution was added NaN3 (1.25 g, 19.2 mmol) and the mixture was heated to 80° C. for 6 h. LCMS indicated the completion of the reaction. The mixture was cooled to RT, water (20 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The rude was purified on silica gel column to give (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-ylcarbamate (1.5 g, 73% for 2 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[NH:5][C:6]=1[CH3:7].[S:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12](=[O:20])[CH2:11]1.C[O-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:11]2[C:12](=[O:20])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:10]2)[NH:5][C:6]=1[CH3:7]
Reactant: O=C1CSc2ccccc2N1
Reactant: Cc1cc(C=O)[nH]c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C=C2Sc3ccccc3NC2=O)[nH]c1C
Temperature: 120 °C

Procedure:
4,5-Dimethylpyrrole-2-carboxaldehyde (0.27 g, 2.19 mmol) was added to a solution of 2H-1,4-benzothiazin-3(4H)-one (0.36 g, 2.19 mmol) and sodium methoxide (0.118 g, 2.19 mmol) in dry DMF (2 ml). The mixture was heated at 120° C. for 48 h, allowed to cool and poured into ice-water (50 ml). The precipitated solid was collected by filtration, washed with water, then dissolved in ethanol. The insoluble black residue was filtered out and the filtrate was concentrated to dryness under reduced pressure. The product was purified by silica gel chromatography using (98:2) dichloromethane:methanol as the mobile phase.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4].C1N2CN3CN(C2)C[N:15]1C3>ClC1C=CC=CC=1.C(OCC)C>[NH2:15][CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])nc1
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: NCC(=O)c1ccc([N+](=O)[O-])nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 1.549 g (6.322 mmol) of 2-bromo-1-(6-nitropyridin-3-yl)ethanone in 25 cm3 of chlorobenzene is added at a temperature in the region of 20° C. to a solution of 0.975 g (6.954 mmol) of hexamethylenetetraamine in 10 cm3 of chlorobenzene. After stirring for 1 hour at this temperature, the suspension is heated for 18 hours at 50° C. The reaction medium is then cooled to 5° C. and then diluted with 200 cm3 of ethyl ether. The precipitate thus obtained is filtered and washed with three times 50 cm3 of ethyl ether. The resulting ammonium salt is stirred in 20 cm3 of ethanol and then 8 cm3 of 37% hydrochloric acid are added at a temperature in the region of 20° C. The solution is then stirred for 16 hours at this temperature. The precipitate formed is filtered, washed with three times 50 cm3 of water, drained and dried to give 1.05 g of 2-amino-1-(6-nitropyridin-3-yl)ethanone in the form of a cream powder. ES+: m/z=182 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([NH:7][NH:8][C:9](=[O:24])[CH2:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=1)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]1[O:24][C:9]([CH2:10][C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[N:8][N:7]=1
Reactant: COc1ccccc1C(=O)NNC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1ccccc1-c1nnc(Cc2ccc(C(=O)O)cc2)o1
Temperature: 100 °C

Procedure:
A solution of tert-butyl 4-{2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoate (0.1 g, 0.26 mmol) in THF (2.5 mL) was treated with Burgess reagent (0.12 g, 0.52 mmol), sealed and heated to 100° C. for 10 minutes in the microwave. The reaction was evaporated in vacuo and purified by flash chromatography (0-2% methanol/methylene chloride) to give the desired product as a white solid. ESIMS calcd 367.2 (M++H), found 367.1 (M++H).