Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:24])[CH2:22][CH3:23]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CCC(=O)N(C)OC
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: CCC(=O)c1ccc(OC)cc1C(=O)O

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methylpropionamide. It is used in crude form in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>N1C=CC=CC=1>[CH3:20][S:21]([NH:1][C:2]1[C:10]2[O:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Temperature: 0 °C

Procedure:
To a solution of 0.62 g. (0.00244mole) of 7-amino-2-nitro-3-phenylbenzofuran in 10 ml. of pyridine is added with stirring 0.3 g. of methanesulfonyl chloride. The reaction is stirred at about 20° C. for about 16 hours, then poured into ice water acidified with hydrochloric acid. This solution is extracted with a mixture of diethyl ether and dichloromethane and the extracts are washed twice with water and then dried. The dried extracts are evaporated to provide a residue which is recrystallized twice from benzene with decolorizing charcoal to provide yellow solid 7-methanesulfonamido-2-nitro-3-phenylbenzofuran, m.p. 169°-171.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In a round-bottom flask, (2S)-2-[(tert-butoxy)carbonylamino]-4-(methoxycarbonyl)butanoic acid (78 mmol, 20.36 g) was dissolved in THF (300 mL). The solution was cooled to −10° C. and N-methylmorpholine (78 mmol, 8.58 mL) and ethyl chloroformate (78 mmol, 7.48 mL) were added, followed by sodium borohydride (234 mmol, 8.85 g). The reaction was stirred for 30 min at this temperature and then quenched by slow addition of saturated solution of ammonium chloride until no further evolution of hydrogen was observed. The reaction mixture was then extracted with ethyl acetate and dried over magnesium sulfate. After filtration, solvent was evaporated and the crude material was purified by column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate) to yield the title compound (11.68 g, 61% yield). ES-MS: 248 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P(S)(=[S:20])(OCC)OCC.C(OCC)(=O)C.CCCCCC>O1CCOCC1.O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[S:20])[NH2:5]
Reactant: Cc1c(C#N)cccc1[N+](=O)[O-]
Reactant: CCOP(=S)(S)OCC
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: O
Product: Cc1c(C(N)=S)cccc1[N+](=O)[O-]
Yield: 77.9 %

Procedure:
A solution of 2-methyl-3-nitrobenzonitrile (4.85 g, 29.9 mmol) and O,O-diethyl S-hydrogen phosphorodithioate (7.53 mL, 44.9 mmol) in 1,4-dioxane (60 mL) and water (50 mL) was heated at 90° C. for 3 days. During this period, two additional portions of O,O-diethyl S-hydrogen phosphorodithioate (2×7.53 mL, 2×44.9 mmol) were added after every 24 hr. The reaction mixture was concentrated under vacuum to a volume of approximate 60 mL. To the residue was slowly added saturated NaHCO3 solution (80 mL), and the mixture was extracted with ethyl acetate (4×60 mL). The combined extract was washed with saturated NaHCO3 solution (60 mL) and dried over anhydrous MgSO4. The desired product, 2-methyl-3-nitrobenzothioamide (4.58 g, 23.3 mmol, 78% yield) was isolated as a pale solid by ISCO (330 g silica gel, solid loading, 20-30% ethyl acetate/hexane, 45 min).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[NH:5]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6]1.CCN(CC)CC>C(#N)C.CCOC(C)=O>[OH:4][CH2:3][CH2:2][N:5]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: OCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCO)C1
Reaction time: 32 h
Yield: 69.2 %

Procedure:
2-Bromoethanol (338 mg, 2.703 mmol) was added to a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg, 2.7 mmol) and Et3N (328 mg, 3.24 mmol) in acetonitrile (5 mL) in a seal tube and stirring was continued at 60° C. for 32 h. Reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with EtOAc, washed it with water followed by brine solution and dried over anhydrous sodium sulphate, concentrated under reduced pressure to afford 430 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:22][CH:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1)[CH3:24]>>[CH:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:26]=1)([CH3:24])[CH3:22]
Reactant: CC(C)c1cc(CN)no1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: CC(C)c1cc(CNC(=O)c2ccc(OCC3CC3)c(-c3ccc(Cl)cc3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAN 154016-49-6) as starting materials, LC-MS (peak area/EIC) 98.2%, 426.4 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.[C:10](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[CH3:10][N:7]1[C:3]([S:2][CH3:1])=[CH:4][C:5]([CH:8]=[O:9])=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: CSc1cc(C=O)n[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C=O)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a mixture of 5-(methylsulfanyl)-1H-pyrazole-3-carbaldehyde (10.0 g), potassium carbonate (9.70 g) and N,N′-dimethylformamide (60 mL) was slowly added methyl iodide (6.6 mL) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (6.38 g, yield 58%) as yellow crystals from the fraction eluted with ethyl acetate-hexane (1:5, volume ratio). melting point 47-48° C. MS: 157 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)#[CH:15].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C

