Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([OH:13])(=O)=[O:11])[C:4]=2[N:3]=[N:2]1.[Cl:14]S(O)(=O)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([Cl:14])(=[O:13])=[O:11])[C:4]=2[N:3]=[N:2]1
Reactant: O=S(=O)(O)Cl
Reactant: O=S(=O)(O)c1cccc2[nH]nnc12
Product: O=S(=O)(Cl)c1cccc2[nH]nnc12

Procedure:
Benzotriazole-4-sulphonic acid (5 g, 23 mM) was added, in portions, to chlorosulphonic acid (50 ml), whilst keeping the temperature of the acid below 0°. The resulting solution was heated at 120° overnight, cooled and carefully poured onto ice (1000 g). The solid which formed was collected by filtration, washed well with water and dried in vacuo. This material was dissolved in boiling ethyl acetate and decolorized using a small quantity of charcoal. The product crystallized from the ethyl acetate solution after petroleum ether (40° to 60°) was added, as a white solid (3.94 g, 72 percent), m.p. 173° to 175° (uncorr).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][N:4]1[C:13]2[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([S:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH2:17][CH:2]([OH:1])[CH2:3][N:4]3[C:13]4[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=4[N:6]=[CH:5]3)[CH2:30][CH2:29]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cn1c(=O)c2c(ncn2CC2CO2)n(C)c1=O
Reactant: c1ccc(SCCCN2CCNCC2)cc1
Solvent: CCO
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCSc3ccccc3)CC2)n(C)c1=O

Procedure:
A solution of ethanol (2 liters) containing 7-(2,3-epoxypropyl)-theophylline (1 mole) and 1-(3-phenylthiopropyl)-piperazine (1 mole) is refluxed for 5 hours. The ethanol is partly removed. The reaction medium crystallizes. The resulting crystals are suction filtered and may be recrystallized from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNCC(=O)OCc1ccccc1
Yield: 66.8 %

Procedure:
A solution of 1.4 g (8.74 mmole) of N-(t-butoxycarbonyl)ethylenediamine (prepared in Example 2, Step A above), 1.35 mL (8.74 mmole) of benzyl 2-bromoacetate, and 1.53 mL (8.74 mmole) of DIEA in 18 mL of acetonitrile was stirred for 18 hr at room temperature. The mixture was then concentrated in vacuo and the residue purified by flash chromatography on 130 g of silica eluting with 2 L of 75:25 hexanes: ethyl acetate then 1 L of 100:4 methylene chloride:methanol to give 1.8 g (67%) of an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]([OH:14])[CH2:9][NH:10][CH:11]([CH3:13])[CH3:12].[O:15]=[C:16](O)[C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18]>O>[O:15]=[C:16]([O:14][CH:8]([C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH3:1])[CH2:9][NH:10][CH:11]([CH3:12])[CH3:13])[C@@H:17]([C@H:19]([C@@H:21]([C@@H:23]([CH2:25][OH:26])[OH:24])[OH:22])[OH:20])[OH:18]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1csc(C(O)CNC(C)C)c1C
Solvent: O
Product: Cc1csc(C(CNC(C)C)OC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c1C

Procedure:
To 1.20 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol in 40 ml of water, 1.96 ml of a 50% gluconic acid solution are added. The mixture is heated in water-bath during 1 hour at 70°, then the solution is lyophilised (2.18 g of the salt obtained are soluble in 5 ml of water and give a pH of 4.6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]([OH:40])[CH2:11][CH2:12][C@H:13]1[C@H:17]([OH:18])[CH2:16][C@H:15]([OH:19])[C@@H:14]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C(=O)[C@H](CCCNC(=N)N)N)=[O:27].[Cl-].[NH4+].Cl.[Cl-].[Na+]>CO.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]([OH:40])[CH2:11][CH2:12][C@H:13]1[C@H:17]([OH:18])[CH2:16][C@H:15]([OH:19])[C@@H:14]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: N=C(N)NCCC[C@H](N)C(=O)OC(=O)CCCCCC[C@@H]1[C@@H](CC[C@@H](O)CSc2ccccc2F)[C@H](O)C[C@@H]1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCCCCC[C@@H]1[C@@H](CC[C@@H](O)CSc2ccccc2F)[C@H](O)C[C@@H]1O
Reaction time: 0.25 h

