Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1Br.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[Br:1])=[CH:16][CH:15]=1
Reactant: Brc1sc2ccccc2c1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3ccccc3c2Br)cc1
Yield: 77.7 %

Procedure:
A mixture of the dibromobenzothiophene (11 g, 37.7 mmol), p-methoxyphenylboronic acid (5.7 g, 37.7 mmol), Pd(OAc) to (58 mg, 0.26 mmol) and tri-ortho-tolyl phosphine (237 mg) in 38 mL THF was treated with 38 mL 2 M Na2CO3 and refluxed in the absence of light overnight. Diluted with 100 mL EtOAc and separated the layers. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layer was dried over MgSO4 and concentrated to an oil which was purified by chromatography (SiO2 ; stepwise 5 then 8% CHCl3 in hexanes) to recover 9.34 g (29.3 mmol, 78%) of the desired compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]#[CH:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].C(O[C:23]1[CH:28]=[CH:27][C:26](I)=[C:25]([CH3:30])[C:24]=1[F:31])(=O)C.C(N(CC)CC)C.O1CCCC1.[C:44]([O:47][CH2:48]C)(=[O:46])C>CCCCCC.[Cu]I>[CH3:48][O:47][C:44](=[O:46])[CH2:30][C:25]1[CH:26]=[CH:27][C:28]([C:12]#[C:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:17][CH3:18])=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)=[CH:23][C:24]=1[F:31]
Reactant: CC(=O)Oc1ccc(I)c(C)c1F
Reactant: C#Cc1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Reactant: CCOC(C)=O
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1F
Yield: 89 %

Procedure:
Following General Procedure F and using 1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.087 g, 0.33 mmol), methyl-2-fluoro-4-iodo phenyl acetate (Reagent H, 0.088 g, 0.30 mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (10 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladiun(II) (0.06 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.122 g, 89%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]=[C:24]=[O:25])=[CH:18][C:17]=1[Cl:26].CCCCCC>C1COCC1>[Cl:26][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:16]=1[Cl:15])[CH2:22][NH:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12])=[O:25]
Reactant: COC(=O)n1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)n1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Reaction time: 3 h

Procedure:
The product of Example 90B (0.19 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0. 25 g). 1H NMR (300 MHz, DMSO-d6) δ 4.38 (d, 2H), 6.97 (t, 1H), 7.36 (dd, 1H), 7.48 (t, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 8.45 (s, 1H), 9.16 (s, 1H).
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]2[CH:21]=[N:20][S:19][N:18]=2)=[C:13]([CH:16]=1)[CH2:14][NH3+:15].[C:22]([O:26][C:27]([NH:29][C@H:30]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@H:30]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH:15][CH2:14][C:13]1[CH:16]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=1[C:17]1[CH:21]=[N:20][S:19][N:18]=1)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: [NH3+]Cc1cc(Cl)ccc1-c1cnsn1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1cnsn1)C1CCCCC1

Procedure:
To a stirred solution of 5-chloro-2-(1,2,5-thiadiazol-3-yl)benzylammonium trifluoroacetate (40.9 mg, 0.13 mmol), 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 45.0 mg, 0.13 mmol), HOAt (22.5 mg, 0.17 mmol) and N-methylmorpholine (0.03 mL, 0.25 mmol) in DMF (0.5 mL) was added EDC (31.7 mg, 0.17 mmol). After 16 h the solution was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO4) and reduced in vacuo. 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide was obtained as an oil. MS m/z=562.6.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[NH2:2].[C:15]([O-])([O-])(OCC)[CH3:16]>C(O)(=O)C>[CH3:15][C:16]1[N:8]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:6][CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: NNc1cccc(-c2ccccn2)n1
Reactant: CCOC(C)([O-])[O-]
Solvent: CC(=O)O
Product: Cc1nnc2cccc(-c3ccccn3)n12

