Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[Na].[N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]=1>CO.C(Cl)(Cl)Cl>[ClH:2].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:31]4[CH:36]=[CH:35][C:34](=[O:37])[CH:33]=[CH:32]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Reactant: O=C1C=CN=CC1
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCn4ccc(=O)cc4)cc23)c1

Procedure:
The free base of this product was prepared from the title product of Example 30 and the sodium salt of pyrid-4-one as described for Example 50. The free base was isolated by flash chromatography with 15% methanol/CHCl3 and converted to the title product according to the procedure described for Example 28 (32%; M.P. 155°-168° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.45 min).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10].[OH:13][C:14]1[CH:23]=[CH:22][C:17]2[CH2:18][CH:19]([CH3:21])[O:20][C:16]=2[CH:15]=1>>[CH3:12][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9][CH3:10])=[CH:3][CH2:2][O:13][C:14]1[CH:23]=[CH:22][C:17]2[CH2:18][CH:19]([CH3:21])[O:20][C:16]=2[CH:15]=1
Reactant: CC1Cc2ccc(O)cc2O1
Reactant: CCC(C)=CCCC(C)=CCBr
Product: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OC(C)C2

Procedure:
1-bromo-3,7-dimethyl-2,6-nonadiene and 6-hydroxy-2-methyl-2,3-dihydrobenzofuran are reacted to form 6-[(3,7-dimethyl-2,6-nonadienyl)- oxy]-2-methyl-2,3-dihydrobenzofuran of boiling point ca. 145° C./0.001 mmHg; nD20 = 1.5286;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[NH:12][C:11](=[O:21])[C:10]=1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:12]([CH3:31])[C:11](=[O:21])[C:10]=1[C:22]1[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (40.0 g, 98.4 mmol) in tetrahydrofuran (500 ml) at 0° C. was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (108.3 ml, 108.3 mmol) dropwise over one hour. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, then treated with methyl iodide (6.75 ml, 15.4 g, 108.2 mmol) dropwise at 0° C. over 10 minutes. Stirring was continued at room temperature overnight and the reaction mixture was quenched with cold saturated aqueous ammonium chloride. The layers were separated, the aqueous phase extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in diethyl ether, stirred for 30 minutes, filtered and dried. Yield: 28.6 g of 4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.5) as a solid, mp 139-141° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.[OH-].[Na+]>[C:14]([O:13][C:11](=[O:12])[CH2:10][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Reaction time: 1 h
Yield: 89 %

Procedure:
To 71.0 g of benzylamine in 100 ml of benzene was added with stirring 25.0 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional 1 hour. At the end of this period, the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 32.7 g (89.0 percent) of N-benzylglycine tert-butyl ester, B.P. 120°-125° C/ 2 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)[O:23][N:22]=1
Reactant: Cc1cc(CCCCCCCI)on1
Reactant: COC(=O)c1cc(O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCCCCCCc2cc(C)no2)cs1
Reaction time: 8 h

