Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42]>CC(C)=O.O.C(OCCCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:40]([CH3:39])[S:41]([CH3:44])(=[O:43])=[O:42])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 60 °C
Yield: 82.5 %

Procedure:
In a 200 L-volume glass-lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 17.9 kg (62.0 mol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine prepared as above, 107.7 kg of butyl acetate, 11.1 kg (80.3 mol.) of potassium carbonate (available from Asahi Glass Works, Co., Ltd., Lot No. 1111632, particle size distribution: 75-250 μm: 14%, 75 μm pass: 86%), and 12.9 kg (67.7 mol.) of p-toluenesulfonyl chloride. The mixture was heated at 60° C. for 2 hours, to carry out reaction. Subsequently, the reaction mixture was cooled to room temperature. To the cooled mixture were added 8.8 kg (80.6 mol.) of N-methylmethanesulfonamide and 12.9 kg (93.3 mol.) of potassium carbonate, and the resulting mixture was heated at 122-125° C. for 3 hours, for carrying reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture were added acetone and water, and the organic liquid portion was separated. The organic liquid portion was then washed successively with aqueous sodium hydroxide solution (3 wt. %) and a saturated aqueous sodium chloride solution. The washed organic liquid portion was concentrated under reduced pressure. Isopropyl alcohol and water were added to the residue, resulting in precipitation of a crystalline product. The crystalline product was filtered on a filter paper and washed with isopropyl alcohol. The washed crystalline product and 85.7 kg of acetone were placed in a 200 L-volume glass lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser. The mixture was stirred at 50-55° C., to dissolve the crystalline product in acetone. The insoluble was removed with a line filter. Subsequently, 58.3 kg of water was added to the solution, to precipitate a crystalline product. The crystalline product was collected on a filter paper and washed with an acetone/water mixture, to give 19.5 kg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][O:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]2[N:61]=[C:62]([CH:64]=O)[N:63]=[C:56]2[N:55]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][O:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:64][C:62]3[N:63]=[C:56]4[N:55]=[C:54]([CH3:53])[CH:59]=[C:58]([CH3:60])[N:57]4[N:61]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: COCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione (Example A(194)) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in that example. 1H NMR (400 MHz, DMSO-d6): δ 1.5–2.0 (m, 11H) 2.46–2.75 (m, 11H), 3.25 (s, 3H), 3.73 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H), 4.32 (s, 2H), 6.70 (d, J=8 Hz, 1H), 6.94–7.04 (m, 3H), 9.20 (s, 1H). Anal. Calcd. For C28H34N4O5.1.5H2O: C, 63.02; H, 6.99; N, 10.50. Found: C, 63.92; H, 6.74; N, 10.42. MS (ESI): 507.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:23]=1[Cl:29].CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[O:18][CH:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][S:16][CH3:17]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CSCCC(Oc1cccc(Cl)c1Cl)C1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(1-Hydroxy-3-methylsulfanylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester (49 mg, 180 mmol) was dissolved in DMF (550 μL). 60% NaH in oil (60:40, NaH:mineral oil, 8.5 mg, 210 μmol) was slowly added, and the mixture was stirred for 15 minutes at room temperature. 1,2-Dichloro-3-fluorobenzene (62 μL, 530 μmol) was added, and the resulting mixture was heated at 90° C. for 24 hours. The reaction was quenched with MeOH, and DMF/MeOH was removed in vacuo. The product was dissolved in 1.25M HCl in EtOH (1.4 mL, 1.8 mmol) and stirred overnight at room temperature. The product was then purified by preparative HPLC to yield the title compound as a mixture of all 4 stereoisomers (R,R, R,S, S,S, and S,R) as mono-TFA salts (20 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NOS, 320.06. found 320.0.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.CS(C1N=C(C2C=NN(C)C=2)C=CN=1)=O.[NH2:32][C:33]1[C:34]([F:41])=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:41][C:34]1[CH:35]=[C:36]([CH3:40])[C:37]([O:39][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[CH:7][N:6]=2)=[CH:38][C:33]=1[NH2:32]
Reactant: Cn1cc(-c2ccnc(S(C)(=O)=O)n2)cn1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cn1cc(-c2ccnc(S(C)=O)n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)cc1Oc1nccc(-c2cnn(C)c2)n1

Procedure:
A mixture of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine from Example A16 (1 g, 4.2 mmol), 5-amino-4-fluoro-2-methylphenol (1.2 g, 8.5 mmol) and K2CO3 (1.2 g, 8.6 mmol) were combined in DMF (10 mL) using a procedure analogous to Example A10 to provide 2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine (420 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 5.02 (br s, 2H), 3.88 (s, 3H), 1.88 (s, 3H); MS (ESI) m/z: 300.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:10]1(=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:8][N:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[O:20])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl

Procedure:
A solution of (3-chloropyrazin-2-yl)-methanol (47 g, 0.33 mol), isoindole-1,3-dione (58.3 g, 0.396 mol, 1.2 eq.), and triphenylphosphine (89.7 g, 0.396 mol, 1.2 eq.) in anhydrous THF (1.5 L) was charged with DIAD (80.2 g, 0.396 mol, 77.1 mL, 1.2 eq.) dropwise at rt, under N2, making sure the internal temperature did not surpass 40° C. The crude material was adsorbed onto silica gel, dry loaded, and purified by chromatography on silica gel [6″×16″ column, 2.75 kg silica gel, eluting with Hex:CH2Cl2 1:1→neat CH2Cl2→MeCN:CH2Cl2 2→10%.] Material was combined and concentrated in vacuo. Residue was dissolved as best as possible in hot CH2Cl2 (500 mL), after which i-PrOH was added and a white crystalline solid began to precipitate out of solution. Solid was filtered, washed with i-PrOH, and oven-dried to remove all traces of solvent, affording the title compound, as an off-white solid; 1H NMR (400 MHz,CDCl3) δ 5.10 (s, 1H), 7.75-7.80 (m, 2H), 7.89-7.94 (m, 2H), 8.26 (1H, d, J=2.45 Hz), 8.31 (1H, d, J=2.49 Hz); MS (ES+): m/z 274.21/276.19 (100/50) [MH+]; HPLC: tR=3.35 min (OpenLynx, nonpolar—7 min).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10]CO)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:45][CH2:46][N:47]([CH:51]([CH3:53])C)[CH:48](C)C.CS(Cl)(=O)=[O:56]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34]([N:37]5[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]5[CH3:44])=[N:35][N:36]=4)[CH:33]=3)[CH2:19][CH2:18]2)=[O:15])[N:8]([CH2:10][CH2:48][N:47]2[CH2:51][CH2:53][O:56][CH2:45][CH2:46]2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCN4CCOCC4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Example 118 (43 mg, 0.07 mmol) in DCM (1.5 mL) was added DIPEA (49 μL, 0.18 mmol) followed by methanesulfonyl chloride (11 μL, 0.11 mmol). The reaction mixture was stirred for 1 h and then quenched with water.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([OH:20])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].C[C:22]([O-])([CH3:24])[CH3:23].[K+].[CH3:27][CH:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CN(C)C=O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([CH2:7][C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:18]([C:8]3[CH:9]=[N:10][C:22]([CH3:23])=[CH:24][CH:7]=3)=[C:17]([O:20][S:30]([CH:28]([CH3:29])[CH3:27])(=[O:32])=[O:31])[CH:16]=2)=[CH:13][N:12]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1I
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)C)c1-c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(3-Ethoxy-5-hydroxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (see example 32 stage a)) (5.9 g; 15.28 mmol) is dissolved in dimethylformamide (150 ml), and potassium tert-butylate (2.57 g; 22.92 mmol) is added. Propane-2-sulphonyl chloride (2.56 ml; 22.92 mmol) is added at 0° C. The mixture is then stirred for one hour at room temperature. The reaction mixture is evaporated and the residue is chromatographed over silica gel with methylene chloride/methanol (19/1) and 0.5% ammonia. The pure fractions are combined and the solvent is evaporated off.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.O.CCN=C=NC[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].Cl.Cl.[O:25]=[C:26]1[NH:34][C:33]2[C:28](=[N:29][C:30]([C:35]3[CH:36]=[N:37][N:38]4[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:39]=34)=[N:31][CH:32]=2)[N:27]1[C@H:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1>CN(C=O)C>[CH3:21][N:20]([CH3:22])[CH2:19][C:18]([N:48]1[CH2:49][CH2:50][CH2:51][C@H:46]([N:27]2[C:26](=[O:25])[NH:34][C:33]3[C:28]2=[N:29][C:30]([C:35]2[CH:36]=[N:37][N:38]4[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:39]=24)=[N:31][CH:32]=3)[CH2:47]1)=[O:10]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of N,N-dimethylglicine (10 mg, 0.095 mmol) in anhydrous DMF (2 mL). HOBt.H2O was added. After 15 min, EDC.HCl (24 mg, 0.126 mmol) and the compound obtained in example 6 (31 mg, 0.063 mmol) were added. The reaction mixture was stirred at room temperature for 2.5 h and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 8.2 mg of the titled compound (29% yield).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][S:8][C:9]1[C:14]2[N:15]=[C:16]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1>O1CCOCC1>[C:4]([N:28]1[CH2:29][CH2:30][N:25]([C:16]2[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH3:7])[C:14]=3[N:15]=2)[CH2:26][CH2:27]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: CSc1ncnc2c(N3CCSCC3)nc(N3CCNCC3)nc12
Reactant: C=C1CC(=O)O1
Solvent: C1COCCO1
Product: CSc1ncnc2c(N3CCSCC3)nc(N3CCN(C(=O)CC(C)=O)CC3)nc12
Reaction time: 0.5 h

