Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:19][S@@](C(C)(C)C)=O)([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:19][C@@:9]([C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH2:10][F:11])[CH2:12][C@H:13]([OH:18])[C:14]([F:16])([F:15])[F:17]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)cnc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)cnc1F
Temperature: 25 °C

Procedure:
(R)-N-((2S,4S)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (3.68 g, 8.12 mmol) was dissolved in 36 mL methylene chloride and 18 mL MeOH. The solution was stirred at room temperature. Hydrogen chloride, 4M in 1,4-dioxane (20.30 ml, 81 mmol) was added and the reaction mixture was stirred for 1.5 h. The reaction was concentrated, then EtOAc and water was added, followed by addition of saturated sodium bicarbonate solution for neutralization. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude material of (2S,4S)-4-amino-4-(5-bromo-2-fluoropyridin-3-yl)-1,1,1,5-tetrafluoropentan-2-ol that was used without further purification.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:19])=O)[CH:12]=3)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[N:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:29][C:25]4[N:24]=[C:23]([C:22]([O:21][CH3:20])=[O:30])[CH:28]=[CH:27][CH:26]=4)=[O:19])[CH:12]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:4]1
Reactant: O=C(O)c1cc(-c2ccc(C3CC3)nc2)ccn1
Reactant: COC(=O)c1cccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1

Procedure:
A solution of 6-cyclopropyl-3,4′-bipyridine-2′-carboxylic acid hydrochloride salt (1.73 g, 6.25 mmol), 6-aminopicolinate methyl ester (1.05 g, 6.87 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 2.85 g, 7.50 mmol), and N-methylmorpholine (1.51 mL, 13.8 mmol) in N,N-dimethylformamide was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL) and dried under reduced pressure to afford methyl 6-(6-cyclopropyl-3,4′-bipyridine-2′-carboxamido)picolinate as a white powder, which was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:14]=[C:13](OCCOCCOCCOCC)[CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+].C(CN(C1C=C(OCCCCCCCCCCCCOC2C=CC=CC=2)C=[C:63]([O:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96]CC)[CH:62]=1)CC(O)=O)(O)=O>CO.O1CCOCC1>[C:7]([CH2:6][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:14]=[CH:13][C:12]=1[O:96][CH2:95][CH2:94][O:93][CH2:92][CH2:91][O:90][CH2:89][CH2:88][O:87][CH2:63][CH3:62])[CH2:4][C:3]([OH:2])=[O:49])([OH:9])=[O:8]
Reactant: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: CCOCCOCCOCCOc1cc(OCCCCCCCCCCCCOc2ccccc2)cc(N(CC(=O)O)CC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOCCOCCOCCOc1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1N(CC(=O)O)CC(=O)O
Yield: 85 %

Procedure:
A solution of 1.15 g (1.67 mmol) of N-[3-[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 1.4 ml (8.4 mmol) of 6 N NaOH in 50 ml of methanol and 10 ml of dioxane was stirred at reflux under argon for 19 hours. After the usual workup the product was crystallized from acetone-hexane to give 0.94 g (85% yield), mp 58°-61°, of N-(carboxymethyl)-N-[3-[2-[2-(2-ethoxyethoxy)-ethoxy]ethoxy]-5-[(12-phenoxydodecyl)oxy]phenyl]glycine.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Yield: 93.2 %

Procedure:
Sodium iodide (10.32 g, 68.88 mmol) was added to a solution of 1-methanesulfonyloxy-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.5 g, 22.96 mmol) in acetone (300 ml), followed by heating under reflux for 12 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.6 g, Yield 93%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].Cl>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 43 %

