Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Mg+2:4].[O-]CC.[C:8](=[O:10])=[O:9].[CH:11]([OH:14])([CH3:13])[CH3:12]>>[CH:11]([O:14][C:8](=[O:9])[O-:10])([CH3:13])[CH3:12].[CH:11]([O:14][Mg+:4])([CH3:13])[CH3:12]
Reactant: O=C=O
Reactant: CC(C)O
Reactant: [Mg+2]
Agent: CC[O-]
Product: CC(C)OC(=O)[O-]
Product: CC(C)O[Mg+]

Procedure:
On Day 1, three kilograms of granulated magnesium ethoxide and carbon dioxide gas are added to two 6.5-gallon flint glass carboys containing 15 liters of ultra-dry isopropanol prepared in Example 2, and reacted as described in Example 4 to form isopropoxy magnesium isopropyl carbonate (PMPC). On completion of the reaction, magnets are inserted in one carboy to provide magnetic filtering, and the concentrates are maintained at 110° F. as described in Example 4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:26][C:27]([F:30])([F:29])[F:28])[CH:19]=3)[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[S-:31][C:32]#[N:33].[K+].[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40]([NH:42][NH2:43])=[O:41]>CO.C(Cl)Cl>[C:7]1([C:13]2[CH:22]=[C:21]([C:23]([NH:33][C:32](=[S:31])[NH:43][NH:42][C:40]([C:36]3[S:35][CH:39]=[CH:38][CH:37]=3)=[O:41])=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:26][C:27]([F:29])([F:28])[F:30])[CH:19]=3)[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12
Reactant: NNC(=O)c1cccs1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NNC(=S)NC(=O)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Oxalyl chloride (129 μL, 1.50 mmol) and methylene chloride (3 mL) were added to a methylene chloride (2 mL) solution of 2-phenyl-6-trifluoromethoxy-4-quinolinecarboxylic acid (100 mg, 0.30 mmol) described in Reference Example 16, and the mixture was stirred at room temperature for 1 hour. After that, oxalyl chloride (129 μL, 1.50 mmol) was added, and the mixture was further stirred for 2 hours. The reaction solution was concentrated, and the residue was dissolved in anhydrous acetonitrile (1 mL). To the solution, potassium thiocyanate (146 mg, 1.50 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, commercially available 2-thiophenecarbohydrazide (64 mg, 0.45 mmol) was added, and the mixture was stirred overnight at room temperature. To the reaction solution, methanol was added, and the mixture was concentrated. To the residue, a saturated aqueous solution of sodium chloride was added, and the deposited crystal was collected by filtration, washed with water, dried, and then purified by silica gel column chromatography to obtain the title compound (71 mg, 0.14 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cccc(Oc2ccccc2)n1
Temperature: 140 °C

Procedure:
A reaction mixture consisting of 1.48 g (10 mmol) of 2,6-dichloropyridine, 6 g (63.75 mmol) of phenol and 2.4 g (60 mmol) of sodium hydroxide in 10 ml of water is heated to 140° C. for 24 hours in a bomb. After cooling the reaction mixture is made strongly alkaline with sodium hydroxide solution and extracted with dichloromethane. The organic phase is separated off and dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=3:1).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][C:7]3([C:19]2=O)[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:18])[C:13]=2[F:17])[CH2:8]3)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[N:29][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:21]=[C:20]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:18])[C:13]=3[F:17])[CH2:8]1)/[C:19]/2=[N:29]/[C:28]#[N:27]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1c2cc(Br)ccc2CC12CCc1c(ccc(F)c1F)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(Br)ccc2CC12CCc1c(ccc(F)c1F)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.4 %

Procedure:
To a solution of 6-bromo-5′,6′-difluoro-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (150 mg, 0.41 mmol) in dried CH2Cl2 (1 mL) was added TiCl4 (1 M solution in DCM, 0.1.24 mmol) dropwise within 15 minutes, and stirred for 1 h. Then to this mixture was added bis-trimethlysilylcarbodiimide (234 mg, 1.24 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (Z)—N-(5-bromo-5′,6′-difluoro-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalene]-3(1H)-ylidene)cyanamide (180 mg, crude), which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:23])(=[O:22])[N:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]=2[CH:28]=1.B([O-])([O-])O[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].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.C1(C)C=CC=CC=1>[CH2:41]([O:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:13]=[CH:14][C:15]([S:18](=[O:23])(=[O:22])[N:19]([CH3:20])[CH3:21])=[CH:16][CH:17]=4)[CH2:10][CH2:9][C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][C:6]=3[CH:28]=2)=[CH:36][CH:35]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccc(S(=O)(=O)N(C)C)cc2)CC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A mixture of methyl 7-bromo-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g), 4-(2-butoxyethoxy)phenyl borate (0.19 g), 1M potassium carbonate solution (2 ml), ethanol (2 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[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:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:22][S:50]([C:47]1[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=1)(=[O:52])=[O:51])[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]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 4 °C