Procedure:
To a mixture of N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (8) (419 mg, 1.11 mmol) and tert-butyl 4-ethynyl-1H-pyrazole-1-carboxylate (4) (277 mg, 1.44 mmol, 1.3 equiv) was added copper(I) iodide (7.4 mg 0.039 mmole) and DMF (4 mL), followed by triethylamine (0.69 mL, 497 mg, 4.92 mmol). The reaction was flushed twice with nitrogen. Bis(triphenylphosphine)palladium chloride (27 mg, 0.038 mmole) was added and the reaction flushed twice more with nitrogen, it was heated at 60° C. for 70 minutes. The reaction was added to water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water (3×20 mL) and with brine, dried and evaporated. The residue was purified on four 2 mm 20×20 cm silica prep tlc plates, eluted with 3:1 ethyl acetate:cyclohexane. The product band was recovered with acetone giving the title compound (251 mg, 51%). 1H-NMR (CDCl3, 500 MHz): δ 1.73 (s, 9H), 3.02 (s, 3H), 6.81 (s, 1H), 7.97 (s, 1H), 8.26 (s, 1H), 8.43 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: ClC1C=CC(C2CC(=[S:16])C3C(=CC=C(Cl)C=3)O2)=CC=1.[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH:25]2[CH2:34][C:33](=O)[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:36])[CH:31]=3)O2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([Cl:36])[CH:31]=3)[S:16]2)=[CH:23][CH:22]=1
Reactant: S=C1CC(c2ccc(Cl)cc2)Oc2ccc(Cl)cc21
Reactant: O=C1CC(c2ccc(Cl)cc2)Oc2ccc(Cl)cc21
Product: Clc1ccc(C2CCc3cc(Cl)ccc3S2)cc1

Procedure:
4',6-dichlorothioflavanone, (m.pt. 125°-127°), was prepared from 4',6-dichloroflavanone by a method exactly analogous to that used in Example 1(c).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH:29]([OH:31])[CH3:30])[CH:25]=[N:26]2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CCN(CC)CC>C(Cl)Cl.O>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([C:29](=[O:31])[CH3:30])[CH:25]=[N:26]2)=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCOc1ccc2cc(C(C)O)cnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCOc1ccc2cc(C(C)=O)cnc2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of oxalyl chloride (987 mg, 7.8 mmol, 1.5 eq.) in dry CH2Cl2 (40 mL) was added slowly DMSO (1.6 g, 20.8 mmol, 4 eq.) at −78° C. under N2 After 30 min, 1-(7-(heptyloxy)quinolin-3-yl)ethanol (1.5 g, 5.2 mmol) was added dropwise at −78° C. The mixture was stirred for 2 h at −78° C., and then Et3N (3.2 g, 31 mmol, 6 eq.) was added at −78° C. After 20 min, the mixture was warmed to room temperature. Then the reaction mixture was added water (30 mL), extracted (DCM), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (PE-EA, 10:1) to give 1-(7-(heptyloxy)quinolin-3-yl)ethanone as yellow solid (1.08 g, yield 73%). ESI-MS: 286 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CN1CCCC1=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:29]([O:28][C:27](=[O:33])[NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:3]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)cc1
Temperature: 150 °C
Yield: 7.8 %