Procedure:
To 1.0 gram of Arginyl 7-((1R,2R,3R,5S)-2-((R)-4-(2-fluorophenylthio)-3-hydroxybutyl)-3,5-dihydroxy cyclopentyl)heptanoate (8) in MeOH/H2O (4:1, 20 mL) is added, dropwise with cooling, at least 5 equivalents of a 3:1 mixture of saturated aqueous ammonium chloride and 1 M hydrochloric acid (Sigma-Aldrich, St. Louis, Mo.), and the solution is stirred for 15 minutes. Saturated aqueous sodium chloride is added along with ethyl acetate. The organic layer is separated; is washed again with brine; the solvents removed in vaccuo, and the material chromatographed to give the free acid, 7-((1R,2R,3R,5S)-2-((R)-4-(2-fluorophenylthio)-3-hydroxybutyl)-3,5-dihydroxy cyclopentyl)heptanoic acid (9).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[C:8]([C:13]([OH:15])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:9]([CH:10]2[CH2:11][CH2:12]2)=[C:8]([C:13]([NH:27][C:28]2[CH:51]=[CH:50][CH:49]=[C:30]([O:31][C:32]3[CH:46]=[CH:45][C:35]4[N:36]=[C:37]([NH:39][C:40]([CH:42]5[CH2:44][CH2:43]5)=[O:41])[S:38][C:34]=4[C:33]=3[C:47]#[N:48])[CH:29]=2)=[O:15])[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: CC(C)(C)n1ncc(C(=O)O)c1C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (71 mg, 0.342 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.420 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (111 mg, 72%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.[CH3:12][CH:13]([CH3:17])[C:14](Cl)=[O:15]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:14](=[O:15])[CH:13]([CH3:17])[CH3:12]
Reactant: COc1cc(F)cc(OC)c1
Reactant: CC(C)C(=O)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(F)cc(OC)c1C(=O)C(C)C
Temperature: 5 °C

Procedure:
Into a 1-liter, three-necked round-bottom flask was placed 20.0 g (0.13 mole) of 1,3-dimethoxy-5-fluorobenzene, 13.6 g (0.0.13 mole) of 2-methylpropanoyl chloride, and 100 ml of nitrobenzene. The mixture was flushed with argon and an equal molar amount of AlCl3 (17.2 g) was added to the reaction mixture while stirring at 5° C. The mixture was stirred at a temperature of 5° C. for about 1 hour after the addition of the AlCl3. The reaction mixture was then mixed with about 100 ml of distilled water and extracted with dichloromethane. The organic layer was washed with NaHCO3 solution, salt water, and then dried. The solvent was removed by vacuum to yield the final product, 1-(2,6-dimethoxy-4-fluorophenyl)-2-methylpropan-1-one. The yield of the reaction was 22.8 g of product (77%).
Reaction SMILES: [Br:1][CH:2]([CH3:10])[CH:3](OCC)OCC.Cl.C([O-])(O)=O.[Na+].[NH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1>CO>[Br:1][C:2]1[CH:3]=[CH:23][C:18]2[N:17]([C:21]([CH3:22])=[CH:20][N:19]=2)[CH:10]=1
Reactant: CCOC(OCC)C(C)Br
Reactant: Nc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc2ccc(Br)cn12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-Bromo-1,1-diethoxypropane (5g) was added to a stirring solution of aq. 1N HCl (15 mL) and heated at 90° C. for 1 h. The clear reaction mixture was cooled to room temperature and treated with solid NaHCO3 till pH 7.0. 2-amino-5-bromopyridine (1.8 G) and MeOH (25 mL) were transferred successively to the above reaction mixture and heated at 90° C. After 8 h, the reaction mixture was concentrated under vacuum by rotary evaporator. The resulting solid concentrate was stirred in CH2Cl2/water (200 mL/75 ml). Organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate was stirred in EtOAc (30 mL) and the solid was collected by filtration to obtain 6-bromo-3-methylimidazo[1,2-a]pyridine as a tan solid (1.6 g). 1H NMR (300 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.50 (d, J=9.5 Hz, 1H), 7.37 (s, 1H), 7.28 (d, J=9.5 Hz, 1H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13](=[O:18])[C:14](=[CH2:17])[CH2:15][CH3:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O>>[O:18]=[C:13]1[C:11]2[C:10](=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[CH:12]=2)[CH2:17][CH:14]1[CH2:15][CH3:16]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CCC1Cc2cc(OCC(=O)O)c(Cl)cc2C1=O