Procedure:
A mixture of 1.0 g of 6'-hydrazino-2,2'-bipyridine, 50 ml of ethyl orthoacetate and 5 drops of acetic acid was heated on a steam bath for 2.5 days. The volatiles were removed under vacuum and the residue crystallized from ether-hexane. These crystals were dissolved in dichloromethane and the solution passed through a short pad of hydrous magnesium silicate. Concentration of the filtrate gave 460 mg of the desired product as crystals, mp 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=[N:12][NH:13][C:14]([NH2:16])=[S:15])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=CC=Cc1ccc(F)cc1
Product: NC(=S)NN=CC=Cc1ccc(F)cc1
Yield: 53 %

Procedure:
The compound is prepared according to the method described in example 1A from 4-fluorocinnamaldehyde (1.5 mmoles) and from thiosemicarbazide (1.5 mmoles). Yield 53%.
Reaction SMILES: C(OC([NH:8][C:9]1([C:24]([OH:26])=O)[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:8][C:9]1([C:24]([NH:36][CH:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH3:35])=[O:26])[CH2:10][CH2:11][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CC(N)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
4-(tert-Butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (362 mg), 1-(4-chlorophenyl)ethanamine (172 mg), N-(3-dimethylaminopropyl)-3-ethylcarbodiimide (231 mg) and 1-hydroxybenzotriazole (163 mg) were stirred together in DMF (2 mL) under nitrogen for 16 hours. The reaction mixture was partitioned between EtOAc (20 mL) and brine (4×20 mL). The organics were combined, dried over MgSO4 and evaporated in vacuo. The resultant white solid was dissolved in 1,4-dioxane (5 mL) and a 4M solution of HCl in 1,4-dioxane (5 mL) was added. The resulting mixture was stirred for 16 hours, then diluted with diethyl ether (50 mL). The crude product was isolated by filtration as the HCl salt which was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (168 mg, 42%). 1H NMR (d6-dmso, 400 MHz) 1.33-1.49 (m, 5H), 1.84-2.04 (m, 2H), 2.12-2.22 (br s, 2H), 3.54 (t, 2H), 4.39 (t, 2H), 4.81-4.92 (m, 1H), 6.55-6.59 (m, 1H), 7.13-7.18 (m, 1H), 7.31-7.39 (m, 4H), 8.12 (s, 1H), 8.30 (d, 1H), 11.62 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:17](C(C)C)CC)(C)C.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([NH:17][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
BOC-Piperazine (1.06 g) was combined with dichloromethane (20.0 mL) and diisopropylethylamine (1.49 mL). Phenylacetylchloride (0.90 mL) was added dropwise and the reaction was allowed to stir at room temperature for 24 hours. The reaction was then washed with HCl (1N in water, 3×5 mL), saturated aqueous sodium bicarbonate (3×5 mL) and brine (5 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated giving 1-BOC-4-phenylacetamidopiperazine (1.73 g). Yield=100% Step 2: The BOC group was removed from 1-BOC-4-phenylacetamidopiperazine according to example 137 giving phenylacetamidopiperazine hydrochloride. Yield=93%. Step 3: Phenylacetamidopiperazine hydrochloride was reacted with 8-ethyl-6-chloropurine (Example 140) according to Example 87. Yield=27%, ES-MS: (M+H)+ 351.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:3].[C:12]([O:20][C@@H:21]1[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]([O:20][C@@H:21]1[C@H:25]([O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:24]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:23][C@H:22]1[N:45]1[C:46]2[N:47]=[C:48]([Cl:55])[N:49]=[C:50]([NH:3][N:2]([CH3:1])[CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:51]=2[N:52]=[CH:53]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(N)CCc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 163.1 %