Procedure:
Using the procedure of Bergel and Stock as set forth in J. Chem. Soc., 2409-2417 (1954) L-phenylalanine (50 g) was treated with a mixture of concentrated sulfuric acid (150 ml), and fuming nitric acid (28 ml) to produce the nitro compound Yield 26.9 g (43%) mp 232°-234° C., [α]D25 =+9.6° (c=1.77, 1N HCl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35]2[S:39][C:38]([C:40]3([O:44][CH2:45][O:46][CH3:47])[CH2:43][CH2:42][CH2:41]3)=[N:37][CH:36]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3C=NN(C)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1>>[Cl:1][C:2]1[C:3]([C:35]2[S:39][C:38]([C:40]3([O:44][CH2:45][O:46][CH3:47])[CH2:41][CH2:42][CH2:43]3)=[N:37][CH:36]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(OC5CCN(C)CC5)cc3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(C)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OC6CCN(C)CC6)cc5)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 47B, 5-(5-chloro-2-(4-(1-methylpiperidin-4-yloxy)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 72A) for 5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 47A). MS ESI(+) m/z 539.0 [M+H]+.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>O1CCCC1>[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[N:21]1
Reactant: Nc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncccc1-c1cn[nH]c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
3-(1-Trityl-1H-pyrazol-4-yl)-pyridin-2-ylamine (2.3 g, 5.71 mmol) described in Manufacturing Example 32-1-3, 2 N hydrochloric acid (15 mL), methanol (15 mL) and tetrahydrofuran (10 mL) were stirred for 30 minutes at 70° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. Saturated sodium bicarbonate solution was added to the separated aqueous layer, which was then extracted with ethyl acetate 6 times. The ethyl acetate layers were combined and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate, then ethyl acetate: methanol=10:1) to obtain the title compound (625 mg, 68.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][C:2]=1[C:10]([NH2:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][C:2]=1[C:10]([NH2:12]=[O:21])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)c1ccnc(C(N)=O)c1
Product: NC(=O)c1ccnc(C(=O)[NH2+][O-])c1

Procedure:
From 1 g of pyridine-2,4-dicarboxamide and 1.2 g of MCPBA.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([NH2:15])=[CH:11][CH:12]=2)[NH:7][C:6]1=O)=O>C1COCC1.O>[NH2:15][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:5]([CH2:3][N:2]([CH3:17])[CH3:1])[CH2:6][NH:7]2)=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)C1Cc2ccc(N)cc2NC1=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CNc2cc(N)ccc2C1
Yield: 95.9 %

Procedure:
To a suspension of N,N-dimethyl-7-amino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (450 mg) in THF (15 ml) was added Borane-THF complex (1M, 12 ml) under ice-cooling. The reaction mixture was heated under reflux for one hour. The reaction mixture was diluted with water (2 ml) under ice-cooling and concentrated. The residue was dissolved in methanol (12 ml), which was heated under reflux with 6N hydrochloric acid (4 ml) for 3 hours. After cooling, the reaction mixture was made basic and extracted with combined solution of THF and ethyl acetate. The organic layer was dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate to ethyl acetate/methanol=20:1) to obtain the entitled compound (380 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:25]([I:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[IH:27].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:25][CH3:26])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Product: I
Yield: 65.2 %

Procedure:
A mixture of 1.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, 1.13 g of ethyl iodide, 0.73 g of triethylamine and 20 ml of N,N-dimethylformamide is heated at 70°-80° C. for 2.5 hours. The solvent is distilled off in vacuo and the residue is suspended in water. The solid is filtered off with suction, rinsed with water and pressed off on clay. 1.15 g of 1-cyclopropyl-6-fluoro-7-(4-ethyl-1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydriodide of decomposition point 306° C. are obtained.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[F:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>>[F:19][C:18]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[CH2:21][F:20])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)CF
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)CF
Yield: 28 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 1-fluoro-2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (6 mg, 28%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[CH3:30][O:31][CH2:32][CH2:33][C:34]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:29])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:28])[N:16]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:39]([C:34]1([CH2:33][CH2:32][O:31][CH3:30])[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:40]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1
Reactant: COCCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(Cc4ccccc4)c3=O)cc2)C(=O)OC)CCCC1
Yield: 58.1 %

