Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:28][C@H:29]([O:38][Si:39]([CH2:44][CH3:45])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20]CC3C=CC=CC=3)=[CH:19][C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[O:31]([CH2:30][C@@H:29]([O:38][Si:39]([CH2:42][CH3:43])([CH2:44][CH3:45])[CH2:40][CH3:41])[CH2:28][NH:8][CH:9]1[CH2:10][C:11]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:12]=2[CH2:13][CH2:14][CH2:15]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C1CCCc2ccc(OCc3ccccc3)cc2C1
Agent: [Pd]
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H](CNC1CCCc2ccc(O)cc2C1)COc1ccccc1
Yield: 95.8 %

Procedure:
A mixture of N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amine (25 g) and 10% palladium on activated carbon (50% wet, 2.5 g) in methanol (250 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5 hours. After filtration, the filtrate was evaporated in vacuo to give 8-[(2S)-3-phenoxy-2-(triethylsilyloxy)propylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (17 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.[F:8][C:9]1[CH:32]=[CH:31][C:12]([CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([OH:29])[C:18](=[O:28])[NH:19][C:20]=3[C:24]([O:26]C)=O)[C:15]2=[O:30])=[CH:11][CH:10]=1.Cl>C1COCC1.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[C:17]([OH:29])[C:18](=[O:28])[NH:19][C:20]=3[C:24]([N:2]([CH3:3])[CH3:1])=[O:26])[C:15]2=[O:30])=[CH:31][CH:32]=1
Reactant: COC(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−10° C.) solution of dimethylamine (2M in THF, 0.002 g, 0.035 mmol) was slowly added trimethylaluminum (2M in toluene, 0.002 g, 0.035 mmol) and stirred for 30 minutes at room temperature. The reaction mixture was cooled to −10° C. and methyl 6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.004 g, 0.012 mmol, Example 1, Step 8) in THF (5 mL) was added. The reaction stirred at room temperature for 2 hours, then transferred via syringe to a solution of 1:1 CH2Cl2:0.5 N aq. HCl at 0° C. and stirred for 1 hour. The product mixture was separated, and the aqueous was extracted three times with CH2Cl2. The aqueous layer was treated with saturated Na2CO3 solution to pH 5 and extracted three times with CH2Cl2 again. The organic combined extracts were dried with Na2SO4 and concentrated under vacuum. The residue was purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:13]Br.CCCCCC>C(Cl)Cl.BrBr>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(Br)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 3′,4′-dichloropropiophenone (81, 5.02 g, 0.247 mol) in CH2Cl2 (100 mL) was added ten drops of bromine. After stirring at room temperature under nitrogen for several min, the characteristic red color of bromine disappeared indicating initiation of the reaction. The remainder of the bromine (1.27 mL, 24.7 mmol) was added dropwise and the reaction solution was allowed to stir at room temperature under nitrogen atmosphere for 1.75 h. Analysis by TLC (silica, 2:1 hexane:CH2Cl2) indicated consumption of starting material. The reaction solution was quenched and brought to a pH of 9 with a saturated aqueous solution of NaHCO3 and concentrated NH4OH. The solution was extracted with CH2Cl2, dried (Na2SO4), filtered, concentrated, and dried to give 7.14 g (100%) of 2-bromo-(3′,4′-dichlorophenyl)propan-1-one as a white solid. Characterization data is similar with data reported in Anderson, W. K.; Jones, A. N., J. Med. Chem. 1984, 27, (12), 1559-1565.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:40][CH2:41][CH2:42][CH2:43][NH:44]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CSc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)c2c(=O)[nH]ccc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)c2c(=O)[nH]ccc2n1