Procedure:
The above hydrochloride salt of 1-methyl-1-(2-phenylethyl)hydrazine (0.67 g, 1.05 mmol), 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3 mmol) and triethylamine (1.24 ml, 9 mmol) were dissolved in 1,4 -dioxan (20 ml). The solution was stirred at ambient temperature for 20 h. The cooled reaction mixture was evaporated to a gum and purified by flash chromatography on silica gel. Bution with cyclohexane/ethyl acetate (4/1) initially and then with a 1/1 mixture of these solvents provided 2',3',5'-tri-O-benzoyl-2-chloro-N-(N-methyl-N-(2-phenylethyl)amino)adenosine (1.28 g, 60%) as a foam, 1H NMR (DMSO-d6)γ 2.63 (3H, s,--CH3), 4.66 (1H, dd, H-5'a), 4.77 (1H, dd, H-5'b), 4.86 (1H, q, H-4'), 6.23 (1H, t, H-3'), 6.36 (1H, t, H-2'), 6.54 (1H, d, H-1'), 7.11-7.98 (20H, m, Ar-H), 8.44 (1H, s, H-8), 9.40 (1H, br s, N-H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]([C:17]1[C:18](=[O:28])[O:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22](O)[CH:21]=2)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1[C:18](=[O:28])[O:19][C:20]2[CH:21]=[C:22]([O:12][CH2:11][CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])[CH:23]=[CH:24][C:25]=2[CH:26]=1)=[O:16]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc2ccc(O)cc2oc1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(OCCN(C)C(=O)OC(C)(C)C)cc2oc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
2-(N-tert-butoxycarbonyl-N-methylamino)ethanol (0.5 g, 3 mmol) and 7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.6 g, 3 mmol) are dissolved in 60 mL of anhydrous tetrahydrofuran. Triphenylphosphine (1.2 g, 4.5 mmol) is added, and diethyl azodicarboxylate (720 μL, 0.45 mmol) is added dropwise and slowly at 0° C. The resulting solution is stirred at room temperature for 24 hours. After the solvent was removed under reduced pressure at 30° C., the residue is mixed with methanol at room temperature. A solid is produced by filtrating under reduced pressure and 0.83 g of the captioned compound is obtained, yield: 72.6%. m.p. 128-129° C. 1H NMR(DMCO-d6): δ=1.40(s, 9H), 2.96(s, 3H), 3.65(s, 2H), 3.81(s, 3H), 4.32(s, 2H), 6.94(d, J=2.2 Hz, 1H), 7.00(dd, J=2.2 Hz, 8.4 Hz, 1H), 7.80(d, J=8.8 Hz, 1H), 8.60 (s,1H); EI-MS(m/z): 377(1, M+), 102(100).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([F:37])[F:38])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(O)cc(F)c2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(F)(F)F)[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 65.7 %

Procedure:
Add acetic anhydride (0.142 mL, 1.51 mmol) to an ice cold solution of (2S,3S,5R)-5-[(1S,2S)-2-Amino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-3-methyl-2-(2,2,2-trifluoro-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (823 mg, 1.43 mmol) in dichloromethane (9 mL). Stir for 50 minutes and add diisopropylethylamine (0.125 mL, 0.717 mmol) and stir for 2 hours. Quench with aqueous 1N hydrochloric acid, wash with saturated aqueous sodium bicarbonate, dry with magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound (493 mg). MS(ESI): m/z=525 [M+H]+.
Reaction SMILES: [C:1]([O:18][CH2:19][C:20]([N:23]([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:17])[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][CH3:16].[CH3:26][I:27]>>[I-:27].[C:1]([O:18][CH2:19][C:20]([N+:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(C)(C)N(C)C
Reactant: CI
Product: CCCCCCCCCCCCCCCC(=O)OCC(C)(C)[N+](C)(C)C
Product: [I-]

Procedure:
A 36 g portion of the ester obtained above was reacted with methyl iodide 15 g as described in Example 2. There was obtained (2-palmitoyloxy-1,1-dimethylethyl)-trimethylammonium iodide, m.p. 170.8° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH3:13])[O:10][CH:9]([CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[CH3:14][CH:9]1[O:10][CH:11]([CH3:13])[CH2:12][N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:29])([F:28])[F:17])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: CC1CN(Cc2ccc(Br)cc2)CC(C)O1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC(C)O1
Temperature: 120 °C