Procedure:
A solution of 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (100 mg, 0.25 mmol), 1-(2-methoxyethyl)cyclopentane carboxylic acid (47 mg, 0.28 mmol), DIEA (200 μL, 1.2 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (2 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 60:40 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (80 mg, 63%). LR-Electrospray: m/z 1123 (2M+Na), 1118 (2M+NH4), 573 (M+Na), 568 (M+NH4), 551 (M+H (1 Cl)). HRMS: Obs. Mass 551.2297. Calcd. Mass 551.2313 (M+H).
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:29][C:30]([C:32]([N:48]([CH3:52])[C:49](=[O:51])[CH3:50])([CH2:44][CH2:45][CH:46]=[CH2:47])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([NH:29][C:30]([C:32]([N:48]([CH3:52])[C:49](=[O:51])[CH3:50])([CH2:44][CH2:45][CH2:46][CH2:47][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: C=CCCC(CCCNC(=O)OC(C)(C)C)(C(=O)NC(C)(C)C)N(C)C(C)=O
Reactant: CC1(C)OBOC1(C)C
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)N(C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCNC(=O)OC(C)(C)C)C(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
While under an atmosphere of argon, a solution of bis(1,5-dicyclooctadiene)diiridium(I)dichloride (6 mg; 0.009 mmol) and diphenylphosphinoethane (7 mg, 0.018 mmol) in dichloromethane (1 mL) was cooled to 0° C. and treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.174 mL, 1.2 mmol). After stirring for 30 min, a solution of tert-butyl 4-(tert-butylcarbamoyl)-4-(N-methylacetamido)oct-7-enylcarbamate (120 mg, 0.3 mmol) in dichloromethane (4 mL) was added and the solution was stirred an additional 16 h. Dichloromethane (10 mL) was added, and the solution was washed successively with water and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated. Purification by column chromatography (3% methanol in dichloromethane) gave tert-butyl 4-(tert-butylcarbamoyl)-4-(N-methylacetamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octylcarbamate (142 mg, 90%). ESI MS found for C27H52BN3O6 m/z [548.7 (M+Na+), 526.7 (M+1), 570.8 (M+HCOO−), 524.6 (M−1)].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
3-Methyl-5-phenyl-4-isoxazolecarboxylic acid (40 mg, 0.197 mmol), 3-phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1535.
Reaction SMILES: [F:1][C@:2]1([C:30]([OH:32])=O)[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.[N:40]1([O:49][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[C:61](NO)([CH3:64])([CH3:63])[CH3:62].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:61]([O:49][NH:40][C:30]([C@@:2]1([F:1])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:10])=[O:32])([CH3:62])([CH3:63])[CH3:64]
Reactant: CC(C)(C)NO
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(F)C(=O)O)cc2)c2ccccc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(F)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To 0.15 g (3 mmol) of (1R,2R)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in DMF (4 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (0.16 g, 1.2 eq), tert-butyl hydroxylamine hydrochloride (0.078 g, 2 eq) and diisopropylethylamine (0.22 mL, 4 eq). The resulting reaction mixture was stirred for 18 h, and then taken up in ethyl acetate, washed with brine, dried over Mg2SO4, filtered and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 50-80% ethyl acetate/hexanes to afford (1R,2R)-N-(tert-butoxy)-1-fluoro-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (0.14 g, 60%, 2 steps). MS: 530.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:43])C=1>ClCCl>[CH3:4][C:2]([S:5]([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:9][O:10][CH2:11]1)(=[O:43])=[O:6])([CH3:1])[CH3:3]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)(=O)C(C)(C)C)COC3)s2)c1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfinamide (Example 59, Step 2, 75 mg, 0.147 mmol) in dichloromethane (1.5 mL) was cooled to 0° C. m-CPBA (37.8 mg, 0.219 mmol) was added and the resulting mixture was warmed to room temperature. The reaction mixture was diluted with dichloromethane, washed with 2M NaOH (2×), saturated NaHCO3 (1×), brine (1×), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfonamide (45.6 mg, 0.086 mmol, 59.0% yield) as a light yellow solid. MS ESI: [M+H]+ m/z 510.1. 1H NMR (500 MHz, dmso) δ 10.29 (s, 1H), 8.83 (d, J=4.9, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.28 (d, J=4.9, 1H), 7.18 (s, 1H), 4.90 (dd, J=6.6, 33.0, 4H), 2.33 (s, 3H), 1.35 (s, 9H). rhSYK activity=+++
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[NH3:30].O1CCOCC1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15]([NH2:30])(=[O:17])=[O:16])[CH2:9]1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with 0.5 M of ammonia in 1,4-dioxane (874 μL, 4.0 eq.) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (16.3 mg). MS m/z: [M+H1]+ calcd for C13H17F3N2O3S, 339.09; found 339.0.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][CH2:18]3)=[CH:13][CH:12]=2)[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([CH:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:9]#[N:10])=[CH:12][CH:13]=3)[CH2:18]2)(=[O:29])=[O:28])[N:24]=[CH:23]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: N#CC(Cc1ccccc1)c1ccc2c(c1)CNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCc3ccc(C(C#N)Cc4ccccc4)cc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of 0.135 mmol 3-phenyl-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)propanenitrile in 2 ml CH2Cl2 were added 0.203 mmol DMAP and 0.162 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride. The mixture was stirred at room temperature for 3 h. Additional 0.162 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride were added and the mixture was stirred for 3 d. The mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated NaHCO3 and H2O. The combined aqueous layers were extracted with CH2Cl2. The combined organic phase was dried over MgSO4 and filtered. Evaporation of the solvent gave 90 mg of the crude material. The material was purified by flash chromatography to yield 53 mg of a white solid (97%).