Procedure:
A solution of 1-O-octadecyl-3-O-trityl-glycerol (173.51 g, 295.63 mmol) in 895 mL water-free pyridine is added dropwise to a solution of p-toluenesulfonyl chloride (88.49 g, 464.15 mmol) in 670 mL water-free pyridine with constant stirring. The reaction mixture is kept at ambient temperature (20-23° C.) for two days. Diethyl ether (2.8 L) is added, and the organic phase is washed six times with water, twice with 0.5 N HCl (500 mL each), twice with diluted aqueous sodium carbonate, and then washed with water until neutral. After drying the organic phase over sodium sulfate, the solvent is removed under vacuum. The residue is triturated with isopropanol (1140 mL) with stirring until the product crystallizes. After cooling to 4° C., the product, 1-O-octadecyl-2-O-p-toluenesulfonyl-3-O-trityl-glycerol, is isolated by filtration, washed with isopropanol and dried under vacuum. Yield: 190.14 g (86.91%); m.p. 56-58° C.; Rf value (TLC on silica gel 60) of 0.38 with benzene as the developing solvent; and Rf value of 0.74 with benzene/methanol (50/2).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]=[CH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Sc1ccccc1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1Cl
Solvent: CCO
Product: CC(C)(C)C(=O)CC(Sc1ccccc1)c1ccc(Cl)cc1Cl
Yield: 81.7 %

Procedure:
A mixture of 25.7 g of 2,4-dichlorobenzalpinacolone, Triton-B (4 drops) and 300 ml of ethanol was heated to 50°-60° C. Thiophenol (12.1 g) was added dropwise to the mixture and refluxed for 6 hours. The reaction mixture was concentrated, ice water was added thereto, and extracted with ether. After the removal of the ether by distillation, the oil residue was treated with n-hexane, and the resulted crystals were dried to give 30 g of the captioned compound. m.p. 79°-80° C.
Reaction SMILES: [CH3:1][C:2]([SiH2:5][O:6][CH:7]1[CH2:12][C:11]2([CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[O:10][CH:9]([CH2:18]/[CH:19]=[C:20](\[CH3:26])/[C:21](OCC)=[O:22])[CH2:8]1)([CH3:4])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:4][C:2]([SiH2:5][O:6][CH:7]1[CH2:12][C:11]2([CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[O:10][CH:9]([CH2:18]/[CH:19]=[C:20](\[CH3:26])/[CH:21]=[O:22])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)/C(C)=C/CC1CC(O[SiH2]C(C)(C)C)CC2(CCCCO2)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(C=O)=C\CC1CC(O[SiH2]C(C)(C)C)CC2(CCCCO2)O1

Procedure:
To a solution of ethyl 4-[4-[(1,1-dimethylethyl)silyl]oxy-1,7-dioxaspiro[5.5]undec-2-yl]-2-methyl-2E-butenoate, (10.0 g; 27.0 mmoles) in methylene chloride (160 ml) is added finely powdered pyridinium chlorochromate (PCC; 8.7 g; 40.5 mmoles) in a single portion with stirring under nitrogen at 25°. After twenty minutes the reaction mixture is diluted with ether (800 ml) and filtered through celite. The chromium salt residue is washed several times with ether, the washes filtered through celite, and the combined filtrates reduced in volume to 100 ml, filtered through silica gel and concentrated in vacuo to an oil. Chromatography (7.5% ethyl acetate/hexane yields the title compound, 4-[4-[(1,1-dimethylethyl)silyl]oxy-1,7-dioxaspiro[5.5]undec-2-yl]-2-methyl-2E-butenealdehyde; (5.42 g; 54.5%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[C:22]1([CH:28]([Zn+])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C(C2C=NC(N3CCNCC3)=NC=2)C)C=CC=CC=1.CO.ClCCl>C1COCC1.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>[C:22]1([CH:28]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC([Zn+])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(c1ccccc1)c1cnc(N2CCNCC2)nc1
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccccc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (4.1 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium (708 mg, 1.0 mmol) in THF (80 mL, dry) was added dropwise a solution of (1-phenylethyl)zinc(II) bromide in THF (20 mL, 1 M, 20 mmol) under nitrogen atmosphere, and the mixture was stirred at 70° C. overnight. The reaction mixture was cooled to RT and filtered through a pad of Celite. The filtration was concentrated and purified by silica gel chromatography to give tert-butyl 4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, yield 23%) as a white solid (ethyl acetate/petroleum ether=1/5 as elute) and 5-(1-phenylethyl)-2-(piperazin-1-yl)pyrimidine (2.4 g, 75%) as a yellow oil (methanol/dichloromethane=1/20 as elute). MS (ES+) C16H20N4 requires: 268. found: 269 [M+H]+.
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:21]([CH3:41])[N:22]=[C:23]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)[C:24](=[O:26])[N:25]=2)[C:8]=1[CH3:42])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:18])(=[O:19])[CH:9]([C:20]2[N:21]([CH3:41])[N:22]=[C:23]([OH:27])[C:24](=[O:26])[N:25]=2)[C:8]=1[CH3:42])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nc(=O)c(O)nn3C)S(=O)(=O)[C@H]12
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
179 mg of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(2-methyl-5-oxo-6-benzhydryloxy-2,5-dihydro-1,2,4-triazin-3-yl)thio-3-cephem 1,1-dioxide, prepared following the experimental procedure described in Example 3, was dissolved in dichloromethane (2 ml) and anisole (0.018 ml) and trifluoroacetic acid (1 ml) were added. After 15 min, TFA was completey removed in vacuo and the residue taken up in dichloromethane (1 ml). Addition of isopropyl ether afforded the title compound (125 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].C(N(CC)C(C)C)(C)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](O)=[O:43].C(Cl)CCl>CN(C=O)C>[NH2:8][C:7]1[N:6]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:5]2[N:4]=[C:3]([C:22]2[CH2:23][CH2:24][N:25]([C:42]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)=[O:43])[CH2:26][CH:27]=2)[C:2]=1[Br:1]
Reactant: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C(O)c1cccs1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1c(Br)c(C2=CCN(C(=O)c3cccs3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (0.035 mmol) was charged to a 20 mL scintillation vial. Then DMF (1 ml), N,N-diisopropylethylamine (0.14 mmol, 25 μL), thiophene-2-carboxylic acid (0.039 mmol, 5 mg), and EDC (0.039 mmol, 7.4 mg) were added, respectively. The resulting reaction mixture was stirred at room temperature for 18 hours. Upon completion, the reaction mixture was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield (4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone (m+H=531.06, retention time=3.74 min). Also recovered was the dehalogenated product, (4-(7-amino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)(thiophen-2-yl)methanone (m+H=453.24, retention time=3.51 min).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:7]3[CH2:8][CH:5]([N:4]([CH3:9])[CH3:3])[CH2:6]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 93.7 %

