Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:2].[CH3:20][Mg]Br>>[OH:2][C@H:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH3:20]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)NCCCc1ccccc1C=O
Product: C[C@H](O)c1ccccc1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 33-5 (0.385 g, 1.462 mmol) in was treated with methylmagnesium bromide (5.1 ml, 15.3 mmol, 3M in diethylether) at 0° C. After stirring overnight at RT, the reaction was quenched with NH4Cl solution. Extracted with Ethyl acetate, washed with brine and dried over sodium sulfate. Material was purified by reverse phase column chromatography (C18 column, 5-95% MeCN in water with 0.1% TFA) to yield a white solid. Racemic material was separated by chiral chromatography (ChiralTech IC column) to yield 33-6.
Reaction SMILES: CN(CCN(C)C)C.[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[C:25]12([P:35]([C:37]34[CH2:46][CH:41]5[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]5)[CH2:38]3)[CH2:44]4)Cl)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>CCCCCC.O>[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[C:16]2[P:35]([C:37]23[CH2:38][CH:39]4[CH2:40][CH:41]([CH2:42][CH:43]([CH2:45]4)[CH2:44]2)[CH2:46]3)[C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: c1ccc(-n2cccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: c1ccc(-n2cccc2P(C23CC4CC(CC(C4)C2)C3)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.6 ml of TMEDA (15 mmol.) are added to a suspension of 1.43 g (10 mmol.) of N-phenylpyrrole in 30 ml of hexane. 6.25 ml of 1.6 molar n-butyllithium solution (10 mmol.) are added at room temperature. The mixture is then heated for 2.5 hours at reflux temperature (solution 1). In another flask, 3.36 g (10 mmol.) of di-1-adamantylchlorophosphane are mixed with 40 ml of hexane and heated to 76° C. (solution 2). The boiling solution 1 is then slowly transferred into solution 2, which is at 76° C., by means of a cannula. The mixture is then boiled for a further 2 hours at reflux, the solution is cooled, and 20 ml of water are added thereto. The organic phase is filtered off over magnesium sulfate. The solution is concentrated in vacuo; 15 ml of toluene are added thereto, and the mixture is heated to 60° C. and then cooled. After one day at room temperature, the product is filtered off. Yield: 3.3 g (75%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:42][C:23]4=[N:24][CH:25]=[C:26]([Br:41])[C:27]([N:28]5[CH2:33][CH2:32][N:31]([CH2:34][C:35]6[N:36]=[C:37]([CH3:40])[S:38][CH:39]=6)[CH2:30][CH2:29]5)=[C:22]4[N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:41][C:26]1[C:27]([N:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]3[N:36]=[C:37]([CH3:40])[S:38][CH:39]=3)[CH2:32][CH2:33]2)=[C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)[NH:42][C:23]2=[N:24][CH:25]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCNCC6)cc5)nc34)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
tert-Butyl-4-(4-(6-bromo-7-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate (0.022 g, 0.033 mmol) was suspended in DCM (2.0 mL) and the mixture cooled in an ice bath. TFA (0.5 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (5 g), the filtrate collected and the solvent removed in vacuo to give the title compound as a solid (0.016 g, 86%); 1H-NMR (500 Mz, DMSO-d6): δ 2.61-2.70 (m, 7H), 2.81-2.89 (m, 4H), 3.15-3.22 (m, 4H), 3.60-3.68 (m, 6H), 7.03 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.32 (s, 1H, thiazole 5-H), 8.02 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.17 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.23 min—553/555 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 553.1522, calculated for C25H30BrN8S (M+H)+: 553.1498.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][O:8][CH:9]([CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][S:11]([CH2:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(N(CC)CC)C>[CH3:7][O:8][CH:9]([CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:10][S:11]([CH2:14][CH2:15][CH2:16][O:17][S:41]([CH3:40])(=[O:43])=[O:42])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CS(=O)(=O)CCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CS(=O)(=O)CCCOS(C)(=O)=O

