Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.[CH2:9]([N:11]1[C:19]2[C:14](=[N:15][C:16]([C:20](OC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:24](=[O:42])[NH:25][CH:26]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=1)[C:27]([F:30])([F:29])[F:28])[CH3:10]>ClCCl>[CH:1]1([NH:4][C:20]([C:16]2[N:15]=[C:14]3[CH:13]=[C:12]([C:24]([NH:25][CH:26]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:39])([F:40])[F:41])[CH:32]=4)[C:27]([F:29])([F:28])[F:30])=[O:42])[N:11]([CH2:9][CH3:10])[C:19]3=[CH:18][CH:17]=2)=[O:21])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCn1c(C(=O)NC(c2ccc(F)c(C(F)(F)F)c2)C(F)(F)F)cc2nc(C(=O)OC)ccc21
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCn1c(C(=O)NC(c2ccc(F)c(C(F)(F)F)c2)C(F)(F)F)cc2nc(C(=O)NC3CC3)ccc21
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon protective gas, cyclopropylamine (58.1 mg, 1.02 mmol) was added to one ml of dichloromethane, and trimethylaluminium (73.4 mg, 1.02 mmol) was added dropwise using a syringe. The mixture was stirred for another 30 minutes, and methyl 1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylate, dissolved in one ml of dichloromethane, was then added dropwise. The reaction mixture was then heated under reflux for six hours and subsequently cooled and hydrolysed, and the residue was, after removal of the volatile components under reduced pressure, chromatographed on silica gel cyclohexane/ethyl acetate (ethyl acetate 0% to 60%). This gave 20 mg (35% of theory) of the target product. HPLC-MS: log P=3.78; mass (m/z): 517.1 (M+H)+; 1HNMR (D6-DMSO): δ 0.54-0.76 (m, 4H), 1.22-1.30 (t, 3H), 2.88-2.94 (m, 1H), 4.48-4.59 (q, 2H), 6.32-6.42 (m, 1H), 7.42 (s, 1H), 7.65-7.71 (t, 1H), 7.98-8.02 (d, 1H), 8.14-8.20 (m, 1H), 8.20-8.24 (d, 1H), 8.26-8.32 (m, 1H), 8.56-8.62 (d, 1H), 9.91 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](=O)[NH:5][C:4]2[CH:10]=[CH:11][CH:12]=[N:13][C:3]1=2.P(Cl)(OCC)(OCC)=O.[N+:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[C-:24].C(O)(=O)C>CN(C)C=O>[CH3:1][N:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]2[CH:24]=[N:23][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:6]2[C:7]1=[O:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cn1c(=O)c(=O)[nH]c2cccnc21
Agent: CCOP(=O)(Cl)OCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c1c(=O)n(C)c1ncccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-pyrido(2,3-b)-pyrazine (5 g) in 50 ml of dry dimethyl formamide (DMF) was added potassium-t-butylate (4 g). The mixture was allowed to stir at room temperature for 15 min whereafter it was cooled to -25° C. and charged with diethyl chlorophosphate (5 ml). Stirring continued at 0° C. for 15 min, then it was cooled to -20° C. whereafter a preformed -30° C. cold solution of ethyl isocyanoacetate (3.9 ml) and potassium-t-butylate (4 g) in 30 ml of dry DMF was added. The resulting solution was allowed to obtain room temperature before acetic acid was added (1,5 ml). The DMF was removed by evaporation in vacuo, whereafter the residue was treated with water to give the crude title compound as pale crystals. Recryst in 96% ETOH M.p. 233°-234° C.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
To a solution of 1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (2.0 g, 5.93 mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9 ml, 29.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, refluxed for an additional 0.5 hours and subsequently concentrated. The remaining residue was dissolved into dichloromethane and washed with 10% HCl (aq.). The organic phase was dried (MgSO4), filtered, and concentrated to give an oil which was purified via flash column chromatography (silica gel, 20% DCM/EtOAc). Concentration of the product-containing fractions gave an oil which solidified on standing. The white solid was washed with EtOAc, leaving 0.47 g of the desired product, m.p. 137-139° C.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.I[CH2:15][C:16]#[N:17].OO>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[C:16]([CH2:15][C:3]1[N:4]2[C:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:1][C:2]=1[C:10]([O:12][CH3:13])=[O:11])#[N:17]
Reactant: COC(=O)c1cc2n(c1)CCCC2
Reactant: N#CCI
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2n(c1CC#N)CCCC2
Yield: 78.4 %