Procedure:
The compound was prepared from N-(3-{[2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl]amino}phenyl)-1-pyrrolidinecarboxamide using mCPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA sequences similar to that described for Example 1 (Scheme 2).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH:42]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH2:31][CH2:32]1
Reactant: CN(C(=O)CN1CCOCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-morpholinomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a 250 mL 3 neck flask equipped with mechanical stirring, condenser, and heating apparatus consisting of a RTD probe hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 ML isopropyl acetate. The mixture was heated slowly to 80° C. After 5 hours, high performance liquid chromatography showed reaction to be 90% complete. After being left overnight at 80° C., reaction was complete. The mixture was then cooled to ambient temperature, after which 60 mL deionized water was added. The mixture was stirred until all solids dissolved. The aqueous layer was separated and discarded.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(CC2CCCN2)cc1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2Cc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-benzylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.79 minutes; C28H26C12N4O2 (521.45); mass spectrum: (M−H)−=520/522/524 (chlorine isotope).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[F:18][C:19]([F:25])([F:24])[CH2:20][CH2:21][CH2:22][NH2:23].C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([NH:23][CH2:22][CH2:21][CH2:20][C:19]([F:25])([F:24])[F:18])=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: NCCCC(F)(F)F
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(ncn2CC(=O)NCCCC(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 mmol from theophylline-7-acetic acid (238 mg) and 4,4,4-trifluorobutan-1-amine (127 mg) was dissolved in 3 ml of DMSO. An equimolar amount of N,N′-dicyclohexylcarbodiimide (206 mg) was added and the solution was stirred for 48 h at ambient temperature. The solvent was filtered and concentrated under high vacuum. The oily residue, dissolved in minimal amount of ethyl acetate was subjected to flash chromatography. The following eluents were used: ethyl acetate:petroleum ether (2:1), ethyl acetate and ethyl acetate:methanol (9:1). The fractions containing the new spot (Rf=0.07, TLC, ethyl acetate) were collected and evaporated. The white powder was recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:24]([CH2:23][Cl:22])(=[O:26])=[O:25])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCl
Reactant: Clc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(CCl)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 2.6 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in dichloromethane with stirring, and to the solution was added 2.1 g. of potassium carbonate and 2.25 g. of chloromethanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and was then worked up as described in Example 3 to obtain 0.6 g. of the desired product, m.p. 98°-100°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A8) (3.34 g, 10.3 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (2.93 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (67 mg, 0.1 mmol) was treated as described in general procedure R using excess 1-methylpiperazine (100 mg, 1 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4′-(4-methyl-piperazin-1-yl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
A mixture of 0.4 g (1.23 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) and 6 ml of butylamine was heated under reflux for 3.0 hours, whilst stirring. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel (using ethyl acetate as the eluent) to afford 0.48 g of the title compound as a white powder.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:20]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[C:25](OC)[C:24]=1[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])([CH3:22])[CH3:21]>O1CCCC1.C1C=CC=CC=1>[CH:20]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[C:25]([C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:24]=1[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])([CH3:21])[CH3:22]
Reactant: Fc1ccc(Br)c(OCc2ccccc2)c1
Reactant: COc1c(C(=O)OC(C)C)c(C(C)C)cc(C(C)C)c1C(=O)OC(C)C
Agent: II
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1c(C(C)C)cc(C(C)C)c(C(=O)OC(C)C)c1-c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A dry flask containing freshly ground magnesium turnings (2.88 g, 120 mmol) and a crystal of iodine was heated until a dark purple iodine atmosphere had formed. The flask was cooled to ambient temperature and a solution of 2-bromo-5-fluorophenyl benzyl ether (33.8 g, 120 mmol, Example 166, Step A) in dry tetrahydrofuran (60 mL) was added in several portions over 40 minutes at a rate sufficient to maintain reflux. Reflux was continued for 45 minutes, then the reaction was cooled to room temperature. This solution of Grignard reagent was transferred via syringe to a second flask containing a solution of the intermediate from Step D (11.0 g, 30.2 mmol) in dry benzene (66 mL). The reaction mixture was held at reflux for one hour, quenched with 10% aqueous hydrochloric acid (300 mL) and extracted with diethyl ether (3×300 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a brown oil which was subjected to flash column chromatography on silica (80 mm×19.5″) using a stepwise gradient elution of dichloromethane:hexanes (1:3, 1:2, 1:1, 4L each). The fractions containing the product were combined and concentrated to afford an inseparable mixture of the product and an unidentified side product in about a 1:1 ratio as a pale yellow gum (5.3 g, 33% mass balance). This material was not fully characterized and was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester and DIPEA in CH3CN gave 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C.[Al]>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.[Cu]I.CN(C=O)C>[CH3:18][O:17][C:7]1[C:6]2[N:5]([N:4]=[CH:3][C:2]=2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#C[Si](C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (860. mg, 2.43 mmol), tetrakis(triphenylphosphine)palladium(0) (281 mg, 0.243 mmol), trimethylsilylacetylene (1.01 ml, 7.29 mmol) and copper (I) iodide (277 mg, 1.46 mmol) were combined in a round bottom flask. DMF (25 mL) and triethylamine (0.677 mL, 4.86 mmol) were added, then the flask was wrapped with aluminum foil and sparged with nitrogen for 5 minutes. The reaction was stirred at ambient temperature for 30 mins, then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The liquid was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-[(trimethylsilyl)ethynyl]pyrazolo[1,5-a]pyridine LRMS (ESI) calculated for C17H21N4OSi [M+H]+, 325.1; found 325.1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH:3]1[O:5][CH2:4]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:4][CH:3]([OH:5])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:4][CH:3]([OH:5])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C1CO1
Reactant: NCCCCCCN
Product: CC(C)(C)C(O)CNCCCCCCNCC(O)C(C)(C)C

Procedure:
Condensation of 3,3-dimethyl-1-butene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3,3-dimethylbutylamine] (I: R = (CH3)3C, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:34])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([CH3:34])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][CH:29]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.16 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.083, 63%). MS (ISP) 436.1 [(M+H)+]; mp 221° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24]([C:30](OCC)=[O:31])=[CH:23]2>C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24]([C:30](=[O:31])[CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:23]2
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C(=O)CC(=O)OC(C)(C)C)cc2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of LHMDS (20.1 mL, 1.0 M in THF, 20.1 mmol) in THF (10 mL), was added tert-butyl acetate (2.71 mL, 20.1 mmol). After 30 min, a solution of the title compound of Example 11 Step A (1.59 g, 6.7 mmol) in THF (10 mL) was added. After 30 min, the reaction mixture was placed in a 0° C. bath, and was stirred at this temperature for 3 h, whereupon it was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS C, tr=2.38 min, m/z 252.2 [M−tBu+H]+; 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J=2.0 Hz, 1H), 7.34 (dd, J=9.0, 2.0 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 7.21 (s, 1H), 4.06 (s, 3H), 3.87 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([CH3:27])([CH3:26])[C:22](OC)=[O:23])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:37]>C(#N)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]3[C:21]([CH3:26])([CH3:27])[C:22](=[O:23])[NH:37][C:18]=3[N:19]=2)=[N:6]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncncc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncncc34)nnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
186 mg (0.438 mmol) of methyl 2-{3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 4 ml (42.913 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 30 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT overnight. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. 127 mg of the target compound were obtained (74% of theory).