Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[CH:1]1([NH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]4)=[CH:23][CH:24]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: O=C(NC1CCCC1)c1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)NC4CCCC4)cc3)cc2)CC1
Yield: 15.1 %

Procedure:
The title compound (14 mg, 12%) was prepared from {4-[(cyclopentylamino)carbonyl]phenyl}boronic acid (47 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3 and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 2H, J=8.4 Hz), 7.59 (d, 2H, J=8.4 Hz), 7.53 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.04 (d, 1 H, J=7.4 Hz), 4.97-4.86 (m, 1H), 4.48-4.37 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 2.83-2.73 (m, 2H), 2.17-2.06 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.78-1.62 (m, 4H), 1.55-1.45 (m, 2H), 1.35-1.26 (m, 2H), 1.24 (d, 6H, J=6.2 Hz); LRMS (ESI), m/z 465 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([OH:16])=O)[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([NH:58][C:59](=[O:76])[C:60]2[CH:65]=[CH:64][C:63]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[C:62]([C:72]([F:75])([F:74])[F:73])[CH:61]=2)[CH:54]=[CH:55][C:56]=1[CH3:57]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:50][C:51]4[CH:52]=[C:53]([NH:58][C:59](=[O:76])[C:60]5[CH:65]=[CH:64][C:63]([N:66]6[CH2:71][CH2:70][O:69][CH2:68][CH2:67]6)=[C:62]([C:72]([F:75])([F:74])[F:73])[CH:61]=5)[CH:54]=[CH:55][C:56]=4[CH3:57])=[O:16])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxylic acid (23 mg, 0.10 mmol) was dissolved in dimethylformamide 1.0 mL, HATU (76 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.081 mL, 0.47 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. N-(3-amino-4-methylphenyl)-4-morpholino-3-(trifluoromethyl)benzoamide (25 mg, 0.066 mmol) was added to the reaction mixture and subjected to a reaction at 45° C. for 17 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (5 mL) and washed with an aqueous sodium hydrogen carbonate solution (5 mL). The organic layer was washed with brine (5 mL×3), dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated reactant was crystallized using ethyl acetate (1 mL) and n-hexane (10 mL) to obtain the title compound as a bright brown solid (34 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH2:23][CH:24]=[C:25]([CH3:31])[CH2:26][CH2:27][C:28]([O-:30])=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11].[CH3:40]N1CCCC1=O.[CH3:47][O:48][C:49]1[CH:70]=[CH:69][C:52]([CH2:53][O:54][CH2:55][Sn](CCCC)(CCCC)CCCC)=[CH:51][CH:50]=1.[F-].[K+]>C(OCC)(=O)C.O>[CH3:47][O:48][C:49]1[CH:70]=[CH:69][C:52]([CH2:53][O:54][CH2:55][C:3]2[C:2]([CH3:1])=[C:10]3[C:6]([C:7](=[O:11])[O:8][CH2:9]3)=[C:5]([O:12][S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[C:4]=2[CH2:23]/[CH:24]=[C:25](\[CH3:31])/[CH2:26][CH2:27][C:28]([O:30][CH3:40])=[O:29])=[CH:51][CH:50]=1
Reactant: CC(=CCc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)[O-]
Reactant: CN1CCCC1=O
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1ccc(OC)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(C)=C/Cc1c(COCc2ccc(OC)cc2)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethanesulfonyloxy-isobenzofuran-5-yl)-4-methyl-4-hexenoate (8.0 g) and N-methylpyrrolidinone (70 ml) is heated to 55° C. p-Methoxybenzyloxymethyltributyltin (7.5 g) is added. After 3 hours the solution is added to water (200 ml), potassium fluoride (5 g) and ethyl acetate (200 ml). The organic solution is dried, filtered through celite and evaporated, and the residue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6-(1,3-dihydro-6-(4-methoxybenzyloxymethyl)-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:24]=O>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[NH:1][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:21]([Cl:20])[CH:22]=2)=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2[nH]1
Product: Clc1ccc(Cn2c(NCc3ccc(Cl)c(Cl)c3)nc3ccccc32)cc1

Procedure:
The title compound was prepared by Procedure C in two steps from 2-aminobenzimidazole, 4-chlorobenzyl chloride and, subsequently, 3,4-dichlorobenzaldehyde. The product was isolated by preparative LCMS to give the title compound as the free base (yellowish oil). Alternatively, the title compound can be prepared in two steps from 2-chlorobenzimidazole, 4-chlorobenzyl chloride and 3,4-dichlorobenzylamine by use of either Procedure B or by Procedure D. MS(ES+) m/z 416 (M+, 100). 1NMR (CDCl3) δ 4.70 (s, 2H), 5.23 (s, 2H), 7.08-7.33 (m, 11H), 7.46-7.50 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH2:11])([CH3:3])[CH3:2].[Br:12]Br>C(O)(=O)C.C(Cl)Cl>[Br:12][C:8]1[CH:7]=[C:6]([CH3:10])[C:5]([NH2:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: BrBr
Reactant: Cc1cccc(C(C)C)c1N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Isopropyl-6-methyl-phenylamine (5 g, 33.5 mmol) was dissolved in acetic acid (20 mL). To this solution was added a solution of bromine (1.8 mL, 35.14 mmol) in acetic acid (5 mL) dropwise over 10 min. After stirring for 1 h at room temperature, the reaction mixture was diluted with methylene chloride, washed with water (2×), saturated sodium thiosulfate (2×), saturated sodium bicarbonate (2×), and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel afforded 7.6 g (quantitative) of the desired product. LC/MS: tR=1.37 min, 230.07 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CC(O)=O>[NH2:1][C:2]1[C:10]([Br:12])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(Br)cc(Cl)cc1C(=O)O
Temperature: 15 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
To a solution of 200 g (1.05 mol) of 2-amino-5-chlorobenzoic acid in 3.4 L of HOAc at 15° C. was added dropwise 184 g (1.15 mol) of Br2. The mixture was stirred at 15° C. for 4 hrs, quenched slowly into 8 L of water, and extracted with 2×2 L of t-BuOMe. The combined extract was washed with water, dried over MgSO4 and concentrated. The crude product was treated with hot hexane, filtered and dried to give 210 g (80%) of 2-amino-3-bromo-5-chlorobenzoic acid as white solid. Mp. 225-2280° C. 1H NMR (DMSO-d6): δ7.70 (d, J=2.6 Hz, 1 H), 7.69 (d, J=2.6 Hz, 1 H), 6.8 (bs, 2 H). 13C NMR (DMSO-d6): δ168.16, 147.06, 136.25, 130.19, 118.22, 112.35,110.34. IR:3480 (m), 3350 (m), 2920 (s), 1670 (s) cm-1. Analysis calcd. for C7H5BrClNO2 : C, 33.53, H, 2.00, N, 5.59; Found: C, 33.63, H, 2.12, N, 5.70. ##STR22##
Reaction SMILES: [C:1]1([C:7](=[O:18])[C:8](=[C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C(O)(=O)C>C(O)C>[NH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:18]
Reactant: CC(=O)C(C(=O)c1ccccc1)=C1CCCCN1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(C=C1CCCCN1)c1ccccc1

Procedure:
12.15 g (0.05 mole) of 1-phenyl-2-(2-piperidinylidene)-1,3-butanedione are introduced into a prepared solution of 3.5 g of sodium in 120 ml of ethanol. The reaction mixture is then refluxed for 40 minutes. After cooling, it is neutralised with glacial acetic acid, and filtered off from the sodium acetate. The filtrate is concentrated in the rotary evaporator, and the residue is dissolved in methylene chloride. The solution is repeatedly extracted with water; the organic phase is dried over sodium sulphate, and the solvent is evaporated off in the rotary evaporator. The oily residue is crystallised from ether/hexane to yield 2-(2-piperidinylidene)-acetophenone, m.p. 59°-60°.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:15]3[CH:14]=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:29]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][O:31][C:29]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[N:13]=[CH:14][C:15]=23)[CH2:23][CH2:24]1)=[O:30]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CC(C)(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)COC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.17 mmol, 70 mg), neopentyl chloroformate (0.25 mmol, 37 μL) and triethylamine (0.51 mmol, 72 μL) were dissolved in DMF (2 mL) and stirred for 60 minutes at room temperature. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water. The product was extracted with ethyl acetate. Removal of organic solvents in vacuo and purification by HPLC provided Compound A124 as a white solid (28 mg, 27%). Exact mass calculated for C23H29N5O5S 487.57, found 488.20 (MH+).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.[C:14](=[O:17])([O-])[O-].[K+].[K+].C[N:21]([CH3:24])C=O>O>[O:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([O:17][CH2:14][CH2:3][CH2:7][CH2:8][CH2:9][C:24]#[N:21])=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 6-boromhexanenitrile, 12 parts of 4-(2-oxazolyl)phenol monohydrochloride, 16.6 parts of potassium carbonate and 282 parts of N,N-dimethylformamide was stirred overnight at 60° C. After cooling, the reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (20.6%) of 6-[4-(4,5-dihydro-2-oxazolyl) phenoxy]hexanenitrile (int. 107).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[CH2:27][O:26]2)[CH:22]=[CH:23][CH:24]=1>C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[CH2:27][C@@H:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=1)[OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: Brc1ccc(CCNCc2ccccc2)cc1
