Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5](O)=O)=O.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#C.C(OC(=O)C)(=O)C>CCCCCC>[C:8]1([N:3]2[CH:4]=[CH:5][C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:1]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C#CC(=O)OCC
Reactant: O=CN(CC(=O)O)c1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(-c2ccccc2)c1

Procedure:
A mixture of 2.69 g (15 mmole) of N-formyl-N-phenyl-glycine prepared in Reference Example 3, 5.47 g (55.8 mmole) of ethyl propiolate, and 15 ml of acetic anhydride was stirred using a magnetic stirrer over an oil bath at 130° C. for 22 hours. The reaction mixture was concentrated under vacuum. 22 ml of toluene was added to the residue and the mixture was evaporated under reduced pressure. This procedure was repeated to obtain a brown oily substance. This oily substance was purified using silica gel column chromatography (No. 9385 silica gel, manufactured by Merck Co., eluted with ethyl acetate:hexane=1:5 v/v) to obtain 2.8949 (yield 89.6%) of a light-yellow oil of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH2:20][C:21]1([C:24]#[N:25])[CH2:23][CH2:22]1)(=O)=O.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:20][C:21]3([C:24]#[N:25])[CH2:23][CH2:22]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OCC1(C#N)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC3(C#N)CC3)c2)OC1(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), (1-cyanocyclopropyl)methyl methanesulfonate (0.14 g, 0.77 mmol), and sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 2 h. After cooling, it was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.15 g of the crude product which was used in the next step reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16](O)=[O:17])[C:10]2=[O:34])[S:6][CH:7]=1)#[N:2].C(C1SC=C(CN2CC[C@H](N(CC(O)=O)S(C3C=CC4C(=CC(OC)=CC=4)C=3)(=O)=O)C2=O)C=1)#[N:36]>>[C:1]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16]([NH2:36])=[O:17])[C:10]2=[O:34])[S:6][CH:7]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4cc(C#N)cs4)C3=O)cc2c1
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(CC(N)=O)[C@H]3CCN(Cc4cc(C#N)cs4)C3=O)cc2c1