Procedure:
6-Chloro-4-p-tolylamino-pyridazine-3-carboxylic acid amide (199 mg, 0.758 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (325 mg, 1.52 mmol) were dissolved in N-methylpyrrolidinone (4.7 mL). The reaction mixture was heated at 150° C. for 16 h, then additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (550 mg, 2.57 mmol total) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate), filtered, and concentrated in vacuo. The residue obtained was purified by chromatography (silica, 0 to 5% methanol in dichloromethane) to give [(1S,2R)-2-(6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (26 mg, 8%) as a light brown amorphous residue. LCMS (EI/CI) m/z: 441 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])NC2SC(SCC(O)=O)=CN=2)[CH:5]=[CH:6][CH:7]=1.C([O:34][C:35](=[O:46])[C:36]([S:39][C:40]1[S:44][C:43]([NH2:45])=[N:42][CH:41]=1)([CH3:38])[CH3:37])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:45][C:43]2[S:44][C:40]([S:39][C:36]([CH3:37])([CH3:38])[C:35]([OH:34])=[O:46])=[CH:41][N:42]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCc2cccc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C(Cl)Cl.C(OC(=O)/C=C/[C@H:10]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[N:11]1[C:24](=[O:28])[CH2:25][CH:26]=[CH2:27])C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(N(CC)CC)C>[F:21][C:19]1[CH:20]=[C:15]([C@H:12]2[N:11]3[C@@H:10]([CH:27]=[CH:26][CH2:25][C:24]3=[O:28])[CH2:14][CH2:13]2)[CH:16]=[C:17]([F:23])[C:18]=1[F:22]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OCC)CC[C@H]1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC=C[C@H]2CC[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A methylene chloride solution (60 mL) of (E)-3-[(2R,5S)-1-(3-butenoyl)-5-(3,4,5-trifluorophenyl)pyrrolidin-2-yl]acrylic acid ethyl ester (1.33 g) and Grubbs catalyst second generation (153 mg) was heated under reflux for 2 hr. The reaction solution was allowed to cool to room temperature, and then triethylamine (0.5 mL) was added thereto. The resulting mixture was stirred for 1 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1 to 0:1) to give 680 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([F:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[F:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ncc(F)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(F)s1
Reaction time: 3 h

Procedure:
2-Amino-5-fluorothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled and filtered to recover the desired product 5-fluorothiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[CH:22]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 416.99 g/mol.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:13][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1ncccc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2-c2ccccc2)CC1

Procedure:
Under General Procedure B: Reaction of 3-phenyl-pyridine-2-carbaldehyde and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (Huang, Y. et al. J. Med. Chem. 2001, 44, 4404-4415) in MeO4 with NaBH4 gave 4-[(3-phenyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) δ 1.22 (m, 3H), 1.41 (s, 9H), 1.70 (m, 2H), 2.52 (m, 1H), 2.72 (m, 3H), 3.84 (s, 2H), 7.21 (q, 1H, J=4.03 Hz), 7.32 (m, 2H), 7.40 (m, 3H), 7.53 (dd, 1H, J=7.79, 1.72 Hz), 8.54 (m, 1H) ppm.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:15]([OH:17])=[O:16])=[C:8]([C:12]([OH:14])=O)[C:9]([NH:11][C:4]2=[CH:3][CH:2]=1)=O.P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:9]1[C:8]2[C:12](=[O:14])[O:17][C:15](=[O:16])[C:7]=2[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1c(C(=O)O)c2ccccc2[nH]c1=O
Solvent: CN(C)C=O
Product: O=C1OC(=O)c2c1c(Cl)nc1ccccc21
Reaction time: 0.33 h

Procedure:
A mixture of 2(1H)-Oxo-quinoline-3,4-dicarboxylic acid (2.0 g), phosphorous oxychloride (10 mL) and 8 drops of dimethyl formamide was refluxed with stirring for 20 min. The reaction mixture was concentrated in vacuo and the residue treated with ice water to afford 4-Chloro-furo[3,4-c]quinoline-1,3-dione as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[CH:18]=2)[CH:13]=[CH:12][N:11]=1.[OH-].[Na+].C1COCC1.[ClH:31]>C(O)C>[ClH:31].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)c1ccc2ccnc(-c3c(F)cc(F)cc3F)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccnc(-c3c(F)cc(F)cc3F)c2c1

