Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].C[O:6][C:7](=O)[CH2:8][S:9][CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(O)(=O)C>C(O)C.C(OCC)(=O)C>[CH3:16][CH:10]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:6])[CH2:8][S:9]1
Reactant: COC(=O)CSC(C)CC(=O)OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1C(=O)CSC1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A three neck flask was charged with NaOEt (21%, 200 mL, 537 mmol) in ethanol. The solvent was removed under vacuum and to the residue was added toluene (500 mL). The mixture was heated to reflux and methyl 3-(2-methoxy-2-oxoethylthio)butanoate (92 g, 446 mmol) was added dropwise. After addition was complete, the mixture was refluxed for 4 hours. After cooling, the mixture was poured into a mixture of acetic acid (200 g) and crushed ice (200 g). The mixture was stirred overnight and then diluted with ethyl acetate (500 mL). The organic phase was separated and washed with saturated Na2CO3 and brine and then dried. The solvent was removed to afford crude methyl 2-methyl-4-oxo-tetrahydrothiophene-3-carboxylate (77.7 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 11.23-11.15 (d, 1H), 7.27-7.16 (m, 2H), 4.33-4.12 (m, 2H), 3.95-3.68 (m, 2H). 3.60-3.15 (m, 1H), 2.60-2.20 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(NC(C)C)(C)C>C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CC(C)(C)O
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1

Procedure:
A stirred mixture of compound 68 (15.00 g, 0.039 mol), 2-methylbut-3-yn-2-ol (7.15 g, 0.085 mol), copper(I) iodide (0.34 g, 1.80 mmol), tetrakis(triphenylphosphine)palladium(0) (2.89 g, 2.50 mmol) and diisopropylamine (150 ml) was heated under reflux in a dry nitrogen atmosphere for 24 h. The resultant mass was dissolved in THF and filtered over hyflo filter aid to remove inorganic materials. Volatile materials were removed in vacuo and the brown solid was recrystallised from ethanol to give a white, fluffy solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:8]([NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: c1ccc(CNc2ccccc2)cc1
Temperature: 85 °C
Yield: 89.8 %

Procedure:
Following general procedure D, a mixture of chlorobenzene (1.02 mL, 10 mmol), benzylamine (1.52 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a yellow oil (1.646 g, 90%). 1H NMR (300 MHz, CDCl3) δ: 7.69-7.61 (m, 5H), 7.53 (t, J=7.5 Hz, 2H), 7.09 (t, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 2H), 4.57 (s, 2H), 4.22 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 148.8, 140.2, 129.9, 129.3, 128.1, 127.8, 118.1, 113.5, 48.7 ppm. IR (neat, cm−1): 3419, 3052, 3026, 2841, 1603, 1506, 1453, 1325, 750, 693. Anal. Calcd. for C13H13N: C, 85.21; H, 7.15. Found: C, 85.04; H, 7.15.
Reaction SMILES: [ClH:1].[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O.CN(C=O)C.CC(OC)(C)C>C1(C)C=CC=CC=1>[ClH:31].[Cl:1][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:16][CH2:15][NH:14][CH:12]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(NCC[C@@H](O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(NCC[C@@H](Cl)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IXa) (20.0 g, 48.796 mmol) is suspended in toluene (140 ml) at 40° C. and phosphoryl chloride (4.3 g, 28.044 mmol) is added drop-wise over 10 minutes. The reaction mixture is stirred two hours at 60° C., then DMF (1.0 g) is added at 40° C., followed by additional phosphoryl chloride (3.2 g, 20.870 mmol). The mixture is stirred at 40° C. overnight and then MTBE (40 ml) is added. Volatiles are removed by repeatedly distilling off under vacuum and restoring MTBE. After that a 1:1 vol/vol toluene/MTBE solution is received, which is heated up to 70° C. and allowed to cool down slowly to 15°-20° C. the so-obtained precipitate is aged at room temperature overnight, then filtered and washed with a 1:1 vol/vol toluene/MTBE mixture (3×12 ml). (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) is obtained as a white powder after exsiccation at 55° C. under vacuum (6.0 g, 14.008 mmol, yield: 28.7%).
Reaction SMILES: C(O[C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[F:24])=[O:5])C.[OH-].[Na+].[NH2:27][O:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:31][CH2:30][C:29]([CH3:33])([CH3:32])[O:28][NH:27][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[F:24])=[O:5]
Reactant: CC(C)(CO)ON
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(SC)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(Nc2c(C(=O)NOC(C)(C)CO)[nH]c3ccncc23)c(F)c1
Temperature: 60 °C
Yield: 4.6 %

