Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][C:48]1[N:49]([C:53]2[CH:54]=[C:55]([CH:57]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:59]=2)[NH2:56])[CH:50]=[CH:51][N:52]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([NH:56][C:55]2[CH:57]=[C:58]([C:60]([F:61])([F:62])[F:63])[CH:59]=[C:53]([N:49]3[CH:50]=[CH:51][N:52]=[C:48]3[CH3:47])[CH:54]=2)=[O:9])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 123 %

Procedure:
3-Nitro-4-methyl benzoic acid (14.8 g, 81.5 mmol) was dissolved in DMF (150 mL), and HATU (62 g, 163 mmol) and DIPEA (57 mL, 326 mmol) were added thereto at room temperature. The reaction mixture was stirred for 15 minutes, 3-(2-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline (13.1 g, 54.3 mmol) was added thereto and stirred at 45° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with sat. NaHCO3 solution. The organic layer was dried with anhydrous MgSO4, filtered with Celite and concentrated. The residue was crystallized with ethyl acetate and hexane to obtain the title compound (27 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>CO>[CH2:6]([NH+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][CH2:2][C:3]([O-:5])=[O:4])=[O:16]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCC(=O)O
Reactant: CCN(CC)CC
Solvent: CO
Product: CC[NH+](CC)CC
Product: O=C([O-])CNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a suspension of glycine (1.50 g, 20 mmol) in 100 ml dry methanol were added triethylamine (3.5 ml, 2.5 g, 25 mmol) and ethyl trifluoroacetate (3.0 ml, 3.55 g, 25 mmol). The mixture was stirred overnight to give a homogeneous solution. The solvents were removed and the resulting oil coevaporated with toluene to remove traces of methanol. The product was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:36][CH3:37])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]#[N:35])=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16](C1CCCCO1)[N:15]=[CH:14]2.[NH2:38][OH:39].[CH2:40]([OH:42])C>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:36][CH3:37])=[C:10](\[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]2[NH:35][C:40](=[O:42])[O:39][N:38]=2)=[CH:30][CH:31]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: CCO
Reactant: CC/C(=C(/c1ccc(/C=C/C#N)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccc(F)cc1Cl
Reactant: NO
Product: CC/C(=C(/c1ccc(/C=C/c2noc(=O)[nH]2)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl

Procedure:
A mixture of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylonitrile (920 mg, 1.8 mmol) and hydroxylamine (0.18 mL, 2.7 mmol, 50% wt. in water) in ethanol (2 mL) was heated at reflux for 16 h. The ethanol was removed in vacuo, and dichloromethane and water were added. The aqueous layer was extracted with dichloromethane (2×), and the combined organics were washed with brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography (0 to 70% EtOAc/hexanes) provided 433 mg of the title compound as a pale yellow foam. LCMS: 461 [(M-THP+H)+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:43]=[C:44]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:45][NH:46][C:47](=[O:61])[C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:50][CH:49]=1>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13]([N:65]1[CH2:66][CH2:67][N:62]([C:44](=[O:43])[CH2:45][NH:46][C:47](=[O:61])[C:48]2[CH:49]=[CH:50][C:51]([O:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[CH:52][CH:53]=2)[CH2:63][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(Cl)cc2Cl)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
DIPEA (0.11 mL, 0.64 mmol) was added drop wise to 2,4-dichlorobenzoic acid (48 mg, 0.26 mmol) in DMF (5 mL). EDCI (102 mg, 0.53 mmol) and HOBT (34 mg, 0.26 mmol) were added consecutively. After 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (80 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 60:40 EtOAc:hexane as eluent) afforded N-{2-[4-(2,4-Dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide: in 64% yield. LC-MS purity: 97%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.7 (s, 1H), 7.5 (m, 4H), 7.2 (t, 1H), 7.1 (m, 4H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([NH:25][CH2:26][CH2:27][NH2:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][CH2:27][NH:28][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available N—BOC-ethylenediamine (1.82 ml, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.41 g, 96%) as a white solid. MS (ISN) 383.0 [(M−H)−], mp 106° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:32])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][N:25]=3)[CH:20]=2)[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:32])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][N:25]=3)[CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CC1(C)CCOc2ccc(C#Cc3ccc(CO)cn3)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCOc2ccc(C#Cc3ccc(C=O)cn3)cc21
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure- equalizing addition funnels fitted with drying tubes. The solution is cooled to -60° C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60° C. for an additional 10 minutes. A solution of 2.82 g (10 mmol) of 2-[2-(4,4-dimethylchroman-6-yl)ethynyl]-5-hydroxymethylpyridine in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 minutes. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CSc1ncc2ncnc(O)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1
Temperature: 100 °C