Procedure:
A 500-mL three-neck round-bottomed flask equipped with an addition funnel, thermometer and charged with methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate 101d (6.70 g, 37.4 mmol), iodoacetonitrile (12.5 g, 74.9 mmol), iron (II) sulfate heptahydrate (5.20 g, 18.7 mmol) and dimethyl sulfoxide (250 mL). Hydrogen peroxide (35%, 18.2 g, 187 mmol) was added dropwise to the mixture in 1 h through a syringe pump at room temperature using a water bath. Iron (II) sulfate heptahydrate (2 to 3 equivalent) was added to the reaction mixture in portions to keep the temperature between 25° C. to 35° C., until the color of the reaction mixture is deep red. If TLCs show the reaction not completed, then more hydrogen peroxide (2-3 equivalent) and more iron (II) sulfate heptahydrate (1-2 equivalent) were added in the same manner until the reaction is completed. After that time, the reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution (200 mL) and ethyl acetate (400 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated Sodium thiosulfate solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 78% yield (6.40 g) of 101e as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 4.23 (s, 2H), 3.94 (t, 2H, J=6.5 Hz), 3.81 (s, 3H), 2.74 (t, 2H, J=6.5 Hz), 2.00 (m, 2H), 1.83 (m, 2H); (APCI+) m/z 219.3 (M+H)
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]([C:13]1([N:18]([CH:20]=[O:21])[CH3:19])[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]>O1CCOCC1>[CH3:9][O:10][C:11]([C:13]1([N:18]([CH:20]=[O:21])[CH3:19])[CH2:17][CH2:16][N:15]([CH2:23][C:24](=[O:25])[N:26]2[CH2:27][CH:28]=[C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:39]=[CH:40][CH:41]=[CH:42][N:43]=4)=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)[CH2:14]1)=[O:12]
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cc2)CC1
Reactant: COC(=O)C1(N(C)C=O)CCNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C1(N(C)C=O)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Added triethylamine (0.3 ml, 2.15 mmol) to a solution of (3-(Formyl-methyl-amino)-pyrrolidine-3-carboxylic acid methyl ester, Hydrochloride.(4T) (90 mg, 0.405 mmol) and 2-Chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone (140 mg, 0.447 mmol) in dioxane (5 ml) at room temperature, then stirred at 90° C. for 5 hours. The reaction was cooled and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 7% MeOH/MeCl2 containing 2% NH4OH yielding 5T as a white solid (100 mg, 53%) ESMS (MH 464).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CCO>[C:21]([O:20][C:19](=[O:25])[NH:18][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][NH:10][C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:17][CH2:16]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Cl)CC1
Temperature: 40 °C
Yield: 98.6 %

Procedure:
To a solution of the above 5-chloro-2,4-dichloropyrimidine (73 mg, 0.4 mmol) in EtOH (2 mL) were added tert-butyl trans-4-aminomethylcyclohexylcarbamate (100 mg, 0.44 mmol) and DIPEA (77 μL, 0.44 mmol). The reaction mixture was heated at 40° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The solution was washed with brine. The aqueous layer was re-extracted with EtOAc (×2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield 148 mg (99%) of {4-[(2,5-dichloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: Br[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)#[CH:17]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I.O>[F:24][C:22]1[CH:23]=[C:18]([C:16]#[C:17][CH:2]=[C:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:19]=[C:20]([F:25])[CH:21]=1
Reactant: C#Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cc(F)cc(F)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of the Compound 49a (0.110 g, 0.40 mmol), palladium tetrakis(triphenylphosphine) (0.023 g, 0.02 mmol), copper(I) iodide (0.0078 g, 0.04 mmol) and 1-ethynyl-3,5-difluorobenzene (49 μL, 0.4 mmol) and TEA (2.5 mL) was heated for 3 h at 80° C. Afterwards, the reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue (0.062 g.), used in the next step without further purification.
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]([O:15]C)=O.N1C2C(=O)CCCC=2C=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:13](=[O:15])[CH2:12][CH:3]3[C:2]([C:11]4[N:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:36]2)=[CH:31][CH:30]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)CC1CCc2cccnc2C1=O
Agent: O=C1CCCc2cccnc21
Product: O=C1CC2CCc3cccnc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-8-oxoquinoline-7-acetate (prepared from 6,7-dihydroquinoline-8(5H)-one according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C@@H:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[O:50]=[S:47]1(=[O:51])[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C@@H:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:45][CH2:46]1
Reactant: O=S1(=O)CCN(CCCl)CC1
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(N)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NCCN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 120 °C
Yield: 62 %

Procedure:
A mixture of methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.091 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (54.1 mg, 0.274 mmol), potassium phosphate (77 mg, 0.365 mmol) and potassium iodide (36.4 mg, 0.219 mmol) in acetonitrile (2 mL) was heated up at 120° C. for 20 hours. The reaction mixture was quenched with distilled water (5 mL), extracted with dichloromethane (3×5 mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product as a yellow solid (40 mg, 62%). LCMS: m/e 709.53 (M+H)+, 2.46 min (method 11).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[N:35][CH:34]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: COc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc(OC)nc4)cc23)c1F
Reaction time: 0.27 h