Procedure:
1.6 gm (0.02 mol) of diketene were slowly poured, while stirring, into a solution of 3.6 gm (0.01 mol) of 8-methylthio-2-piperazino-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 177°-179° C.) in 50 ml of dioxane. After stirring for 30 minutes more, the solvent was evaporated in vacuo, and the residue was taken up in about 100 ml of water. The precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: N[CH:2]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>O>[ClH:16].[ClH:16].[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:2]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: ClCCN1CCCCC1
Reactant: CC(C)CCC(N)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC(CCN1CCCCC1)C(O)c1ccccc1
Product: Cl
Yield: 36.1 %

Procedure:
A mixture of (1RS,2SR)-2-amino-5-methyl-1-phenylhexan-1-ol (1.04 g, 5 mmol) and 1-(2-chloroethyl)piperidine (0.74 g, 5 mmol) was melted at 70° C. in a nitrogen atmosphere. The mixture was then heated at 110° to 120° C. for 3 hours. After being cooled, the reaction mixture was dissolved in water. The solution was basified with 2N-NaOH and then extracted with ether. The ethereal extract was washed twice with water and once with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was dissolved in acetone (20 ml), followed by addition of concentrated hydrochloric acid (0.74 ml). Precipitated crystals were collected by filtration and washed with acetone. The crystals were recrystallized from ethanol (10 ml)-ether (2 ml) to obtain 0.34 g of the title compound as white crystals (yield: 17%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[Cl:21][C:20]1[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([NH2:22])[CH:19]=1
Reactant: Oc1ccccc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.2 %