Procedure:
148 g of 4-hydroxy-6-methylthiopyrimido[5,4-d]pyrimidine, 286 ml of hexamethyldisilazane, 333 g of 3-chloro-4-fluoroaniline and 15 g of p-toluenesulphonic acid are heated at 140° C. for 23 hours. The reaction mixture is cooled and, after addition of 4 l of methanol, heated at 100° C. for one hour. The methanol is distilled off and the residue is triturated three times with diethyl ether and filtered off with suction.
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[Br:15]Br.Br.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:15][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:10][CH:9]=1
Reactant: CCCCC(CC)Cc1ccccc1
Reactant: BrBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC(CC)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
The procedure was adapted from Weinshenker, N. M. et al., J. Org. Chem. 1975, 40, 1966. A 100-mL round bottom flask was charged with (2-ethylhexyl)-benzene (12 g, 0.063 mol), carbon tetrachloride (20 mL), and anhydrous ferric chloride (0.10 g). A 3.9 mL solution of bromine (0.076 mol) in 10 mL of carbon tetrachloride was added. The resultant mixture was exothermic and proceeded with evolution of hydrogen bromide gas (and some bromine gas) that was neutralized with sodium hydroxide. The reaction was completed as the evolution of hydrogen bromide was finished. The solution was stirred at ambient temperature for an additional hour. After addition of aqueous sodium hydroxide (10%), the mixture was extracted with diethyl ether (3×100 mL). The combined organic layer was washed with aqueous sodium hydroxide (10%) until no yellow/brown color in the aqueous phase was observed. The organic phase was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was distilled under vacuum to yield 13.8 g (81%) of colorless oil.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[C:8]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:7]=1)(=[O:4])=[O:3].[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C([O-])(=O)C.[Na+]>ClCCl>[CH3:27][S:24]([O:23][C:8]1[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:10][C:9]=1[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[C:32]2[S:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)c(OS(C)(=O)=O)c1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c(OS(C)(=O)=O)c1
Temperature: 175 °C
Reaction time: 0.33 h
Yield: 69.2 %

Procedure:
0.887 g (2.14 mmole) 4-[2-(4-formylphenoxy)ethyl]-3-(methylsulfonyloxy)phenyl methanesulfonate was dissolved in 8 ml dichloromethane. 0.314 g (2.68 mmole) 2,4-thiazolidinedione and 0.439 g (5.35 mmole) sodium acetate were added and everything was mixed together. The solvent was evaporated in vacuo and the mixture was heated under vacuum to 175° C. and kept at this temperature for 20 minutes (the mixture melted at ca. 100° C.). After cooling the reaction mixture was stirred in water and acetone. Acetic acid was added and the precipitate was collected by filtration, washed with acetone/water, pure water and dried to give 0.76 g (yield 69%) of 5-(4-[2-(2,4-dimethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [OH:1][C:2]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:3]=1[C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].Cl[C:25]1C(Cl)=C(O)[C:28](=C[CH:33]=1)[C:29](O)=[O:30].C(OCC(OC1C(Cl)=CC(Cl)=CC=1C(O)=O)=O)(=O)C.[C:55]([O:58][CH2:59][C:60]([O:62][C:63]1[C:71]([Cl:72])=[CH:70][C:69]([Cl:73])=[CH:68][C:64]=1[C:65]([Cl:67])=[O:66])=[O:61])(=[O:57])[CH3:56]>>[C:55]([O:58][CH2:59][C:60]([O:62][C:63]1[C:71]([Cl:72])=[CH:70][C:69]([Cl:73])=[CH:68][C:64]=1[C:65]([Cl:67])=[O:66])=[O:61])(=[O:57])[CH3:56].[CH2:25]([O:17][C:15](=[O:16])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:6])[CH3:33].[C:29]([O:1][C:2]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:3]=1[C:4]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])(=[O:30])[CH3:28]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc(Cl)cc(Cl)c1O
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1O
Agent: CC(=O)OCC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)Cl
Agent: CC(=O)OCC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)O
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CCOC(=O)[C@@H](N)Cc1ccccc1