Procedure:
N,N-dimethylazetidin-3-amine (Intermediate 26, 144 mg, 0.83 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 312 mg, 0.75 mmol) and DIPEA (0.460 mL, 2.64 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (347 mg, 93%) as an orange solid after trituration with diethyl ether; 1H NMR: 2.14 (6H, s), 3.09-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.01-4.11 (2H, m), 6.28 (1H, s), 6.98 (1H, t), 7.13-7.20 (1H, m), 7.46 (1H, d), 8.15 (1H, s), 8.23 (1H, d), 8.37 (1H, s), 8.47 (1H, s), 8.49 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 494.16.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[NH:44][C:43](C(N3CCS(=O)(=O)CC3)=O)=[CH:42]4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1C2C(=CC=CC=2)CC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:44]3[C:45]5[C:41](=[CH:40][CH:39]=[CH:47][CH:46]=5)[CH2:42][CH2:43]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCc4ccccc43)cc2c1)N1CCN(C2CCCC2)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), indoline (commercially available) and N,N-diisopropyl-ethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (49%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[C:19]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH3:20].CC1(C)C(C)(C)OB([C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][NH:44]3)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.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>[NH:44]1[C:45]2[C:41](=[C:40]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([C:27]5[CH:28]=[C:23]([NH:22][C:19](=[O:21])[CH3:20])[CH:24]=[CH:25][CH:26]=5)=[C:8]([CH3:12])[C:6]=4[N:7]=3)[CH:48]=[CH:47][CH:46]=2)[CH:42]=[N:43]1
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1cccc(-c2sc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3c2C)c1
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine from Example 12 (0.1 g, 0.3 mmol), 3-Acetamidobenzeneboronic acid (50 mg, 0.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13 μmmol) in 1 M aqueous Na2CO3 (0.5 mL) and acetonitrile (0.5 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (122 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13 μmol), 1 M aqueous Na2CO3 (1 mL), and acetonitrile (1 mL) were added into the same pot. The reaction mixture was heated to 150° C. in a sealed microwave reactor for 20 min. The mixture was extracted with EtOAc and CH2Cl2. The combined organics were concentrated to yield 359 after reverse phase HPLC purification (10 mg). MS (Q1) 485 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N#CC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and piperidine-4-carbonitrile (880 mg, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (100 mL) and dichloromethane (100 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 0-100% ethyl acetate in cyclohexane) to afford the title compound (1.10 g, 99%). 1H NMR (CDCl3, 300 MHz): 7.46-7.41 (m, 2H); 7.21-7.15 (m, 2H); 3.44 (s, 2H); 2.70-2.57 (m, 3H); 2.38-2.22 (m, 2H); 1.99-1.74 (m, 4H). LCMS (Method B): RT=1.82 min, M+H+=280.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([OH:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH2:30]([O:32][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:31]
Reactant: CCO
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with sodium hydride and ethanol in dioxane and DMF. ES-MS m/e (%): 414 (M+H+, 100).