Procedure:
3-(2-Fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.13 g, 0.38 mmol) was dissolved in IMS (5 ml) before 1M NaOH (0.45 ml, 0.45 mmol) was added and the mixture heated at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in THF (3 ml). 2-Aminooxy-2-methyl-propan-1-ol (100 mg, 0.56 mmol), DIPEA (0.20 ml, 1.1 mmol) and HATU (210 mg, 0.56 mmol) were added and the mixture stirred at room temperature. On completion of the reaction, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried (MgSO4), and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM:MeOH, gradient 99:1 to 90:10) to give an orange solid. The orange solid was then purified by reversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl 0.1% HCO2H in water on a gradient of acetonitrile) to provide the title compound (semiformate) as a yellow solid (7 mg, 5%). LCMS (method A): RT=5.87 min, M+H+=405. 1H NMR (d6-DMSO, 400 MHz) 1.10 (6H, s), 2.42 (3H, s), 3.20 (2H, s), 6.58 (1H, t, J=8.58 Hz), 6.91 (1H, dd, J=8.42, 2.06 Hz), 7.20 (1H, dd, J=12.05, 2.11 Hz), 7.37 (1H, dd, J=5.84, 1.11 Hz), 7.81 (1H, s), 8.23 (1H, d, J=5.83 Hz), 8.52 (1H, d, J=1.07 Hz).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:19].[NH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2O[Si](C(C)(C)C)(C)C)[N:22]=1.C1C[O:48]CC1>>[ClH:19].[NH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([C:31]2[CH:36]=[CH:35][C:34]([OH:48])=[CH:33][CH:32]=2)[N:22]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C1Cc2ccccc2C(N)=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: NC1=NC(c2ccc(O)cc2)Cc2ccccc21
Reaction time: 0.25 h

Procedure:
Tetra-n-butylammonium fluoride (1.0M in THF, 3.3 ml) was added to a stirred solution of 1-amino-3-(tert-butyldimethylsilyloxyphenyl)-3,4-dihydroisoquinoline hydrochloride (638 mg, 1.11 mmol) in THF (10 ml). After 15 min., the mixture was evaporated and the residue purified by flash chromatography on untreated neutral alumina, eluting with 5% methanol in dichloromethane, increasing the gradient to 40% methanol in dichloromethane to give a colourless solid (172 mg). This was recrystallised from methanol/dichloromethane (1:2) to give the product as a white powder. M+ 239; 360 MHz 1H n.m.r (d6 -DMSO) 9.65 (1H, br.s), 8.15 (1H, d, J 7.8 Hz), 7.69 (1H, t, J 7.5 Hz), 7.52 (1H, t, J 7.6 Hz), 7.45 (1H, d, J 7.5 Hz), 7.19 (2H, d, J 8.6 Hz), 6.77 (2H, d, J 8.6 Hz), 4.87 (1H, t, J 7.3 Hz), 3.25 (2H, d, J 7.3 Hz).
Reaction SMILES: C(O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(OC(=O)C)(=O)C>>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: O=C(O)CCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=CCCCCC(=O)O
Temperature: 255 °C
Yield: 367 %

Procedure:
In a procedure similar to example 3, a mixture of suberic acid (20.0 g, 0.115 mol), acetic anhydride (11.7 g, 0.115 mol) , and chlorocarbonyl bis(dimethylphenylphospine)rhodium (0.509 g, 0.00115 mol) was heated under reduced pressure (100 torr) using an oil bath maintained at 255° C. and the product collected as it distilled from the reactor. The material removed was continuously replaced with a mixture of suberic acid and acetic anhydride (1:1 molar mixture; a total of 90.0 g of suberic acid was used in the feed mixture) in a rate that maintained the initial level of the reactor contents throughout the course of the entire reaction. The formation of product ceased after about 90 minutes of reaction time. The distillate product collected was fractionally distilled to provide 54.1 g of 6-heptenoic acid (bp 95°-100° C./10 torr) which was found by GC analysis to be >98% of the α-olefin. This amount of product corresponds to a catalyst TON of 368. Considering the amount of unreacted suberic acid containing residue recovered in the distillation pot (19.6 g), the isolated yield of 6-heptenoic acid relative to the suberic acid in the feed mixture was nearly quantitative.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.BrBr.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(O)C.CO.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: CO
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a mixture of 3 ml of dioxane and 1 ml of methanol were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 10 minutes. To the reaction liquid were then added 7.5 g of 4-benzylpyridine, 100 ml of ethanol and 3.28 g of anhydrous sodium acetate, and the mixture was refluxed under heating for 5 hours. The reaction mixture was then treated in the same manner as described in Example 27, whereby 11.2 g (72.6%) of ifenprodil were obtained as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2nccn2)cc1
Yield: 66.4 %