Procedure:
100 mg of 4-(4-Bromo-benzyl)-2,6-dimethyl-morpholine was combined with 100 mg of 2-(Trifluoromethyl)phenyl boronic acid, 20 mg of tetrakis(triphenylphosphine)palladium(0), 1.179 mL of 2M sodium carbonate solution, 3.2 mL toluene and 1.6 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 350.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@H:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@H:36]([N:40]4[CH:44]=[CH:43][N:42]=[N:41]4)[C@H:35]([NH:45][C:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
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
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (47 mg, 0.12 mmol), tert-butyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-3-yl]carbamate (40 mg, 0.11 mmol), and HATU (100 mg, 0.27 mmol), in DMF (0.4 mL), DIPEA (0.056 mL, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated under reduced pressure. After concentration, the residue was purified by flash chromatography on silica using a CombiFlash® apparatus (0-100% EtOAc in hexanes) to give the sub-title compound as a light yellow powder (109 mg). LCMS calc. for C36H39BrN9O5 (M+H)+: m/z=756.2. Found: 756.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:32])[C:9]=1[N:10]1[C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=2[C:12]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:11]1)[C:5]#[N:6].CS(C)=[O:35].C(=O)([O-])[O-].[K+].[K+].OO>O>[F:32][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[N:10]1[C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=2[C:12]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[N:11]1)[C:5]([NH2:6])=[O:35]
Reactant: CS(C)=O
Reactant: N#Cc1cc(F)c(-n2nc(-c3ccc(N4CCOCC4)cc3)c3c(=O)[nH]ccc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cc(F)c(-n2nc(-c3ccc(N4CCOCC4)cc3)c3c(=O)[nH]ccc32)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5-difluoro-4-(3-(4-(morpholin-4-yl)phenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile (120 mg) obtained in Step D of Example 244 in a mixed solvent of DMSO (3 mL) and water (0.25 mL) were added potassium carbonate (45.9 mg) and aqueous hydrogen peroxide (concentration 30 w/v %, 0.085 mL), and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration, and washed with DMSO and water to give the title compound (64 mg).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]1>>[O:26]=[S:23]1(=[O:27])[CH2:24][CH2:25][N:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:22]1
Reactant: O=S1(=O)CCNCC1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Product: COc1ccc(Nc2nc3c(N4CCS(=O)(=O)CC4)cccn3n2)cc1

Procedure:
8-(1,1-dioxidothiomorpholin-4-yl)-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyri din-2-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and thiomorpholine 1,1-dioxide (25.0 mg, 0.185 mmol) in a manner analogous to Example 30. Product isolated as a tan solid (0.052 g, 89%). MP=231-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (dd, J=6.4, 1.1 Hz, 1H), 7.50-7.45 (m, 2H), 6.94-6.89 (m, 2H), 6.77 (dd, J=7.7, 6.7 Hz, 1H), 6.73 (dd, J=7.6, 0.9 Hz, 1H), 6.57 (s, 1H), 4.12-4.06 (m, 4H), 3.81 (s, 3H), 3.28-3.23 (m, 4H). MS=374 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:25][CH:24]=1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1

Procedure:
The title compound was prepared by treating 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (0.3 g, 1.04 mmol) with 4-methylsulfanyl-phenylamine (0.15 g, 1.04 mmol) according to the procedure as described above.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Rh]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1
Agent: [Rh]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
A mixture of 4-fluorophenyl 4-nitrophenyl sulfone (1.89 g, 6.72 mmol) in methanol (80 mL) is treated with Rhodium on carbon (5%, 95 mg) and hydrogenated at 20 psi for 24 hr. The mixture is filtered, rinsing with methylene chloride (2×100 mL) and methanol (100 mL). The filtrate is concentrated to near dryness and refiltered, rinsing with minimal methanol. The solid is dried in the vacuum oven at 50° to give the desired amine, mp=204-205°: IR (drift) 3473, 3373, 1638, 1592, 1489, 1303, 1294, 1285, 1231, 1159, 1144, 1107, 834, 713 and 689 cm−1; NMR (300 MHz, CDCl3) 7.80-7.95, 7.60-7.75, 7.13, 6.60-6.75 and 4.17 δ; MS (EI) m/z 251 (M+), 140, 108, 95, 92, 80, 65, 65, 63 and 51.