Procedure:
The tiltle compound is prepared as described in EXAMPLE 127, Part C, substituting 2-[[1-(4-cyanothiophene-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid for 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid. The title compound is obtained as a white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])C=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[O:30]1CCC[CH2:31]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:31]([OH:30])[C:25]2[CH:22]=[CH:21][C:20]([O:19][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:27]([O:28][CH3:29])[CH:26]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: C1CCOC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Product: COc1cc(C(O)c2ccc(Br)cc2)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,4-dibromobenzene (25.72 g, 109 mmol) in dry tetrahydrofuran (50 ml) at isopropanolg/dry ice bath temperature under argon was added n-butyl lithium (43.6 ml of 2.5 M solution in hexane, 109 mmol) dropwise. This was stirred for one hour during which time a slurry formed. This slurry was added via cannula to a solution of 3-cyclopentoxy-4-methoxybenzaldehyde (20.0 g, 90.8 mmol) in dry THF (140 ml) at isopropanol/dry ice bath temperature. After one hour, the reaction was allowed to gradually warm to room temperature and stirred for an additional 4 h. The reaction was quenched with water then extracted three times with diethyl ether. The combined organic extract was washed successively with 1% hydrochloric acid, water, brine, then dried and evaporated. Purification by flash chromatography (silica gel, 17% ethyl acetate/83% hexane) provided the title compound as a pale white solid (36.78 g, 100% crude yield). MS (m/e): 359 [(M+1H2O)+]
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]([NH:3][C@@H:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]([CH3:6])[CH3:7])=[O:39])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N[C@@H](C(=O)N2CCC(C3CCN(C)CC3)CC2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
1-D-Valinyl-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride (15.6 g, 44.1 mmol) is slurried in anhydrous CH2Cl2 (400 mL); and to the slurry is added triethylamine (19.7 mL, 141.0 mmol), followed by p-anisoyl chloride (7.9 mL, 52.9 mmol). The reaction is allowed to stir for about 30 min and then quenched with the addition of saturated NaHCO3 (300 mL), followed by the separation of the phases. The organic layer is washed with saturated NaHCO3 (2×300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel, eluting with 2.5% (2 M NH3 in MeOH)/CHCl3 to give 16.3 g (89%) of the title compound as a white foam.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccc(Cl)cc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,4-dichlorobenzene and isolated as colorless gum (6.5 mg, 36%). MS (m/e): 441.3 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:46])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C@H:35]([O:40][CH3:41])[CH2:36][C:37](O)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:48][O:49][C@@H:50]([C@@H:68]1[CH2:72][CH2:71][CH2:70][NH:69]1)[C@@H:51]([CH3:67])[C:52]([NH:54][C@H:55]([C:63]([O:65][CH3:66])=[O:64])[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[S:53].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:46])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C@H:35]([O:40][CH3:41])[CH2:36][C:37]([N:69]3[CH2:70][CH2:71][CH2:72][C@H:68]3[C@H:50]([O:49][CH3:48])[C@@H:51]([CH3:67])[C:52]([NH:54][C@@H:55]([CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:63]([O:65][CH3:66])=[O:64])=[S:53])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=S)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #8 (247 mg, 0.387 mmol, 1 eq.), #39 (186 mg, ≦0.450 mmol, 1.2 eq.), dichloromethane (10 mL, 0.04 M), N,N-dimethylformamide (2 mL), HATU (176 mg, 0.464 mmol, 1.2 eq.) and triethylamine (189 mL, 1.35 mmol, 3.5 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 25% acetone in heptane) to give #40 (410 mg, 90% over 2 steps) as an off-white solid. LC-MS: m/z 984.7 [M+H+], 1006.7 [M+Na+], retention time=1.15 minutes; HPLC (Protocol C): retention time=9.683 minutes (purity >99%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (br d, J=7 Hz) and 10.49 (br d, J=8 Hz), total 1H], 7.90 (d, J=7.5 Hz, 2H), 7.60-7.65 (m, 2H), 7.38-7.45 (m, 2H), 7.29-7.35 (m, 2H), 7.14-7.28 (m, 5H), [5.20 (ddd, J=11, 7, 4 Hz) and 5.35-5.43 (m), total 1H], 3.65 and 3.69 (2 s, total 3H), [1.15 (d, J=6.5 Hz) and 1.18 (d, J=6.4 Hz), total 3H].
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=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.COCCOC>[C:32]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[C:33]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1cccc2ccccc12
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: COCCOC
Product: O=C1Nc2cccc(-c3cccc4ccccc34)c2/C1=C/c1ccc[nH]1
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.119 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (119 μL , 0.238 mmol), (Ph3P)4Pd (3 mg, 0.003 mmol) (Aldrich), and 1-naphthaleneboronic acid (22.5 mg, 0.131 mmol) (Lancaster) in 3 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes then 30% ethyl acetate-hexanes elution) to yield a crude solid. Recrystallization from chloroform-pentane provided pure (Z)-1,3-dihydro-4-(1-naphthalenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 31 mg, 78%) as yellow crystals (mp 210-212° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:49][C@@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@H:51]1[NH2:56]>CN(C)C=O>[NH2:49][C@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]1[NH:56][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
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: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
2-Methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C, 590 mg, 2.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (646 mg, 5 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.05 g, 2.7 mmol) were added. After 5 minutes of stirring at room temperature cis-1,2-diaminocyclohexane (570 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-N-(2-amino-cyclohexyl)-2-methylsulfanyl-4-trifluoromethyl-benzamide as a light yellow solid (282 mg, 34%), MS: m/e=3331.1 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.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>[CH3:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: Cc1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2ccc(C(=O)Nc3ccc4cccnc4c3)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) in toluene (2 ml) and ethanol (0.4 ml) under an argon atmosphere was added 3-methyl-phenylboronic acid (21 mg, 0.153 mmol), 2M sodium carbonate solution (0.15 ml) and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.05 mmol). The reaction was heated at reflux for 18 h, then cooled to room temperature and diluted with EtOAc. The mixture was washed with sat. aq. sodium bicarbonate solution and water, dried over MgSO4 and concentrated to give the crude product which was purified by SPE column chromatography. Elution with 50% EtOAc in 40-60° C. petroleum ether gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.19 (d, 1H), 8.13 (m, 3H), 8.01, (d, 2H), 7.86 (d, 1H), 7.75 (d, 2H), 7.46 (m, 2H), 7.36 (m, 2H), 7.25 (m, 1H), 2.46 (s, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:24][C:25]1[C:30]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]([O:9][CH2:10][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: O=C([O-])CCCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(CCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1cccc2c1Cc1ccccc1-2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Fluorenylmethyl glutarate (2.5 kg) and pentafluorophenol (1.63 kg) were dissolved in ethyl acetate (25 L). The solution was treated with a solution of dicyclohexylcarbodiimide (1.83 kg) in ethyl acetate (7.5 L) and the mixture was stirred at 20° C. overnight. The resulting slurry was filtered and the solids were washed through with ethyl acetate (10 L). The filtrate was evaporated at atmospheric pressure to a volume of 7.5 L and diluted with hexane (75 L). The slurry was filtered at 60–65° C. then allowed to cool to room temperature and stirred overnight. The slurry was cooled to 0° C. for 1 hour, the solid collected by filtration and washed with 10:1 hexane/ethyl acetate (15 L). The solid was dried in vacuo at 45° C. to afford the title compound as a white crystalline solid. Yield: 3.553 kg, 93%. HPLC; >99 A %.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:28])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[C@H:14]([CH3:26])[NH:15]C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCOCC>Br.C(O)(=O)C>[CH2:1]([NH:6][C:7](=[O:28])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[C@H:14]([CH3:26])[NH2:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.5 %