Procedure:
To 100 ml of ethyl acetate are added 4.5 g of 3-[(2-methoxy-3-(3,7,11,15-tetramethylhexadecyloxy)propyl)sulfonyl]propanol and 1.54 ml of triethylamine, to which is further added 0.85 ml of methanesulfonyl chloride dropwise at room temperature with stirring. After being stirred at room temperature for 3 hours, the reaction mixture is washed with water, dilute hydrochloric acid, an aquoues sodium bicarbonate and water. After drying, the solvent is distilled off to leave 5.16 g of the captioned compound as an oily substance.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Na].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[OH:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CCC(O)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCC(O)C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a solution of (±)-2-hydroxybutanoic acid, sodium salt (2.54 g, 20.1 mmol) in dry DMF (30 ml) was added benzyl bromide (2.9 mL, 1.2 eq) and anhydrous KI (330 mg, 0.1 eq). The suspension was heated at 100° C. for 24 hours and the DMF was distilled off under reduced pressure. The residue was taken up in ether, washed with water and saturated Na2S2O3, dried (MgSO4), and concentrated. Distillation of the residual oil afforded 3.7 g (95%) of benzyl (±)-2-hydroxybutanoate as a colorless oil, b.p. 95° C. (0.45 Torr).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[N:27]([CH2:28]OCC[Si](C)(C)C)[C:26]2[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=2[N:24]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[N:27]([CH3:28])[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=2)[CH2:2][CH2:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3ccccc3n2C)c2ncccc21
Temperature: 120 °C
Reaction time: 10 h
Yield: 8.2 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (101 mg) in NMP (2 mL) was stirred at 120° C. for 10 h, treated with saturated NaHCO3 solution and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (2 mL), and then iodomethane (0.022 mL) and Cs2CO3 (0.176 g) were added. The mixture was stirred at room temperature for 3 h, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in CH3CN and the precipitate was filtered off. The residue was purified by prep. HPLC, and then chromatographed on silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (12 mg).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.O1CCCC1.CO.[BH4-].[Na+]>O>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)N2CCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To 4-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline(0.7 g) are added tetrahyrdofuran (10 ml) and methanol (10 ml). To the mixture is added sodium borohydride (0.1 g) in portions and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=20:1), and recrystallized from ethanol to give 4-hydroxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 215-217° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[C:8]([CH2:13][NH:14][C:15](=O)[CH2:16][C:17]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[C:8]2[N:9]([C:15]([CH2:16][C:17]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])([CH3:19])[CH3:18])=[N:14][CH:13]=2)[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccnc1CNC(=O)CC(C)(C)N1C(=O)c2ccccc2C1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)COc1cccn2c(CC(C)(C)N3C(=O)c4ccccc4C3=O)ncc12
Temperature: 0 °C
Yield: 55.3 %

Procedure:
A solution of (2-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-butyrylamino]-methyl}-pyridin-3-yloxy)-acetic acid ethyl ester (2.79 g, 6.349 mmol) in 100 ml of neat phosphoryl chloride is stirred at 75° C. for 16 hours. The reaction mixture is poured on 200 g of crushed ice and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The residue is purified via flash chromatography on silica gel using a methylene chloride/methylene chloride-ethanolic ammonia gradient (100 to 96:4) to give 1.48 g of {3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-methyl-propyl]-imidazo[1,5-a]pyridin-8-yloxy}-acetic acid ethyl ester (55%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[CH:7]=[N:8]2)=[CH:4][N:3]=1
Reactant: Clc1ncc2[nH]cnc2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ncc2c(ncn2C2CCCCO2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A 100-mL, round-bottom flask was charged with 2-chloro-7H-purine (0.200 g, 1.29 mmol), toluene (20 mL), p-toluene sulfonic acid (0.011 g, 0.06 mmol), 3,4-dihydro-2H-pyran (0.328 g, 3.90 mmol), and the resulting solution stirred for 2 h at 80° C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting 1:5, with ethyl acetate/petroleum ether) to afford 2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (0.245 g, 79%) as brown oil. MS (ESI, pos. ion) m/z 239 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:10][C:11]1[CH:12]=[N:13][N:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:15]=1
Reactant: Brc1cn[nH]c1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1cccc(-n2cc(Br)cn2)c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
3-Fluorobenzonitrile (4.4 mL, 40 mmol), 4-bromopyrazole (6 g, 40 mmol) and potassium carbonate (11 g, 80 mmol) were weighed into a flask and flushed with Ar(g). Dry DMF (80 mL) was added and the reaction mixture was stirred at 140° C. for 18 h. The reaction mixture was then cooled to rt and partitioned between EtOAc (200 mL) and brine (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (3×150 mL), the combined organic layers were washed with brine (3×50 mL), dried over Na2SO4, filtered and concentrated to afford a solid. This was recrystallized from EtOAc/hexane to give 3-(4-bromo-1H-pyrazol-1-yl)benzonitrile as a beige solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([CH2:30][CH2:31]O)[C:24]=2[CH:23]=[CH:22]1.C(Cl)(Cl)(Cl)[Cl:34].C(#N)C>>[Cl:34][CH2:31][CH2:30][CH:25]1[CH2:26][CH2:27][CH2:28][C:29]2[N:21]([CH3:20])[CH:22]=[CH:23][C:24]1=2
Reactant: Cn1ccc2c1CCCC2CCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cn1ccc2c1CCCC2CCCl
Reaction time: 3 h
Yield: 43 %

Procedure:
Triphenylphosphine (2.46 g, 9.38 mmol) is added to a solution of 2-(1-methyl-4,5,6,7-tetrahydro-1H-indol-4-yl)ethanol (1.68 g, 9.38 mmol) in CCl4/Acetonitrile 1:1 (20 mL) at room temperature and the mixture is maintained under stirring for 3 hours monitoring the reaction by TLC. The solution is concentrated to half the volume at reduced pressure, CH2Cl2 is added and washed with water. The organic phase is separated and evaporated to dryness. The crude is treated with diethyl ether and the precipitated is filtered. The diethyl ether is evaporated at reduced pressure, and the resulting crude is purified by column chromatography, giving 4-(2-chloroethyl)-1-methyl-4,5,6,7-tetrahydro-1H-indole (0.8 g, 4.05 mmol, 43%, oil). (ESI-MS m/z 198 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][C:15]1[C:16]2[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=2[S:18][C:19]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)O>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:20]([C:19]1[S:18][C:17]2[CH:28]=[CH:29][CH:30]=[CH:31][C:16]=2[C:15]=1[CH3:14])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Reactant: Cc1c(C(O)c2ccccc2)sc2ccccc12
Product: Cc1c(C(C2=C(O)C(C)(c3ccccc3)C2=O)c2ccccc2)sc2ccccc12