Procedure:
Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (9, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 2-methoxypyrimidine-5-boronic acid (10, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (≈1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimetheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound P-0001. MS(ESI)[M+H+]+=487.9.
Reaction SMILES: Cl/[C:2](=[N:8]\[OH:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C>CCOCC>[C:12]1([C:10]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C#Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (3.03 g, 20 mmol) and ethynylbenzene (4.39 mL, 40 mmol) in ether (80 mL) at room temperature was added a solution of triethylamine (5.58 mL, 40.0 mmol) in ether (20 mL) dropwise over 60 minutes. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to a yellow oil which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-12%) to afford ethyl 5-phenylisoxazole-3-carboxylate (3.06 g, 14.09 mmol, 70% yield) as a white solid. The compound had an HPLC retention time=2.99 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+H)=218.12. 1H-NMR (400 MHz, CDCl3) δ ppm 1.45 (t, J=7.3Hz, 3H), 4.48 (q, J=7.3, 2H), 6.93 (s, 1H), 7.45-7.53 (m, 3H), and 7.77-7.85 (m, 2H).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2].[CH3:11][N:12]([CH3:16])[C:13](=[S:15])[S-:14].C[NH2+]C>C(=S)=S>[CH3:11][N:12]([CH3:16])[C:13](=[S:14])[S:15][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])C=Cc1ccco1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccco1

Procedure:
As in Example 17, reaction of 2-(2-nitrovinyl)furan with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave α-(nitromethyl)furfuryl dimethyldithiocarbamate melting at 67° C.-68° C. after recrystallization from methanol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([OH:16])[C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:4]=[N:3]1.[Br:17]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:17][C:15]1[CH:14]=[N:13][N:11]2[CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[C:9]([OH:16])[C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2cc(O)c3ccnn3c2)cn1
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Reaction time: 0.5 h

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (75.0 mg, 0.350 mmol) was suspended in acetonitrile (4 ml). N-bromosuccinimide (68.5 mg, 0.385 mmol) was added and the mixture was allowed to stir. After 30 minutes, additional N-bromosuccinimide (6.9 mg, 0.039 mmol) was added and the mixture was allowed to stir for 1 h. The reaction mixture was diluted in dichloromethane, washed with water and 1 N aqueous sodium hydroxide. The pH of the combined aqueous layers was adjusted to pH 7 with 6 N HCl, then the aqueous layers were extracted with ethyl acetate (2×) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to afford 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([N:10]=[N+:11]=[N-:12])[C:8](=[O:13])[NH:7]1)(=O)=O.[Br-:21].[Li+].CN(C)C=O>C(OCC)(=O)C>[N:10]([C@H:9]1[C:8](=[O:13])[NH:7][C@H:6]1[CH2:5][Br:21])=[N+:11]=[N-:12]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N=[N+]=[N-])cc1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CBr
Yield: 94.1 %

Procedure:
A mixture of 0.413 g (1.40 mmol) of cis-3-azido-4-oxo-2-azetidinylmethyl tosylate, 0.434 g (5.0 mmol) of anhydrous lithium bromide and 5 ml of anhydrous dimethylformamide is heated to 100° under argon for one hour. The solution is allowed to cool to 25°, poured into ethyl acetate and extracted copiously with water. The ethyl acetate layer is dried and evaporated to give 0.270 g (94%) of the title product.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[SH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>O>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:11][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Sc1ccc2ccccc2c1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccccc1Sc1ccc2ccccc2c1

Procedure:
A well stirred mixture of 37.2 g. (0.15 mole) of o-iodobenzoic acid, 34.0 g. (0.15 mole) of 2-mercaptonaphthalene, 20.6 g. (0.15 mole) of potassium carbonate and 300 ml. of pyridine is heated at 50° C. for 1 hour, then 5 g. of cuprous chloride is added and the stirred mixture is heated at reflux for 18 hours. The mixture is poured into 1.2 liters of water and filtered. The filtrate is acidified and the resulting mixture is extracted into methylene chloride. The extracts are dried, concentrated, and the solid residue is recrystallized to give 2-(2-naphthylthio)benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1ccc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccc(C)nc3)nc12

Procedure:
From (6-methyl-pyridin-3-yl)-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[I-:47].[NH2:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=2[CH3:64])=[CH:53][CH:52]=1>ClCCCl>[I-:47].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:48][CH2:49][CH2:50][C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=4[CH3:64])=[CH:55][CH:56]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C[n+]1ccccc1Nc1ccc(CCN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4cccc[n+]4C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.13 mmol), CDI (33 mg, 0.2 mmol), DIPEA (0.14 mL, 0.81 mmol) and 2-{[4-(2-aminoethyl)phenyl]amino}-1-methylpyridinium iodide hydrochloride (55 mg, 0.14 mmol) in DCE (1.0 mL).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[OH-].[Na+].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: CC1=NCCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CC1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of 1-methyl-3,4-dihydroisoquinoline was dissolved in 7.0 ml of conc. nitric acid at 0° C., and 14.0 ml of fuming nitric acid was added dropwise to the solution. The solution was stirred for one hour at the same temperature, and overnight at room temperature. The reaction mixture was poured into ice, neutralized with aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was purified by silica gel column chromatography to obtain 1.08 g of 1-methyl-7-nitro-3,4-dihydroisoquinoline, which was white crystal (yield: 82%).