Procedure:
(1-Oxo-2-ethyl-6-chloro-5-indanyloxy)acetic acid is prepared by following substantially the same procedure as described in Example 1, Step A, using the following reagents: [2-chloro-4-(2-methylenebutyryl)phenoxy]acetic acid (41.32 g., 0.154 mole) and conc. sulfuric acid (165 ml.). The crude yield of the product is 38.8 g. (94%), m.p. 132°-138° C. Recrystallization from benzene gives (1-oxo-2-ethyl-6-chloro-5-indanyloxy)acetic as white prisms, m.p. 142°-144° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6].[O-2].[Ca+2].[H][H]>[Pd].COCCO>[OH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1)=[O:6]
Reactant: [H][H]
Reactant: O=C(NCCO)c1cnccn1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: COCCO
Product: O=C(NCCO)C1CNCCN1
Yield: 100 %

Procedure:
A mixture of 53.7 parts of N-(2-hydroxyethyl)-2-pyrazinecarboxamide, 20 parts of calcium oxide and 500 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 55.4 parts (100%) of N-(2-hydroxyethyl)-2-piperazinecarboxamide as a residue (intermediate 23).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[C:17]([CH3:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 617.2 [(M−H)−]; mp 271° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[OH:15].CC(C)([O-])C.[K+].CS(O[C@H:27]1[CH2:30][C@@H:29]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:28]1)(=O)=O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[O:15][C@H:27]1[CH2:28][C@H:29]([CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:30]1
Reactant: COc1cc(CN2CCCC2)ccc1O
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](CN2CCOCC2)C1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCCC2)ccc1O[C@H]1C[C@H](CN2CCOCC2)C1

Procedure:
A solution of intermediate 42, 2-Methoxy-4-(pyrrolidin-1-ylmethyl)phenol (0.66 g, 32 mmol) and potassium tert-butoxide (0.36 g, 32 mmol) in DMSO (10 mL) was heated to 100° C. under vigorous stirring in a flow of argon. The solution was stirred at this temperature for 15 min. Then a solution of intermediate 41, cis-3-(Morpholin-4-ylmethyl)cyclobutyl methanesulfonate (0.4 g, 16 mmol) in DMSO (10 mL) and tetrabutylammonium bromide (0.16 g, 0.48 mmol) were added. The mixture was stirred at 100° C. for 1 h, cooled, diluted with EtOAc (50 mL), washed with water (50 mL), 1 N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel 63-100 μm, 25 mL, CHCl3/hexane 20:80→100:0, CHCl3/MeOH 100:0% 80:20) to give the title compound (400 mg, 69%) as yellow crystals. LC MS-data: M+ 361.2, (calculated for C21H32N2O3 360.50). 1H-NMR (400 MHz, J, Hz)-data (dmso-d6): 6.87 (d, 1H, J=1.8, Ar—H), 6.75 (dd, 1H, J1=8.1, J2=1.8, Ar—H), 6.63 (d, 1H, J=8.1, Ar—H), 4.72 (dddd, 4H, J=6.3, CHOAr), 3.73 (s, 3H, ArOCH3), 3.53-3.57 (m, 4H), 3.46-3.49 (m, 2H), 2.38-2.52 (m, 7H), 2.31-2.36 (m, 4H), 2.10-2.20 (m, 4H), 1.64-1.74 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccsc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), thiophen-3-ylboronic acid (64 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 40-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (6.4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 6.61 (d, 1 H) 7.63 (d, J=8.34 Hz, 2 H) 7.84 (dd, J=5.18, 2.91 Hz, 1 H) 7.93 (dd, J=5.18, 1.14 Hz, 1 H) 8.04 (d, J=8.34 Hz, 2 H) 8.23-8.40 (m, 2 H) 9.12 (dd, J=3.03, 1.26 Hz, 1 H) 11.24 (s, 1 H). ESI-MS: m/z 379.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:18])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 120 °C
Yield: 77.5 %