Procedure:
4-Fluoronitrobenzene (21 g) was reacted with 1H-1,2,3-triazole (12.4 g) in the same manner as in Reference Example 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and purified by silica gel chromatography (eluent:dichloromethane to dichloromethane/acetone=8/1). The first eluted fraction was recrystallized from dichloromethane-diisopropyl ether to give 2-(4-nitrophenyl)-2H-1,2,3-triazole (18.8 g) as pale yellow prisms.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](OCC)=[O:18])[CH:13]=[N:14]2)=[N:9][CH:8]=1.OC1C=C2C(C=C(C(OCC)=O)C=N2)=[N:28]C=1.C([O-])([O-])=O.[Cs+].[Cs+].FC1C=C(C=CC=1)CCl>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]([NH2:28])=[O:18])[CH:13]=[N:14]3)=[N:9][CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(F)c3)cnc2c1
Reactant: CCOC(=O)c1cnc2cc(O)cnc2c1
Agent: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cnc2cc(OCc3cccc(F)c3)cnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
Ethyl 7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate. To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (Intermediate 4, 1.0 g, 4.59 mmol) in DMF (20 mL) was added Cs2CO3 (2.2 g, 6.75 mmol), followed by 3-fluorobenzyl chloride (0.6 mL, 5.02 mmol). The reaction was stirred at ambient temperature for 72 h. The crude reaction mixture was poured into EtOAc and water. The aqueous later was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (1.0 g, 69%). 1H NMR (400 MHz, CDCl3) δ 9.44 (t, J=2.0 Hz, 1H), 9.00-8.94 (m, 1H), 8.88 (t, J=2.3 Hz, 1H), 7.74-7.65 (m, 1H), 7.47-7.33 (m, 1H), 7.28-7.26 (m, 1H), 7.21 (d, J=9.4 Hz, 1H), 7.07 (t, J=8.6 Hz, 1H), 5.25 (s, 2H), 4.59-4.38 (m, 2H), 1.52-1.41 (m, 3H). [M+H]=327.2.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[S:18]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:20])(=[O:19])[NH2:21]
Reactant: NS(N)(=O)=O
Reactant: COC(=N)CCCCc1csc(NC(=N)N)n1
Solvent: CO
Product: N=C(N)Nc1nc(CCCCC(=N)NS(N)(=O)=O)cs1
Reaction time: 8 h
Yield: 43 %

Procedure:
1.3 g of methyl 5-(2-guanidinothiazol-4-yl)pentanoimidate and 1.1 g of sulfamide were dissolved in 4.3 g of methanol, and the solution was allowed to stand overnight at room temperature. The solvent was distilled away under reduced pressure and the residue was purified by a silica gel column chromatography using a mixture of acetone and methanol as the developing solvent. The obtained crystals were dissolved in 0.4 ml of acetic acid, 4 ml of ehtanol and 8 ml of water, and the solution was treated with activated charcoal. To the filtrate was added 6.6 ml of N--NaOH, and the precipitated crystals were filtered off to provide 0.70 g of N-sulfamoyl-5-(2-guanidinothiazol-4-yl)pentanoamidine having a melting point of 156°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([CH:14]=2)N)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:20]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([Br:20])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 120 ml) is added dropwise to a suspension of 5-(4-chlorophenyl)-2-methylaniline (21 g, 0.09 mol) in water (80 ml), and the mixture stirred until the solid is dissolved. The mixture is cooled to −5° C. and a solution of sodium nitrite (10.12 g, 0.14 mol) in water (50 ml) is added dropwise, maintaining the temperature at 0-5° C. The reaction mixture is stirred for 1 hour, then added to a pre-cooled solution of cuprous bromide (17.9 g, 0.12 mol) in hydrobromic acid (48% wt. in water, 120 ml) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature overnight. The mixture is extracted with ethyl acetate, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 2% ethyl acetate in hexane to give 5-(4-chlorophenyl)-2-methyl-1-bromobenzene (15.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[CH3:22][Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(c2cc(Br)ccc2O)OCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ccc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solution of 3.11 g (12 mmol) of 2-(2-hydroxy-5-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran was added dropwise succesively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1ccc(Cl)c(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(F)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro-1-fluorobenzene and isolated as white solid. MS (m/e): 459.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6]2=[O:12].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:19]([O-:21])=[O:20])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6]2=[O:12]
Reactant: CN1Cc2c(ccc(F)c2Br)C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1Cc2c(Br)c(F)cc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 4-bromo-5-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 31F, 1.5 g, 6.1 mmol) in sulfuric acid (3.0 mL, 56 mmol) was cooled in an ice bath to 0° C. and then charged with nitric acid (2.0 mL, 43 mmol). The reaction mixture was allowed to stir overnight while gradually warming to rt. The reaction mixture was quenched by adding the mixture dropwise into a separatory funnel containing ice and then extracted with DCM (15 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using DCM/EtOAc (100:0→90:10) as eluent to afford the product compound as a yellow solid (493 mg, 28%). 1H NMR (CDCl3, 400 MHz): δ 7.60 (d, J=7.6 Hz, 1H) 4.39 (s, 2H) 3.23 (s, 3H). MS (ESI): m/z=290.96 [M+H]+. UPLC: tR=1.23 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:25]3[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 11.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (34 mg. 0.10 mmol), 4-piperidone hydrochloride (46 mg, 0.30 mmol) and sodium triacetoxyborohydride (25 mg, 0.12 mmol) to afford 5 mg (12%) of the desired product after purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH2:26][CH2:27][CH3:28])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][CH2:26][CH2:27][CH3:28])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCCO/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 38.1 %

Procedure:
To 218 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(propoxyimino)ethyl]-2-(trifluoromethyl)benzamide in 3 ml of acetonitrile, 5 mg of benzophenone was added, and the mixture was irradiated with light for 48 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 25:75 to 35:65) as the eluent to obtain 83 mg of the desired product as white crystals.