Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([O-:26])=[O:25].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CC(N(C)C)=O.C(OCC)(=O)C>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:8]([C:19]3[NH:23][CH:22]=[CH:21][N:20]=3)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=3)=[O:31])[N:10]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-c2nc(NCCNC(=O)c3cccc([N+](=O)[O-])c3)ncc2-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.9 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzenecarbonitrile (30 mg, 0.098 mmol), 3-nitrobenzoic acid (17 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (19 mg, 0.1 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (14 mg, 0.1 mmol), and 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) in DMA (500 uL) were stirred at room temperature. After 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The resulting product, N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)(3-nitrophenyl)carboxamide weighing 32 mg (70% yield) was approximately 95% pure by LCMS and HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.[NH2:18][CH2:19][C@@H:20]([OH:22])[CH3:21]>C1COCC1>[CH:13]1([C:12]2[C:3]3[C:4](=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=3[NH:18][CH2:19][C@H:20]([OH:22])[CH3:21])[NH:10][N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C[C@H](O)CN
Reactant: CSc1nc(Cl)c2c(C3CCCC3)n[nH]c2n1
Solvent: C1CCOC1
Product: CSc1nc(NC[C@@H](C)O)c2c(C3CCCC3)n[nH]c2n1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
4-Chloro-3-cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.860 mmol) was dissolved in 25 mL dry THF, and (S)-1-Amino-propan-2-ol (1.758 mL, 22.32 mmol) was added. The reaction mixture was heated to reflux for three hours, then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water, washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 0.56 g of (R)-1-(3-Cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-propan-2-ol. Mass Spec. M+H=309.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.OC1C([N+]([O-])=O)=C(O)C=C(C)N=1.OC1C([N+]([O-])=O)=C(O)C(C)=C(C)N=1.Cl.[CH2:46]([O:53][CH2:54][CH2:55][NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH2:46]([O:53][CH2:54][CH2:55][NH:56][C:13]1[CH:12]=[C:11]([CH3:19])[N:10]=[C:9]([Cl:8])[C:14]=1[N+:15]([O-:17])=[O:16])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NCCOCc1ccccc1
Agent: Cc1cc(O)c([N+](=O)[O-])c(O)n1
Agent: Cc1nc(O)c([N+](=O)[O-])c(O)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCOCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 23 h
Yield: 25.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (40.4 mL, 290 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (12.0 g, 58.0 mmol), prepared according to the general method of Part A of Example 1 using 2,4-dihydroxy-6-methyl-3-nitropyridine in lieu of 2,4-dihydroxy-5,6-dimethyl-3-nitropyridine, in anhydrous N,N-dimethylformamide (DMF) (200 mL). To the resulting dark brown solution was added 2-(benzyloxy)ethylamine hydrochloride (11.97 g, 63.76 mmol), and the mixture was stirred at room temperature for 23 hours. The volatiles were then removed under reduced pressure, and the residue was mixed with water and ethyl acetate. The organic layer was washed with water (3×200 mL), aqueous sodium bicarbonate (2×200 mL), and brine (3×250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The crude product (18.1 g) was purified by column chromatography on silica gel (700 g, eluting with 80:20 hexane:ethyl acetate) to provide an oil which was triturated with 80:20 hexane:ethyl acetate. The resulting crystals were isolated by filtration and dried to provide 4.7 g of [2-(benzyloxy)ethyl]-(2-chloro-6-methyl-3-nitropyridin-4-yl)amine as a yellow solid.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]1=[O:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40](N(CC)C(C)C)([CH3:42])[CH3:41].C(Br)C=C>C(Cl)Cl>[CH2:42]([N:33]([C:34]1[S:35][CH:36]=[CH:37][N:38]=1)[S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]2=[O:39])=[CH:25][CH:26]=1)(=[O:31])=[O:32])[CH:40]=[CH2:41]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1=O)(c1ccccc1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Yield: 83.9 %

Procedure:
Prepared according to general procedure 48. The reaction was set up (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (50.0 g, 86.6 mmol), CH2Cl2 (200 mL), N,N-diisopropylethylamine (30.2 mL, 173.2 mmol), and allylbromide (15.0 mL, 173.2 mmol). The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (45.0 g, 72.7 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ. 7.85-7.79 (m, 6H), 7.70 (dd, J=1.6, 7.7 Hz, 2H), 7.49-7.40 (m, 6H), 7.36 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.90-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H), 4.97 (d, J=1.3 Hz, 1H), 4.56-4.52 (m, 3H), 3.76-3.72 (m, 1H), 3.56-3.48 (m, 1H), 2.28-2.25 (m, 1H), 2.19-1.98 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[C:18]([OH:19])=[CH:17][N:16]=[C:15]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=[CH:22][C:14]=12>CN(C=O)C>[F:12][C:13]1[C:18]([O:19][CH2:2][CH2:3][O:4][CH3:5])=[CH:17][N:16]=[C:15]2[NH:20][CH:21]=[CH:22][C:14]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc2[nH]ccc2c1F
Temperature: 65 °C
Yield: 49.7 %

Procedure:
1-Bromo-2-methoxyethane (0.586 g, 4.21 mmol) and potassium carbonate (1.16 g, 8.43 mmol) to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (1.3 g, 4.21 mmol; Example 119, Step A) in DMF (13 mL). The reaction was heated to 65° C. in a sealed tube for 18 hours, cooled down and then filtered. The filtrate was concentrated and purified by reverse chromatography (SP4, 25M, water/ACN 90/10→0/100, 30CV) to yield 4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 49.7% yield) as an oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.[NH2:18][C:19]1[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].O>[CH2:24]([N:23]1[C:19]([NH:18][C:2]2[C:3](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:20][CH:21]=[N:22]1)[CH3:25]
Reactant: CCn1nccc1N
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nccc1Nc1ccc(OC)cc1C(=O)O
Yield: 99.9 %

Procedure:
A mixture of 2-bromo-5-methoxybenzoic acid (39.3 g, 0.17 mol), DMF (150 ml), 5-amino-1-ethylpyrazole (18.5 g, 0.17 mol), potassium carbonate (23.5 g, 0.17 mol) and Cu(OAc)2 (0.6 g) is refluxed for about 2 days. The reaction mixture is cooled, poured into water and acidified to a pH of 5. A precipitate forms which is collected by filtration, washed with water and dried to afford 44.37 g (62%) of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13](O)=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN.C1C=CC2N(O)N=[N:36][C:34]=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH:36][CH3:34])=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=NC(C(=O)O)=C2NC(C)(C)Cc3ccccc32)cc1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)C(N=Nc1ccc(C(C)=O)cc1)=C1NC(C)(C)Cc2ccccc21
Temperature: 25 °C

Procedure:
(4-acetyl-phenylazo)-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetic acid, methylamine, HOBt (Advanced ChemTech Corp., USA) and triethylamine are dissolved in DMF, and a dichloromethane solution of HBTU (Advanced ChemTech Corp., USA) is added thereto. The mixture is then stirred at room temperature. The mixture is washed with a saturated aqueous sodium chloride solution and a 5% aqueous sodium hydrogen carbonate solution. The reaction product is dried with anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: Cl[CH:2]([C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][CH:22]=[N:21][C:20]=2[CH:19]=1)[N:3]1[CH2:8][CH2:7][CH:6]([S:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])(=[O:11])=[O:10])[CH2:5][CH2:4]1.[NH2:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>>[NH2:33][C:34]1[N:39]=[CH:38][C:37]([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:25]3[S:26][C:18]([CH2:2][N:3]4[CH2:8][CH2:7][CH:6]([S:9]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])(=[O:11])=[O:10])[CH2:5][CH2:4]4)=[CH:19][C:20]=3[N:21]=2)=[CH:36][N:35]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CN(C)C(=O)CS(=O)(=O)C1CCN(C(Cl)c2cc3ncnc(N4CCOCC4)c3s2)CC1
Product: CN(C)C(=O)CS(=O)(=O)C1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[1-(Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidine-4-sulfonyl]-N,N-dimethyl-acetamide was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 309. NMR (CDCl3): 1.98-2.08 (2H, m), 2.18-2.28 (4H, m), 3.04 (3H, s), 3.13-3.17 (2H, m), 3.22 (3H, s), 3.45-3.53 (1H, m), 3.85 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 4.08 (2H, s), 5.20 (2H, br), 7.27 (1H, s), 9.30 (2H, s). MS (ESI+): MH+561.20 (100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]#[CH:25])[C:16]([CH3:26])=[C:15]([CH3:27])[N:14]=1.C(N(CC)CC)C>ClCCl>[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][C:24]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:25]=2)[C:16]([CH3:26])=[C:15]([CH3:27])[N:14]=1
Reactant: ON=C(Cl)c1ccc(F)cc1
Reactant: C#CCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2cc(-c3ccc(F)cc3)no2)c1C
Temperature: 40 °C
Yield: 76.7 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (52.0 g, 225 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine (26.92 g, 112.3 mmol) in anhydrous dichloromethane (1 L) at room temperature. Triethylamine (25 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16 hours, diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to a suspension. The suspension was filtered to isolate a yellow solid, which was washed with diethyl ether and dried under vacuum to provide 32.45 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)=O.CC(C)=O.C([Li])CCC.CON(C)[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of tetrahydrofuran is stirred under nitrogen at −78° C. in a bath of cardice/acetone. 100 mL (160 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over about 1 hour, while taking care to ensure that the temperature does not exceed −70° C. About half way through the introduction, the formation of a beige-coloured precipitate that corresponds to the formation of the lithium carboxylate is noted. After the addition, the mixture is stirred at −78° C. for 1 hour, and a solution of 15.9 g (80 mmol) of N,4-dimethoxy-N-methylbenzamide in 20 mL of THF is added dropwise. The reaction medium is stirred at −78° C. for 1 hour and the bath of cardice/acetone is then removed and the reaction medium is stirred, while allowing the temperature to return gradually to room temperature, for 18 hours. The mixture is hydrolysed with 100 mL of water, basified to pH=12 with 2N NaOH solution and then extracted with tert-butyl methyl ether. The aqueous phase containing the carboxylate is acidified with 5N HCl solution to pH 1 and extracted with dichloromethane. The dichloromethane phase is washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The product is crystallized from isopropyl ether; after filtering and drying, 14.6 g of white crystals are obtained (yield=64%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O1CCCC1>CO>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc4ccccc34)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-napthalene-ylmethyl-piperidine-4-carboxylic acid ethyl ester (6.3 g, 13 mmol) dissolved in methanol (30 mL), 10 N sodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.3 g (36%). yellow solid mp 226-228° C., MS: 440.0 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution of (S)-(−)-1-Boc-2-pyrrolidine methanol (0.267 g, 1.33 mmol), phenol (0.38 g, 4.02 mmol) and triphenylphosphine (0.71 g, 2.71 mmol) in DCM (5 mL) was cooled in an ice-bath and a solution of diisopropyl azodicarboxylate (0.55 g, 2.71 mmol) in toluene (3 mL) was added. The ice-bath was removed and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with ether and washed with sodium hydroxide (3 M), then brine, dried over sodium sulfate and evaporated. The resultant solid was suspended in ethyl acetate and cyclohexane and the resultant white crystalline solid was removed by filtration. The filtrate was evaporated and the crude material was purified by column chromatography using a 10 g Si II cartridge eluting with 10% ethyl acetate in cyclohexane to afford (S)-2-phenoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil (0.22 g).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH2:9](I)[CH3:10]>[Ag]=O.CN(C=O)C>[CH2:9]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:10]
Reactant: CCI
Reactant: CCOC(=O)[C@H](C)O
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)OCC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 20 g of (s)-(-)-ethyl lactate, 100 ml of N,N'-dimethylformamide, 38 g of ethyl iodide and 30 g of silver oxide was stirred at room temperature for 40 hours. The insoluble materials were separated by filtration and water and hexane were added to the filtrate to separate N,N'-dimethylformamide. The aqueous layer was subsequently extracted twice with hexane, and the hexane layers were dried over anhydrous sodium sulfate. The product was distilled under reduced pressure to give 18.5 g of a fraction having a boiling point of 86°-88° C./75 mmHg. Nuclear magnetic resoanance spectroscopy led to the determination that this fraction was the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[O:16][N:15]=[C:14]([CH3:17])[C:13]=3[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)NC3CCCCC3)cc2)c1C

Procedure:
This compound was prepared from 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzene-sulfonamide and cyclohexyl isocyanate according to the method in Example 110 in 75% crude yield. Further purification was achieved by preparative HPLC (76% recovery), furnishing the pure product as a white solid, m.p. 190°-195° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Temperature: 140 °C
Yield: 33 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), p-toluidine (56.4 mg, 526 μmol), BINAP (10.9 mg, 17.5 μmol), palladium (II) acetate (19.7 mg, 87.7 μmol) and sodium tert-butoxide (84.3 mg, 877 μmol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-45% ethyl acetate in hexanes) gave N-tert-butyl-2-(p-tolylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 116 μmol, 33%) as a brown gum. MS (EI/CI) m/z: 454.4 [M+H].
Reaction SMILES: N1CCOCC1.[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S-:23])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:10])([CH3:9])[CH3:8].Br[CH2:29][C:30]([NH2:32])=[O:31]>C1COCC1>[C:7]([Si:11]([CH3:27])([CH3:26])[O:12][CH2:13][CH2:14][CH2:15][C:16]1[C:17]([C:24]#[N:25])=[C:18]([S:23][CH2:29][C:30]([NH2:32])=[O:31])[NH:19][C:20](=[O:22])[CH:21]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c([S-])c1C#N
Reactant: NC(=O)CBr
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)(C)[Si](C)(C)OCCCc1cc(=O)[nH]c(SCC(N)=O)c1C#N
Temperature: 25 °C
Yield: 360.4 %

Procedure:
To a solution of 0.940 g (2.28 mmol) of the above morpholine salt in THF (15 mL), cooled to 0° C., was added 0.315 g (0.280 mmol) of 2-bromoacetamide as a solid in one portion. The mixture was stirred and allowed to slowly warm to room temperature over a 2 h period during which time salts precipitated from solution. The mixture was filtered through diatomaceous earth to remove solids and the filter pad was washed with EtOAc. The mixture was concentrated under reduced pressure to provide 0.385 g (44%) of 2-{4-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-3-cyano-6-oxo-1,6-dihydro-pyridin-2-ylsulfanyl}-acetamide as an orange foam.