Procedure:
6.42 g (40.60 mmol) of methyl 4-hydroxy-2-thiophenecarboxylate (XIa) and 11.88 g (38.67 mmol) of 5-(7-iodoheptyl)-3-methyl-isoxazole (IX) are heated under reflux with 5.34 g (40.60 mmol) of potassium carbonate (K2CO3) in 130 ml of anhydrous acetone for 8 hours. After the mixture has been left to stand overnight, it is concentrated, the residue is partitioned between 2N NaOH and ether and the aqueous phase is extracted several times with a total of 150 ml of ether. The organic phase is dried over sodium sulfate/active charcoal and evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:15])OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccnc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
4.22 g (0.02 mole) of ethyl N-(4-nitrophenyl)carbamate, 1.80 g (0.0167 mole) of 3-aminomethyl-pyridine and 3.18 g (0.0173 mole) of tributylamine are dissolved in 25 ml of dry toluene, and the mixture is boiled for 5 hours. The separated product is filtered off, washed twice with 10 ml of acetone, each, and dried. 4.33 g (85.1%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 222°-224° C. (the authentic sample melts at 223°-225° C.).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6]Br.[C:17]([NH:20][C@H:21]([C:32]([OH:34])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)(=[O:19])[CH3:18]>>[C:17]([NH:20][CH:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[C:32]([O:34][CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1)=[O:33])(=[O:19])[CH3:18]
Reactant: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Product: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the method of Example 1, 3,5-bistrifluoromethylbenzyl bromide (6.16 g) and N acetyl-L-tryptophan (4.92 g) gave the title compound which was recrystallised from ethyl acetate/petroleum ether (3.7 g), m.p. 147°-148° C. 1H NMR (360 MHz, CDCl3) δ8.01 (1H, s), 7.83 (1H, s), 7.61 (1H, s), 7.51 (1H, d, J=8 Hz), 7.32 (1H, d, J=8 Hz), 7.17 (1H, t, J=7 Hz), 7.09 (1H, t, J=7 Hz), 6.91 (1H, d, J=2 Hz), 5.98 (1H, s), 5.13 (1H, d, J=13 Hz), 5.06 (1H, t, J=13 Hz), 4.96 (1H, t, J=6 Hz), 3.31 (2H, m), 1.98 (1H, s); Found: C, 56.08; H, 3.79; N, 5.74. C22H18N2F6O3 requires C, 55.84; H, 3.84; N, 5.93%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH2:4][CH2:3]1.Cl[C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])[C:18]([Cl:34])=[CH:17][N:16]=1.O>CO>[Cl:34][C:18]1[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])=[N:20][C:15]([NH:13][C:11]2[CH:10]=[N:9][N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:12]=2)=[N:16][CH:17]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: CN1CCC(n2cc(N)cn2)CC1
Solvent: O
Solvent: CO
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C)CC3)c2)ncc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 2 %

Procedure:
A stirred solution of 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.117 g, 0.648 mmol), 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (0.060 g, 0.185 mmol) in MeOH (10 mL) and water (1.0 mL) was stirred at 70° C. for 16 hours. Additional 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.052 g, 0.29 mmol) was added and the reaction was stirred for 16 hours at 70° C. After cooling the solvent was removed to afford an oil which was purified by HPLC (Gradient: 30-100%, acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) to give the title compound 44 as a red gum (0.0018 g, 2% yield). LCMS-C: rt 4.28 min; m/z 468 [M+H]+.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][CH:10]([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[F:9][CH:10]([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:34]2[CH2:35][CH2:36][N:32]([C:24]3[S:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:22]([CH3:21])[N:23]=3)[C:33]2=[O:37])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)nc1C
Yield: 88 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(difluoromethoxy)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 88% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.37 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 6.48 (t, JF-H=73.8 Hz, 1H), 4.46 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 4.07 (t, J=7.8 Hz, 2H), 3.45 (t, J=7.8 Hz, 2H), 2.56 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ES+) m/z 412.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=NO.Cl.C=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:16]
Reactant: Cc1cccc([N+](=O)[O-])c1C=NO
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1C=O

Procedure:
At 65° C., 14 g of 2-methyl-6-nitrobenzaldoxime (80 mmol) are stirred in a mixture of 55 ml of 5% strength hydrochloric acid, 37 g of a 37% strength solution of formaldehyde, 50 ml of water and 100 ml of tetrahydrofuran for 24 hours. The phases are subsequently separated, and the dark phase is extracted with methylene chloride/water. The organic phase is dried with sodium sulfate and concentrated. This gives 10.1 g of crude product which is purified by filtration over silica gel using toluene as mobile phase.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:31].O[CH2:33][C:34]([CH3:43])([CH3:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[CH3:33][C:34]([CH3:43])([CH2:42][O:31][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[N:18]=3)=[CH:10][N:9]=2)=[CH:7][C:2]=1[CH3:1])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1O
Product: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1OCC(C)(C)C(=O)OC(C)(C)C
Yield: 34.5 %