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (3-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 409.5 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].I[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C1COCC1.O.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.[Cu]I>[NH2:6][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)c1
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of 3-ethynylaniline (1.16 g, 9.87 mmol) and tert-butyl (3-iodophenyl)carbamate (3.0 g, 9.4 mmol) in THF (28 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (330 mg, 0.47 mmol), copper(I) iodide (140 mg, 0.75 mmol) and N,N-diisopropylethylamine (3.27 ml, 18.8 mmol), and stirred at 25° C. overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.42 g, 49%). LCMS for C19H21N2O2 (M+H)+: m/z=309.1.
Reaction SMILES: FC(F)(F)S(OC1C=CC=CC=1CC1CCC2C(=CC=C(OC)C=2)C1)(=O)=O.C(N)C1C=CC=CC=1.[CH2:36]([NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH:51]1[CH2:60][CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:61]C)[CH:57]=2)[CH2:52]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH:51]1[CH2:60][CH2:59][C:58]2[CH:57]=[C:56]([OH:61])[CH:55]=[CH:54][C:53]=2[CH2:52]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc2c(c1)CCC(Cc1ccccc1NCc1ccccc1)C2
Agent: COc1ccc2c(c1)CCC(Cc1ccccc1OS(=O)(=O)C(F)(F)F)C2
Solvent: NCc1ccccc1
Product: Oc1ccc2c(c1)CCC(Cc1ccccc1NCc1ccccc1)C2

Procedure:
Synthesized from 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl trifluoromethanesulfonate (1.4 g) and benzylamine (650 mg) according to an analogous synthetic method to Example 116, benzyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl]amine was used according to an analogous synthetic method to Example 785 to provide the title compound (440 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:20][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {4-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (90.2 g, 0.732 mmol) in dichloromethane (10 mL) was added carbon tetrabromide (0.485 g, 1.464 mmol) and triphenylphosphine (0.384 g, 1.464 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with 10-20% ethyl acetate/hexane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.18 (s, 1H), 8.06 (d, J=7.54 Hz, 1H), 7.67 (d, 1H), 7.56 (t, J=7.73 Hz, 1H), 4.72 (m, 2H), 2.48 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([CH3:43])=[C:21]([NH:20][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Reactant: CCn1nccc1C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1C
Yield: 58 %

Procedure:
In the same manner as in Example 55 and using 1-ethyl-1H-pyrazole-5-carboxylic acid (56.0 mg, 0.400=mol), tetrahydrofuran (5 mL), thionyl chloride (69.1 μL, 0.796 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (117 mg, 0.362 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (93.5 mg, 58%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:35])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and ammonium chloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.41 (m, 3 H) 1.54-1.86 (m, 7 H) 3.32 (s, 3 H) 3.93 (s, 3 H) 4.17 (t, J=12.5 Hz, 2 H) 4.44-4.55 (m, 1 H) 7.33 (s, 1 H) 7.55 (d, J=8.3 Hz, 1 H) 7.59 (s, 1 H) 7.99 (s, 1 H) 8.13 (d, J=8.1 Hz, 1 H) 8.24 (s, 1 H) 8.61 (s, 1 H). [M+H] calc'd for C22H26F2N6O3 461; found 461.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH:7]=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
185 g of dimethylformamide and 82.8 g (0.6 mol) of potassium carbonate were placed in a flask, and 61 g (0.5 mol) of salicylaldehyde were added dropwise thereto. 75.9 g (0.6 mol) of benzyl chloride were then added dropwise to the resulting mixture at a temperature of 50° C. for one hour. After the addition, the mixture was stirred at a temperature of 70° C. for two hours. The resulting reaction mixture was washed with 185 g of toluene and 330 g of water. The solvent was distilled out of the mixture at an inside temperature of 90° C. under a reduced pressure of 10 mmHg thereby providing 104.5 g of 2-benzyloxybenzaldehyde as bottom in the form of brown liquid having a purity 97.9% in a yield of 96.5%.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+].[Na+].[Cl-:8].[Na+].[C:10](=[O:13])([O-:12])[O-:11].[Na+].[Na+]>>[C:10](=[O:11])([OH:13])[O-:12].[Cl-:8].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Product: O=C([O-])O

Procedure:
It is a further object to selectively leach sodium sulfate, sodium chloride and burkeite from a salt mixture containing sodium carbonate, -bicarbonate, -chloride and -sulfate, burkeite and trona, to form trona, which is converted to sodium carbonate, and to separate any residual sodium sulfate, sodium chloride and other impurity salts from the carbonate in a non-convective, solar pond to obtain high purity sodium carbonate monohydrate.