Procedure:
2.5 g of N-benzyloxycarbonyl-L-alanyl-L-proline n-pentylamide were dissolved in 15 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred for 1 hour at room temperature. 150 ml of dry ether were added. An oil precipitated out and was allowed to settle. The ether was decanted off and the procedure repeated using 150 ml of fresh ether. On evaporation there were obtained 2.5 g of L-alanyl-L-proline n-pentylamide in the form of a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32]C(=O)OC(C)(C)C)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])[N:6]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of tert-butyl 2-(5-acetyl-2-(2-methoxy-4-morpholinophenyl amino)pyrimidin-4-ylamino)phenylcarbamate (100 mg) in DCM (5 ml), TFA (1 ml) was added at 0° C., and the mixture was stirred for 1 h at rt. TLC showed completion of starting material (TLC system: 5% methanol in DCM (Rf): 0.5). After removal of TFA under reduced pressure, the residue was triturated with diethyl ether to give the desired compound as a yellow solid 85 mg (Yield: 98%). MS: m/z 435.2 (ES+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3](C)[CH:2]=1.C([Mg]Br)C.[Mg].BrCC.[CH2:17]=[O:18].C1C[O:22][CH2:21]C1>CN1CCCN(C)C1=O.C1(C)C=CC=CC=1>[OH:18][C:17]1[CH:5]=[CH:4][C:3]([O:22][CH3:21])=[CH:2][C:1]=1[CH:6]=[O:7]
Reactant: C=O
Reactant: Cc1ccc(O)cc1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Solvent: CCBr
Product: COc1ccc(O)c(C=O)c1
Temperature: -10 °C

Procedure:
p-Cresol (100 g) in dry THF(100 ml) was added dropwise to a mechanically stirred, freshly prepared solution of ethyl magnesium bromide [magnesium (25.0 g) and bromoethane (75 ml)]in THF (500 ml) under nitrogen at a rate which maintained a slow reflux (about 30 mins). After a further 30 mins toluene (1.21) was added, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (125 ml), and paraformaldehyde (70 g). The mixture was then heated at reflux for 16 h. The mixture was concentrated by distillation and aqueous hydrochloric acid (2M, 600 ml) then added. Water (600 ml) was added and the mixture filtered through "hyflo". The organic phase was separated, dried, filtered and concentrated in vacuo to give a brown oil. The oil was steam distilled and the product extracted from the distillate with ether (1 liter). The organic extract was dried, filtered and concentrated in vacuo to give a pale yellow slurry which was cooled to -10° C., triturated with ether (precooled to -78° C., 100 ml), filtered off rapidly and washed with ether (precooled to -78° C.) to give the title compound as colourless needles, (131.4 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5](I)=[CH:6][C:7]=1[CH3:8].[Na].[CH3:11][OH:12]>>[OH:1][CH2:2][C:3]1[S:4][C:5]([O:12][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: CO
Reactant: Cc1cc(I)sc1CO
Agent: [Na]
Product: COc1cc(C)c(CO)s1
Temperature: 80 °C

Procedure:
10.0 G. (0.125 mol) of cupric oxide and 11.0 g. (0.0433 mol) of 2-hydroxymethyl-3-methyl-5-iodothiophene was added to a solution of 10.0 g. (0.435 mol) of sodium in 90 ml. of methanol. The resulting reaction mixture was heated to 80° C. for 18 hrs. with vigorous stirring. The cold solution was filtered, the filtrate poured into ice water and extracted with ether/hexane (ratio 4:1). The organic extracts were washed with 10% sodium thiosulfate solution and saturated sodium chloride solution, dried and evaporated to yield 2-hydroxymethyl-3-methyl-5-methoxythiophene as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[N+:17]([C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:25]3[CH:24]=[C:23]4[C:27]([CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=[CH:22]4)=[N:26]3)[N:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: Nc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc2cn(-c3nccc(Nc4ccc(Cl)cc4)n3)nc2c1

Procedure:
Was prepared according to Method A from 2,4-dichloropyrimidine, 4-chloroaniline and 6-nitroindazole. LC-ESI-HRMS of [M+H]+ shows 367.0717 Da. Calc. 367.071027 Da, dev. 1.8 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Nc1ccc(OS(=O)(=O)c2ccc(-n3ccnc3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 57.8 %

Procedure:
15.6 g of 2-amino-5-(4-fluorophenylsulfonyloxy)nitrobenzene were combined with 20.7 g imidazole in 100 ml dimethylformamide in a round bottom flask. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. Reaction mixture was then precipitated by addition of water filtered and precipitate was washed with water and dried. Residue was resolubilized in hot ethyl glycol, crystallized by cooling and the crystals were washed with methanol and dried, yielding 10.4 g of 2-amino-5-(4-[1-imidazolyl]-phenylsulfonyloxy)nitro-benzene (melting point 209° C.).