Procedure:
A mixture of methyl 1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (228 mg), a 1M aqueous sodium hydroxide solution (4 mL), THF (3 mL), and ethanol (3 mL) was stirred at room temperature for 24 hours. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitate was collected by filtration to obtain 1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylic acid hydrochloride (200 mg).
Reaction SMILES: [N:1]1([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:16]1[CH:21]=[C:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[N:19]2[N:26]=[CH:27][C:28]([CH:29]=[O:30])=[C:18]2[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:23]1([NH:22][C:20]2[N:19]3[N:26]=[CH:27][C:28]([CH:29]=[O:30])=[C:18]3[N:17]=[C:16]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:6][CH2:5]3)[CH:21]=2)[CH2:24][CH2:25]1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Temperature: 95 °C
Yield: 35 %

Procedure:
In a reaction flask, 2-(piperazin-1-yl)nicotinonitrile (22 mg, 0.11 mmol) was mixed with 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (27 mg, 0.11 mmol) in DMF (0.5 mL) along with potassium carbonate (32 mg, 0.23 mmol). The reaction was heated at 95° C. for 12 hours then partitioned between water and ethyl acetate. The organic layer was washed with water then saturated NaCl solution. The ethyl acetate layer was isolated, dried of anhydrous sodium sulfate, filtered, and evaporated to dryness. The product, 2-(4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile, was recovered in 35% yield (16 mg) after recrystallization from ethyl acetate/hexanes. LCMS (M+1=389)
Reaction SMILES: C[Si](C[Si](Br)(C)C)(C)C.[CH:10]1[C:22]2[N:21]([CH2:23][CH2:24][CH2:25][P:26](=[O:33])([O:30]CC)[O:27]CC)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH:10]1[C:22]2[N:21]([CH2:23][CH2:24][CH2:25][P:26](=[O:27])([OH:30])[OH:33])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CCOP(=O)(CCCn1c2ccccc2c2ccccc21)OCC
Agent: C[Si](C)(C)C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CCCn1c2ccccc2c2ccccc21
Reaction time: 1.5 h
Yield: 78 %

Procedure:
Trimethylsilyl(TMS)-bromide (1.12 mL, 8.67 mmol) was added via syringe to a solution of diethyl 3-(9H-carbazol-9-yl)propylphosphonate (1.00 g, 2.89 mmol) in ˜20 mL dry DCM in a 50 mL rbf. The flask was greased and capped and allowed to stir for 90 minutes. The volatile organics were removed under vacuum and 30 mL of 1:1 MeOH:H2O were added. The solution turned a cloudy whitish/grey. The solvents were removed and the product recrystallized from 2:1 H2O:acetone (grey powder, 612 mg) and 1:1 H2O:MeOH (PJH-II-5c, glassy grey solid, 42 mg). Both recrystallization solvents yielded pure product. Total yield was 78%. 1H NMR (400.14 MHz, DMSO) δ 8.15 (d, J=8.00 Hz, 2H), 7.65 (d, J=8.00 Hz, 2H), 7.45 (dt, J=15.41, 1.00 Hz, 2H), 7.19 (t, J=14.81 Hz, 2H), 4.48 (t, J=13.60 Hz, 2H), 2.03-1.89 (m, 2H), 1.59-1.46 (m, 2H). 13C{1H} NMR (100.62 MHz, DMSO) δ 140.01 (2C), 125.76 (2C), 122.07 (2C), 120.33 (2C), 118.78 (2C), 108.33 (2C), 42.48 (d, J=17.31 Hz), 25.00 (d, J=137.35 Hz), 22.67 (d, J=4.13 Hz). 31P{1H} NMR (161.97 MHz, DMSO): δ 26.78. Analysis found (calculated) %: C, 62.27 (62.28); H, 5.56 (5.58); N, 4.73 (4.84). MS (FAB, m/z): 290 ([M+H]+, 100%). Exact mass found (calculated for [M+H]+, m/z): 290.09405 (290.09461).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23]C)=[O:22])[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]3)=[O:14])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCN(C(=O)N2CCN(c3ccncc3)CC2)CC1
Agent: Cl
Product: O=C(O)C1CCN(C(=O)N2CCN(c3ccncc3)CC2)CC1

Procedure:
Prepared by reacting methyl N-[[4-[4-pyridyl)-piperazin-1-yl]carbonyl]piperidin-4-carboxylate with semiconcentrated hydrochloric acid analogously Example 4.