Procedure:
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol), 4-fluorobenzotrifluoride (73 μL, 0.58 mmol) and potassium carbonate (80 mg, 0.58 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (87 mg, 78%) as an off white solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:26][C:27]1[CH:31]=[CH:30][O:29][CH:28]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 1.14 g (3.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 30 ml of anhydrous DMF and, at room temperature, carefully added to a suspension containing 0.24 g (6.05 mmol) of 60% sodium hydride. This mixture was stirred for 30 minutes and 8.2 ml (4.92 mmol) of a freshly prepared 0.6 M solution of 3-bromomethylfuran in ethyl ether were dropwise added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude mixture was extracted between ethyl acetate and water. The organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel affording 1.4 g (97% of yield) of the expected product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]1[N:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:23])[CH2:15][CH2:14][CH:13]1[C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=1[F:32].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:51]=[N+:52]=[N-:53])(=O)=O)(C)C.CC(O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[N:51]([CH:15]1[CH2:14][CH:13]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[C:25]=2[F:32])[CH:12]([CH3:11])[N:17]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:16]1=[O:23])=[N+:52]=[N-:53]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CC1C(c2cc(F)cc(F)c2F)CCC(=O)N1CC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1C(c2cc(F)cc(F)c2F)CC(N=[N+]=[N-])C(=O)N1CC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 36 mL, 36 mmol) in THF (180 mL) at −78° C. was added a cold (−78° C.) solution of (5S,6R & 5R,6S)-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-2-one (9.68 g, 29.8 mmol) in THF (100+20 mL) dropwise, keeping the internal temperature of the reaction mixture below −65° C. The resulting mixture was stirred at −78° C. for 30 min, then a cold (−78° C.) solution of 2,4,6-triisopropylbenzenesulfonyl azide (Harmon et al. (1973) J. Org. Chem. 38, 11-16) (11.97 g, 38.7 mmol) in THF (100 mL) was added dropwise, keeping the internal temperature of the reaction mixture below −65° C. The reaction mixture was stirred at −78° C. for 45 min, then AcOH (7.8 mL, 140 mmol) was added. The resulting mixture was allowed to warm slowly to ambient temperature and was poured into saturated aqueous sodium bicarbonate (750 mL) and the mixture was extracted with CH2Cl2 (2×750 mL). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:Et2O—100:0 to 0:100, to give the title compound. MS: m/z=367.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]>CCO.[Pd]>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:19]
Reactant: CCN(CC)CCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCn1ccc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Diethyl-[2-(5-nitroindol-1-yl)ethyl]amine (1.6 g, 6.1 mmol) was dissolved in absolute EtOH (100 mL) and syringed into a flask containing 10% Pd over carbon (160 mg) under an argon atmosphere. The reaction mixture was placed under H2 atmosphere (1 Atm pressure) and stirred at RT for 3 h. The reaction was filtered over a Celite pad and washed well with EtOH. Evaporation of the volatile solvent gave the title compound (1.4 g, 99%) as a brown solid. TLC (10% MeOH/DCM), Rf=0.20; LC MS m/z 232.3 (MH+).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Thiosalicylic acid 15.419 g(0.1M) was dissolved in 150 mL of dimethylformamide (DMF) and 41.463 g(0.3M) of K2CO3, was added to the mixture with stirring. To the above solution, 4-methoxybenzyl chloride 15.661 g(0.1M) was added and the mixture was refluxed for 10 hours. The solution then was cooled to room temperature and 150 mL of water was added and the mixture was acidified with 3M HCL. The precipitated material was collected by gravity filtration and washed with acetone to give 27.364 g(99.7%) of white powder with a melting point of 225-227° C. and the following specifications: