Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]1[CH2:27][CH:26]1[CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[C:10]([C:9]=2[CH:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:19][CH2:20]1
Reactant: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1c(N2CCN(CC3CO3)CC2)n(-c2ccccc2)c2ccccc12
Yield: 41 %

Procedure:
A stirred mixture of 1-phenyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (438 mg, 1.37 mmol), epibromohydrin (188 mg, 1.37 mmol), potassium carbonate (758 mg, 5.49 mmol) and acetonitrile (20 ml) is heated at reflux for 2.5 hr. The reaction is cooled and the solids are removed by filtration. The filtrate is concentrated and the residue is purified by chromatography eluting with dichloromethane-1 to 5% methanol. Fractions containing the desired product are combined and concentrated to afford 2-(4-oxiranylmethylpiperazin-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (41% yield) as a yellow solid. LC/MS: MS 376 (M+H); RT 2.65 min; NMR (CDCl3): 10.28 (1H, s), 8.26 (1H, d), 7.43-7.65 (3H, m), 7.17-7.42 (3H, m), 7.13 (1H, t), 6.96 (1H, d), 3.49 (4H, m), 3.03 (1H, m), 2.56-2.86 (4H, m), 2.30-2.50 (2H, m), 1.74 (2H, m), 1.56 (2H, s).
Reaction SMILES: [CH2:1]([N:8](CC)[C:9]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]1[C:18](=[O:36])[C:19]([O:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=[C:10]21)[C:2]1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[CH2:1]([NH:8][C:9]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]1[C:18](=[O:36])[C:19]([O:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=[C:10]21)[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N(CC)Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNC12CCC(CC1)Cn1c2nc(C(=O)OCC)c(OC(=O)c2ccccc2)c1=O

Procedure:
To a mixture of ethyl 10-(benzyl(ethyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (120 mg, 0.233 mmol) in methanol (5 mL) was added 1N HCl (0.256 mL, 0.256 mmol) followed by Pd/C (24.77 mg, 0.023 mmol) and the mixture stirred under 1 atm hydrogen for 18 h. The mixture was filtered and the solids thoroughly washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried under high vacuum overnight to afford the title compound.
Reaction SMILES: [OH:1][C:2]([P:15]([OH:18])([OH:17])=[O:16])([CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3]([OH:5])=[O:4]>[Pd].O>[OH:1][C:2]([P:15]([OH:17])([OH:18])=[O:16])([CH2:6][CH2:7][N:8]=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(O)(CCNc1ccccn1)P(=O)(O)O
Agent: [Pd]
Solvent: O
Product: O=C(O)C(O)(CCN=C1CCCCN1)P(=O)(O)O
Reaction time: 48 h

Procedure:
A mixture of 2-Hydroxy-2-phosphono-4-(2-pyridylamino)butanoic acid (1.5 g), 100 ml of distilled water, and 0.5 g of palladium on carbon catalyst is hydrogenated at 40 PSI on a Parr apparatus for 2 days. The catalyst is removed by filtration, and the filtrate is evaporated to dryness under vacuum. The resulting crude product is purified by recrystallization from water/ethanol to yield 2-hydroxy-2-phosphono-4-((2-piperidinylidene)amino)butanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1Br)=[O:4].[CH2:18](C([Sn])=C(CCCC)CCCC)[CH2:19]CC>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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:8][C:9]=1[CH:18]=[CH2:19])=[O:4]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)OC
Temperature: 110 °C
Yield: 77.2 %

Procedure:
Dissolve 3-bromo-5-(4-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester (570 mg, 1.72 mmol) in toluene (10 mL) and add tributylvinyltin (0.55 mL, 1.89 mmol), and tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol). Heat the mixture to 110° C. for 17 h. Cool the mixture to room temperature and concentrate in vacuo. Purify by chromatography eluting with 5% ethyl acetate/hexane to give 0.37 g (77%) of the title compound. LC-MS/ES m/z (35Cl) 279.0 [M+H]−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30](O)=[O:31])=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:20][CH:19]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:30]([C:25]1[C:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:28][N:27]([CH3:29])[N:26]=1)=[O:31]
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2nc3ccccc3s2)n1

Procedure:
The title compound (0.210 g) was prepared from 2-piperidin-2-ylmethyl-benzothiazole, D30 (0.135 g) and 4-(4-fluorophenyl)-1-methyl-1-H-pyrazol-3-carboxylic acid (0.135 g) using the procedure described in Example 60.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH2:14]([C:19]1[CH:24]=[CH:23][C:22](OB(O)O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:14]([C:19]1[CH:20]=[CH:21][C:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]3)=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: CCCCCc1ccc(OB(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
At first, 55 g of 6-bromo-1-chloro-2-naphthol (S1-2), 12.3 g of 4-pentyl-phenylboric acid (S1-3), 1.0 g of tetrakis(triphenylphosphine) palladium, 13.6 g of sodium carbonate and 100 ml of a mixed solvent of toluene/ethanol/water=3/3/1 were added to a reactor in nitrogen atmosphere and refluxed for 10 hours. The reaction solution was cooled to room temperature, added with toluene, and then washed with 1N HCl(aq) and water, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using toluene as an eluting solvent, and then dried under a reduced pressure to obtain 15 g of 6-(4-pentylphenyl)-1-chloro-2-naphthol (S1-4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]1>CN(C=O)C>[O:62]=[S:59]1(=[O:63])[CH2:60][CH2:61][N:56]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (73 mg, 55%) as a white solid. MS: m/e=446.1 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:4]1.O=S(Cl)[Cl:16]>C(Cl)(Cl)Cl>[Cl:16][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: CCCC(=O)N1CCCC(CO)C1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N1CCCC(CCl)C1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 1-(3-hydroxymethyl-piperidin-1-yl)-butan-1-one (Starting material 1-01e, 1.33 g, 7.20 mmol) in dry chloroform (10 ml) is cooled down to 0° C. with an ice-water bath. A solution of SOCl2 (1.43 g, 876 μl, 12 mmol) in dry chloroform (10 ml) is added dropwise. The mixture is allowed to stir at reflux for 30 min. The solution is cooled down to rt, SOCl2 (0.48 g, 0.3 ml, 4.1 mmol) is added dropwise and the resulting solution is allowed to stir at reflux for another 30 min. Evaporation of the solvents under reduced pressure gives a brown liquid which is purified by column chromatography on silica-gel (AcOEt/heptane, 35:65), yielding the title compound (1.15 g) in 78% as a colourless liquid: 1H-NMR (CDCl3): The product is a (1:1) mixture of rotamers: δ (ppm) 0.95 (t, 3H, CH3), 1.33-1.54 (m, 2H), 1.58-1.95 (m, 3H), 1.68 (quint., 1H, CH2CH2CH3), 2.32 (dd, 2H, CH2C═O), 2.60 (t, 0.5H), 2.83 (t, 0.5H), 2.99 (m, 2H), 3.36-3.55 (m, 2H), 3.77 (d, 0.5H), 3.93 (d, 0.5H), 4.30 (d, 0.5H), 4.54 (d, 0.5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[Na+].[I-:28].CNCCNC.O1CCOCC1>CCOC(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([I:28])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)c2cc(I)ccc2n1-c1ccc(OC(C)C)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A mixture of 5-bromo-3-chloro-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (2.80 g, 6.44 mmol) (prepared in accordance with the procedure described in Example 35, Method 1, step (b)), CuI (122 mg, 0.64 mmol), NaI (1.94 g, 12.9 mmol), N,N′-dimethyl-1,2-diaminoethane (142 μL, 1.28 mmol) and 1,4-dioxane (10 ml) was stirred at 120° C. for 24 h. The mixture was cooled to room temperature and diluted with EtOAc (200 ml). The combined organic phase was washed with diluted NH4OH solution (2×200 mL), HCl (0.1 N solution; 2×200 mL), brine (100 mL) and dried over Na2SO4. Filtration and concentration of the organic phase gave the sub-title compound (3.02 g 97%).
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:27]([F:26])([F:36])[F:37])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNS(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(C=C2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 110 °C
Yield: 54.9 %

Procedure:
A mixture of N-isobutyl-4-(1-methanesulfonyl-piperidin-4-ylidenemethyl)-benzenesulfonamide (375 mg, 0.97 mmol), 2-(trifluoromethyl)benzyl bromide (289 mg, 1.22 mmol) and K2CO3 (201 mg, 1.46 mmol) in DMF (5 mL) was heated at 110° C. for 6 hours. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and concentrating the residue from Et2O gave the title compound (290 mg, 55%). 1H NMR (400 MHz, DMSO) δ 7.83 (d, J=8.3 Hz, 2H), 7.70-7.73 (m, 3H), 7.49 (t, J=8.1 Hz, 3H), 6.51 (s, 1H), 4.46 (s, 2H), 3.22 (dt, J=30.4, 5.7 Hz, 4H), 2.96 (d, J=7.3 Hz, 2H), 2.89 (s, 3H), 2.49-2.50 (m, 4H), 1.39-1.40 (m, 1H), 0.70 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 544.9 [M+1]+.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH:26](=O)[CH3:27]>C(Cl)Cl.CN(C=O)C.[Cu](Cl)Cl>[CH3:26][C:27]1[N:4]2[C:5]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=3[N:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: Cn1cc(-c2cc3nc(NN)cnc3n2COCC[Si](C)(C)C)cn1
Reactant: CC=O
Agent: Cl[Cu]Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nnc2cnc3c(cc(-c4cnn(C)c4)n3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
To a flask was added 2-hydrazinyl-6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.100 g, 0.278 mmol, Preparation #P.2.1) and acetaldehyde (0.079 mL, 1.3 mmol) in DCM (3 mL). The mixture was stirred at rt for about 90 min. The mixture was concentrated in vacuo to give a residue. The residue was transferred to a flask and copper(II) chloride (0.075 g, 0.56 mmol) in DMF (3 mL) was added. The mixture was heated to about 90° C. for about 2 h. The mixture was cooled to rt, diluted with ice water (50 mL) and the solid was collected by filtration. The solid was taken up in DCM/MeOH and the insoluble solids were collected by filtration while the mother liquor was purified by flash chromatography (25 g silica gel column, DCM/EtOAc/MeOH 1:0:0 to 0:1:0 to 9:0:1) to give a solid. The solids were combined to give 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.04 g, 37%): LC/MS (Table 2, Method c) Rt=1.48 min; MS m/z 384 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH2:20][C:21]#[CH:22])[C:13]2=[O:23])=[CH:10][C:5]([NH:6]C(=O)C)=[C:4]([F:24])[CH:3]=1.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(O)C>[NH2:6][C:5]1[C:4]([F:24])=[CH:3][C:2]([Cl:1])=[C:11]([N:12]2[C:17](=[O:18])[NH:16][C:15](=[O:19])[N:14]([CH2:20][C:21]#[CH:22])[C:13]2=[O:23])[CH:10]=1
Reactant: C#CCn1c(=O)[nH]c(=O)n(-c2cc(NC(C)=O)c(F)cc2Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 4'-chloro-2'-fluoro-5'-[hexahydro-2,4, 6-trioxo-3-(2-propynyl)-s-triazin-1-yl]acetanilide (3.00 g, 8.5 mmol), and 3N hydrochloric acid (25 mL) in ethanol (50 mL) is refluxed for 3 hours, cooled to room temperature, and poured into ethyl acetate. 3N sodium hydroxide solution (25 mL) is added to the organic solution, and the phases are separated. The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution and brine, and concentrated in vacuo to give the title product as a beige solid (2.17 g, mp 118°-121° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([F:32])[CH2:28]1)=[O:26])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CCCC)=[O:19])[CH2:14][CH2:13]1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+].S(=O)(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([F:32])[CH2:28]1)=[O:26])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)C1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C1CCC(C(=O)O)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material prepared in Step B (3.0 g, 6.1 mmol) in THF (30 mL) was added methanol (10 mL) followed by 1N aqueous lithium hydroxide (30 mL). After 24 h at ambient temperature the mixture was brought to pH 1 with 1N aqueous sodium bisulfate. The mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo, affording the title compound. This was used without further purification. LC/MS 406.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:23]1[S:22][C:21]([S:18]([NH:17][C@@H:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][OH:16])(=[O:19])=[O:20])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CO)NS(=O)(=O)c2ccc(Cl)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(N[C@H](CO)C1CCNCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
To a solution of 4-[1-(5-chloro-thiophene-2-sulfonylamino)-2-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (0.204 g, 0.48 mmol (see example 209)) dissolved in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.5 mL). The reaction was allowed to warm to 25° C. and stir overnight. The mixture was then concentrated and dichloromethane was added and evaporated 6 times to yield a crude solid. Purification by HPLC. (C-18 column, (21×75 mm) with elution system 60-100% acetonitrile-water+0.1% TFA, 20 min gradient) gave the product as an oil (0.0166 g, 11%). MS (ESI) m/z 325 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[S:12][C:13]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:37]>C(O)C>[ClH:37].[CH3:1][NH:2][CH2:10][C:11]1[S:12][C:13]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: CN(Cc1nc(-c2ccccc2)c(S(=O)(=O)c2ccccc2)s1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1nc(-c2ccccc2)c(S(=O)(=O)c2ccccc2)s1
Reaction time: 14 h
Yield: 53 %