Procedure:
The invention also provides a method for synthesizing N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine, comprising: converting 3-5 dichlorosalicylic acid into 2-acetoxyacetoxy-3,5-dichlorobenzoic acid; converting 2-acetoxyacetoxy-3,5-dichlorobenzoic acid into 2-acetoxyacetoxy-3,5-dichlorobenzoic acid chloride; reacting 2-acetoxyacetoxy-3,5-dichlorobenzoic acid chloride with L-phenylalanine ethyl ester to form N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine; and converting N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine into N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine. In some embodiments, the converting comprises hydrolyzing of ester functions in N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COC(=O)c1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cc1
Yield: 76 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.66 g) and methyl 4-(bromomethyl)benzoate (0.31 g) as starting materials, methyl 4-[(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate (0.61 g) was obtained.
Reaction SMILES: [CH2:1]([Br:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br-:19].[C:33]1([P+:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 1 h

Procedure:
Triphenyl-n-octadecylphosphonium bromide is prepared by refluxing n-octadecyl bromide (1000 grams) and triphenyl phosphine (787 grams) in about 1400 ml. of toluene for 16 hours at about 110° C. The product is precipitated from the cooled solution by the addition of about 500 ml. of ethyl acetate and the crystals filtered from solution. These crystals, 1550 grams, are added to 890 grams of sodium 3,5-dicarbomethoxybenzenesulfonate in 3000 ml. of water which is heated to 80°-85° C. and stirred for 1 hour. The oil layer is washed twice with about 2000 ml. of room-temperature water, then dried at 50° C. under nitrogen for 16 hours at a pressure less than 100 torr. The product, triphenyl-n-octadecylphosphonium 3,5-dicarbomethoxybenzenesulfonate, solidifies on cooling.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=1>C(O)(C)C>[BrH:15].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([I:9])=[CH:11][CH:12]=2)[N:5]=1)[CH3:8]
Reactant: CCc1nnc(N)s1
Reactant: BrCc1ccc(I)cc1
Solvent: CC(C)O
Product: Br
Product: CCc1nn(Cc2ccc(I)cc2)c(=N)s1
Yield: 62.5 %

Procedure:
To isopropyl alcohol (10 ml) was added 2-amino-5-ethyl-1,3,4-thiadiazole (645 mg) and 4-iodobenzyl bromide (1.49 g), followed by heating under reflux for 2 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration and dried, whereby 1.33 g of the title compound was obtained.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7](I)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCC1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nn2C1CCC1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg, 0.190 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (64.4 mg, 0.194 mmol), Na2CO3 (50.5 mg, 0.476 mmol), and Pd(PPh3)4 (13.7 mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixture was heated under nitrogen to 80° C. (bath temp.) for 17 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated and chromatographed on an SCX column (1 g/6 mL barrel). The amine-containing fraction was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-11)→1% MeOH in CH2Cl2 (12-28)→2% MeOH in CH2Cl2 (29-46)], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (mc, 2H), 2.86-2.98 (mc, 2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H), 7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.49-8.52 (m, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.99 (−), 29.91 (2C, −), 50.61 (+), 98.68 (Cquart), 119.59 (+), 126.53 (+), 126.97 (Cquart), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +), 129.00 (+), 129.53 (+), 134.83 (Cquart), 136.53 (+), 139.14 (Cquart), 143.40 (Cquart), 148.22 (Cquart), 154.00 (Cquart), 155.53 (+), 157.92 (Cquart), 158.18 (Cquart). MS (ES+): m/z 393.1 (53) [MH+]. HPLC: tR=3.1 min (OpenLynx, nonpolar—5 min), 3.6 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=3[C:9]([NH2:21])=[N:8][C:7]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:10]=3[C:9]([N:21]3[CH2:31][CH2:30][NH:29][CH:28]([CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH2:33]3)=[N:8][C:7]=2[CH:22]=1
Reactant: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Reactant: COCCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCCC1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 57.1 %

Procedure:
Combine 8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride (0.201 g, 0.606 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.192 g, 1.21 mmol), and diisopropylethyl amine (0.106 mL, 0.606 mmol) in a mixture of toluene (3 mL) and dimethylsulfoxide (1 mL) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 7% 2N ammonia-methanol in dichloromethane gives 8-fluoro-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine (0.151 g, 0.346 mmol, 57%) as a yellow oil. Mass spectrum (APCI): m/z=437.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:36])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(O)(=O)C>O>[C:2]([OH:7])(=[O:3])[CH3:1].[OH:36][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Yield: 216.6 %

Procedure:
3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (0.283 g) was stirred with acetic acid (8 ml) and water (4 ml) at 700 for 35 min before evaporating to dryness. The residue was re-evaporated twice with toluene to give the title compound (0.318 g) LCMS RT=2.34 min, ES+ve 495 (MH)+.