Solvent: CCO
Product: O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of N-benzyl-2-(4-bromophenyl)ethanamine (13.5 g) in ethanol (270 ml) was added (2R)-2-(3-chlorophenyl)oxirane (8.63 g) and the solution was refluxed for 48 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent:hexane/ethyl acetate=9/1) to give (1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.6 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.O>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:1]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=[CH:3]2)#[N:11]
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cccc(C#N)c21
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 1H-indole-7-carbonitrile (2.0 g, 14.08 mmol, 1.0 equiv.) in dry DMF (10 ml) was added at 0° C. to a suspension of NaH (0.845 g, 21.12 mmol, 1.5 equiv. 60% in mineral oil) in DMF (10 ml), and the mixture was stirred for 30 min. Ethyl bromoacetate (1.9 ml, 16.9 mmol, 1.2 equiv.) was added at 0° C., and stirring was carried out for 1 h at RT. When the reaction was complete (TLC monitoring), the mixture was cooled and diluted with water (60 ml). Extraction with ethyl acetate (3×80 ml) was carried out, and the combined organic phases were washed with sat. NaCl solution (2×100 ml), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, 8-10% ethyl acetate/hexane) and the desired product was isolated in the form of a yellow solid. Yield: 80% (2.6 g, 11.37 mmol)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[F:34]>ClCCl>[ClH:24].[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([F:34])[CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@@H:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)nc2)C1)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@@H](c2ccc(C(F)(F)F)nc2)C1)C(F)(F)F
Temperature: 50 °C

Procedure:
In a 25 mL round-bottom flask, (2S)-1,1,1-trifluoro-3-(2-(6-(trifluoromethyl)pyridin-3-yl)morpholino)propan-2-ol (384 mg, 1.12 mmol) was combined with dichloromethane (12 ml) to give a colorless solution. TEA (113 mg, 155 μl, 1.12 mmol) was added. 1-chloro-2-fluoro-4-isocyanatobenzene (211 mg, 1.23 mmol) was added. The reaction mixture was warmed at 50° C. overnight. Reaction was complete by LCMS. Two major close-running spots of similar intensity could be seen by TLC (silica 25% EtOAc in hexanes eluent), a front-running spot and a later-running spot. The crude material was purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes). Mixed fractions were purified by flash chromatography (silica gel, 80 g, 5% to 20% EtOAc in hexanes). Fractions from both columns that contained pure later-running product were concentrated, dissolved in ether and treated with 1M HCl in ether to form the HCl salt. The resultant salt formed a gummy solid, which was scraped on the sides of the flask to form an off-white solid. This solid was filtered and washed with ether. A portion of the product was lost during the transfer. The resultant solid was placed on the pump to afford (4-chloro-3-fluorophenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(S)-2-(6-trifluoromethyl-pyridin-3-yl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride (60 mg) as an off-white solid. (M+H)+=516 m/e.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:29])[O:22][N:21]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[C:20]([CH3:19])=[N:21][O:22][C:23]=2[CH3:29])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 3,5-dimethylisoxazole-4-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenyl amino)phenyl)-3,5-dimethylisoxazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.2 (s, 3H), 2.4 (s, 3H), 5.8 (s, 1H), 6.0 (dt, 1H), 5.95 (s, 1H), 6.9 (s, 1H), 7.0 (q, 1H), 7.2 (m, 3H), 7.4 (dd, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=2)=[C:16]([CH:20]=1)[C:17]([O:19][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:18]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(C#N)c2)c1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