Procedure:
To a solution of tert-butyl methyl{[4-phenyl-5-(phenylsulfonyl)-1,3-thiazol-2-yl]methyl}carbamate (0.18 g) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) at room temperature, and the mixture was stirred for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as white crystals (yield 80 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1.C1COCC1.O.C([O-])(O)=O.[Na+].Cl[C:33]([O:35][CH3:36])=[O:34]>O>[Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: C[C@H](N)CNc1nccc(-c2[nH]c(C3CC3)nc2Br)n1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CC3)nc2Br)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture of (S)—N1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (13.3 g, 27.3 mmol, assumed theoretical yield) in 1:1 THF-water (200 mL) was cooled to 0° C. and solid NaHCO3 (20.6 g, 245 mmol) was added in portions. Methyl chloroformate (3.74 mL, 27.3 mmol) was added dropwise over 20 minutes and stirred for an additional 30 minutes. LCMS of an aliquot indicated complete reaction. Water (300 mL) was added and the resulting mixture was extracted with EtOAc (3×500 mL). The EtOAc layer was washed with brine (2×1 L), dried (Na2SO4) and concentrated. The resulting solid was suspended in a mixture of EtOAc (7 mL) and ethyl ether (25 mL) and the resulting suspension was allowed to settle at 0° C. The solids were collected and washed with cold Et2O (20 mL) to afford (S)-methyl 1-(4-(4-bromo-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (9.56 g, 24.1 mmol, 89%) as an off-white solid: LCMS (m/z) 395.1 (MH+), tR=0.61 minute; 1H NMR (400 MHz, CDCl3) δ 0.91-1.03 (m, 2H), 1.08-1.19 (m, 2H), 1.22 (d, J=6.6 Hz, 3H), 1.77 (br s, 1H), 2.13-2.26 (m, 1H), 2.70-2.90 (m, 1H), 3.70 (s, 3H), 3.90-4.03 (m, 1H), 4.18-4.32 (m, 1H), 4.46-4.86 (m, 1H), 5.48-5.60 (m, 1H), 7.46 (d, J=5.5 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][C:29]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CCOCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:7]2[C:2]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:29]=3[CH3:28])=[N:3][C:4]([CH3:27])=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: COc1ccccc1COc1ccc(S(=O)(=O)c2ccc(C)nc2Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2nc(C)ccc2S(=O)(=O)c2ccc(OCc3ccccc3OC)cc2)c(C)c1
Temperature: 70 °C
Yield: 15 %

Procedure:
2-Bromo-3-[4-(2-methoxybenzyloxy)-benzenesulfonyl]-6-methylpyridine from part F (75 mg, 0.167 mmol), 2-methyl-4-methoxyaniline (26 μL, 0.200 mmol), Pd(dba)3 (3 mg, 0.0033 mmol), dppp (3 mg, 0.0067 mmol), and NaOt-Bu (22 mg, 0.234 mmol) were suspended in toluene in a tightly capped conical vial. The reaction mixture was heated at 70° C. for 4.5 h. The mixture was cooled to rt, and diluted with ether. The organic layer was washed with brine (2×), dried over MgSO4, filtered, and concentrated. Purified by preparative TLC (1000 μM silica gel plate, 15% ethyl acetate in hexanes) to furnish the desired product (13 mg, 15% yield) as a pale yellow solid: mp 70–72° C.; 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.77 (d, J=9.2 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.30–7.22 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.90 (d, J=7.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.68 (d, J=9.1 Hz, 2H), 6.53 (d, J=8.0 Hz, 1H), 5.23 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H); HRMS (ESI) m/z 505.1807 [(M+H)+, calcd for C28H29N2O5S, 505.1797].