Procedure:
To a solution of phenol (0.500 g, 5.31 mmol) in dry DMF (20 mL) was added solid sodium t-butoxide (0.510 g, 5.31 mmol). The mixture was heated to 100° C. for 60 min, then 4,5-dichloro-2-nitro-phenylamine (1.00 g, 4.83 mmol) was added and the reaction mixture was heated at 100° C. for 19 h. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was added to water and extracted with EtOAc. The combined organic layers were washed with 1M Na2CO3, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 5% to 30% over 20 minutes) to yield the titled compound as an orange solid (0.821 g, 64%). 1H NMR (400 MHz, CDCl3): 8.27 (s, 1H), 7.50-7.34 (m, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.10 (dd, J=8.6, 1.1 Hz, 2H), 6.02 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]2[C:39]3[C:31](=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]([C:40](O)=[O:41])[CH2:33]4)[CH:30]=[CH:29]2)=[O:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10](=[CH2:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1.[CH:43]1[C:47]2=[C:48]3[C:52](=[CH:53][CH:54]=[C:46]2[NH:45][CH:44]=1)[NH:51][CH:50]([C:55]([N:57]1[C:68]2[C:60](=[C:61]4[C:65](=[CH:66][CH:67]=2)[NH:64][CH:63]([C:69]([O:71][CH3:72])=[O:70])[CH2:62]4)[CH:59]=[CH:58]1)=[O:56])[CH2:49]3.[C:73](O)(C(F)(F)F)=O.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]2[C:39]3[C:31](=[C:32]4[C:36](=[CH:37][CH:38]=3)[NH:35][CH:34]([C:40]([N:45]3[C:46]5[C:47](=[C:48]6[C:52](=[CH:53][CH:54]=5)[NH:51][CH:50]([C:55]([N:57]5[C:68]7[C:60](=[C:61]8[C:65](=[CH:66][CH:67]=7)[NH:64][CH:63]([C:69]([O:71][CH3:72])=[O:70])[CH2:62]8)[CH:59]=[CH:58]5)=[O:56])[CH2:49]6)[CH:43]=[CH:44]3)=[O:41])[CH2:33]4)[CH:30]=[CH:29]2)=[O:27])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)/[C:10](/[CH3:13])=[CH:11]/[CH:12]=[CH2:73])=[CH:5][CH:4]=1
Reactant: COC(=O)C1Cc2c(ccc3c2ccn3C(=O)C2Cc3c(ccc4[nH]ccc34)N2)N1
Reactant: C=CC(=C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)O)C3)(c1ccccc1)c1ccc(OC)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=C/C=C(\C)C(NCCCCCC(=O)n1ccc2c3c(ccc21)NC(C(=O)n1ccc2c4c(ccc21)NC(C(=O)n1ccc2c5c(ccc21)NC(C(=O)OC)C5)C4)C3)(c1ccccc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To a solution of 9 (213 mg, 0.36 mmol) and methyl 3-(pyrrolo[4,5-e]indolin-7-ylcarbonyl)pyrrolo[4,5-e]indoline-7-carboxylate (which had been prepared by TFA deprotection of 182 mg of the corresponding t-Boc precursor, Boger et al., supra) in 50 ml of anhydrous DMF was added EDC (200 mg). The reaction was stirred for 20 h 25° C. The resultant precipitate was collected by filtration, then washed with MeOH and ether. Drying under vacuum afforded 313 mg (90%) of the desired product as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:19]([CH2:23][CH2:24][Br:25])[C:20]([O-:22])=[O:21].O1CCC[CH2:27]1>>[CH3:27][O:22][C:20](=[O:21])[CH:19]([O:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH2:23][CH2:24][Br:25]
Reactant: C1CCOC1
Reactant: O=C([O-])C(Br)CCBr
Reactant: Oc1ccc(OCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(CCBr)Oc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To an ice-cold solution of 0.5 g (2.5 mmol) 6-benzyloxy-3-hydroxypyridine (commercially available) in 5 mL tetrahydrofuran, 0.12 g (2.7 mmol) sodium hydride (55% dispersion in mineral oil) was added portion wise. After vigorous gas evolution had ceased, the reaction mixture was stirred for another 20 min. at 0° C. and then 0.44 mL (3.1 mmol) 2,4-dibromobutyrate (commercially available) were added dropwise. The light brown suspension was stirred for 23 h at room temperature and then poured onto water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and filtered. To the filtrate silica gel was added and the slurry evaporated. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the product as a colorless oil (59%). MS (Turbo Spray): m/z=382.1 [M+H].
Reaction SMILES: C[C@H:2]([OH:6])[CH2:3][CH2:4][CH3:5].[H-].[Na+].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10].O1CCC[CH2:19]1>>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][O:6][CH2:2][CH2:3][CH2:4][CH2:5][CH3:19])[CH3:10]
Reactant: C1CCOC1
Reactant: CCOC(CBr)OCC
Reactant: CCC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Product: CCCCCOCC(OCC)OCC
Reaction time: 0.5 h

Procedure:
35 g of (S)-2-pentanol was dissolved in tetrahydrofuran, and 16 g of 60% sodium hydride was added thereto. After stirring for 30 minutes, 80 g of bromoacetaldehyde diethylacetal was added thereto, and the mixture was refluxed for 6 hours. After the reaction solution was concentrated and water and ether were added thereto, the mixture was shaken for mixing. The organic layer was collected and was dried with magnesium sulfate to remove the solvent off. Purification was carried out by column chromatography to obtain 2-(4-methylbutyloxy)acetaldehyde diethylacetal (54).
Reaction SMILES: I[Si](C)(C)C.[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][C:25]([C:30]#[N:31])=[C:26]([O:28]C)[N:27]=2)[CH2:19][CH2:18]1)=[O:15]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][C:25]([C:30]#[N:31])=[C:26]([OH:28])[N:27]=2)[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C#N
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
Iodotrimethylsilane (0.02 ml, 0.13 mmol) was added to a suspension of 3,4-dichloro-N-[1-(5-cyano-4-methoxy-1,3-thiazol-2-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 269, 0.04 g, 0.1 mmol) in DCM:CHCl3 (1:1). After stirring for one hour the reaction was complete. Partitioning with EtOAc and water, drying organic portion with MgSO4 and concentrating yielded a yellow oil which, after triturating with ether, gave a yellow solid.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[C:31]([C:36]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:8][CH2:7][CH2:6]4)[C@H:2]3[CH2:9][NH:10][C:11]([C:13]3[N:20]4[C:16]([S:17][CH:18]=[CH:19]4)=[N:15][C:14]=3[CH3:21])=[O:12])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(-c2ccccc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: COc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methoxy-biphenyl-2-carboxylic acid.