3-Cyanobenzylbromide (542 mg, 2.76 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 ml) over 1 min. The reaction mixture was then stirred at 56° C. for 24 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (100 ml) and evaporated in vacuo to yield the title compound as an off white solid. 411 mg.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:6]=2[CH:5]=1)(=O)[CH3:2].[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C.C(O)(=O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([C:1]3[NH:20][C:14]4[C:19]([CH:2]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:5][C:6]=2[CH:12]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1cc2cc(Br)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccc2oc(-c3cc4ccccc4[nH]3)cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 2-acetyl-5-bromobenzo[b]furan (commercially available, 5.0 g, 1 eq.) is initially charged in absolute ethanol. Phenylhydrazine (97%; 2.33 g, 1 eq.) is introduced. 20 drops of glacial acetic acid are added to this mixture and the reaction is stirred at room temperature for 24 h. Then phenylhydrazine (97%; 0.36 g, 0.15 eq.) is added and the mixture is stirred at room temperature for a further 5 h. The solids are filtered off and washed with distilled water. Dried under reduced pressure at 65° C. This gives 6.65 g of intermediate. This is introduced gradually into polyphosphoric acid (60 g), and the mixture is heated to 120° C. and stirred for a further 1 h. 0.5 l of distilled water is cautiously added dropwise to the reaction and the mixture is stirred for a further 2 h. The suspension obtained is neutralized with 50% sodium hydroxide solution. The suspension is filtered with suction and the solids are washed with distilled water. The solids obtained are dried under reduced pressure. This gives 6.07 g of slightly contaminated product (crude yield 93%). This is used in the next stage without purification.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[CH2:19]([O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])=[N:26][CH:27]=1)[CH3:20].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:21][C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:31])=[N:24][CH:23]=1)[CH3:20]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: CCOc1cnc(-c2ccccc2C(=O)O)nc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 116 mg, 0.41 mmol), 2-(5-ethoxypyrimidin-2-yl)benzoic acid (Intermediate 47; 100 mg, 0.41 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (84 mg, 0.61 mmol), EDC (118 mg, 0.61 mmol) and triethylamine (0.171 ml, 1.23 mmol) in dry DCM (4 ml) was stirred at room temperature for 4 hours. The reaction was partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) and then by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[N:24]([C:2]2[N:11]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:23]=1
Reactant: Cc1ccccc1N
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3ccccc3C)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, o-toluidine and 3,5-dimethylpyrazole. Mp. 240.1-244.4° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]2[N:8]=1>CN(C)C=O>[CH2:3]([S:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]2[N:8]=1)[CH3:4]
Reactant: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1nn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
50% Sodium hydride in mineral oil (1 g) is suspended in anhydrous dimethylformamide (50 ml) and stirred for 10 minutes. Then a solution of ethanethiol (1.5 ml) in anhydrous dimethylformamide (10 ml) is slowly added thereto and the resulting mixture is stirred at room temperature for 30 minutes. Finally 6-chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (5.9 g) is added and the reaction mixture is heated at 50° C. for five hours. The solvent is evaporated off under vacuum and the obtained residue is washed a few times with water and then is crystallized from isopropanol yielding 4.7 g of the compound of the title. M.p. 190°-91° C.