Procedure:
By using 2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)-imidazol-2-yl]-2-pyridyl]phenol (224 mg) and tert-butyl 3-hydroxy-2,2-dimethylpropanoate (284 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain tert-butyl 2,2-dimethyl-3-[2-methyl-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]propanoate (104 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([Cl:28])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17][N:18](C)C)[CH2:11]2)[C:6]1=[O:21].O.[NH2:30]N>C(O)C>[Cl:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:2]([Cl:1])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]3[C:12](=[CH:17][NH:18][N:30]=3)[CH2:11]2)[C:6]1=[O:21]
Reactant: NN
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC(=O)C(=CN(C)C)C3)C2=O)c(Cl)c1
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)c(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(3-dimethylaminomethylene-4-oxo-cyclohexyl)-pyrrolidin-2-one in ethanol (Preparation 24) (50 mL), and hydrazine hydrate (2.6 mL, 54 mmol) stir the resulting orange solution for 3 days at room temp. Concentrate the mixture to dryness, dilute with ethanol (15 mL) and ether (20 mL), cooled to 0° C. and filter to give 3.6 g, 68%, as a tan solid. MS (m/z): 394 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.[ClH:31]>C(O)C>[ClH:31].[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(NCc2ccccc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NCc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of ethyl 2-(benzylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.026 g, 0.10 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.015 g, 0.10 mmol) in 2M hydrochloric acid in ethanol (1.0 mL) was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.024 g, y. 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18][CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 3-piperidin-4-yl-1H-indole (9.9 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C24H23N3O2: 385.1790, found 385.1797.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][OH:12])[N:5]=1)(=[O:3])[CH3:2].[C:13](Cl)([Cl:15])=[O:14]>ClCCl.C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13]([Cl:15])=[O:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)n(CCO)n1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)c1cc(C)n(CCOC(=O)Cl)n1
Reaction time: 1.5 h

Procedure:
3-Acetyl-1-(2-hydroxyethyl)-5-methylpyrazole (505 mg, prepared as described in Example 12, Preparation 1) in dry dichloromethane (5 ml) under an atmosphere of argon was treated with a solution of phosgene in toluene (12.5% w/w, 5.22 ml) and the mixture stirred for 1.5 h. The solvents were then removed, dichloromethane was added and removed using a rotary evaporator to give 3-acetyl-1-[2-(chlorocarbonyloxy)ethyl]-5-methylpyrazole; νmax (CH2Cl2) 1777 and 1684 cm-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27](Cl)[CH3:28])=[CH:23][N:22]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:27]([C:24]3[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH3:28])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1ccc(Cl)nc1
Reactant: CCC[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Product: CCC[C@H](CO)N(C)c1nc(S[C@@H](C)c2ccc(Cl)nc2)nc2nc(N)sc12
Yield: 15.7 %

Procedure:
The title compound was prepared using General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)(methyl)amino]pentan-1-ol (96 mg, 0.32 mmol) and 2-chloro-5-[(1R)-1-chloroethyl]pyridine (85 mg, 0.48 mmol). Purification by flash column chromatography (eluent DCM:ethyl acetate) yielded 22 mg (16% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]#[N:17]>C(#N)C.C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: N#CCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CN1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A mixture of 1-methyl piperazine (0.55 mL, 5.0 mmol), potassium carbonate (3.49 g, 25 mmol) and chloroacetonitrile (0.34 mL, 5.6 mmol) in acetonitrile (3 mL) was stirred at room temperature 8 h. The mixture was diluted with diethyl ether and filtered and concentrated to yield the title compound as yellow crystals (536.6 mg, 77% yield). 1H NMR (500 MHz, CDCl3) δ: 3.50 (s, 2H), 2.66 (t, 4H, J=4.58), 2.52 (bs, 4H), 2.33 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[C:6](=[CH:14]\[C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8])=[CH:2]1.FC(F)(F)C(O)=O>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3](/[C:6](=[CH:14]\[C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8])=[CH:2]1
Reactant: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(/C=C(/C(=O)O)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.75 h

Procedure:
Combine (E)-2-(thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester and trifluoroacetic acid (10 mL). After 45 min, evaporate in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with water. Evaporate the organic layer in vacuo to obtain a residue. Triturate with pentane containing a small amount of ether to give a solid. Recrystallize the solid from cyclohexane/ethyl acetate, filter, and dry to give the title compound: mp 197-200° C. (dec); 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.95 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.5 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.25 (d, 1H, J=1.7 Hz), 7.08 (d, 1H, J=2.8 Hz), 7.08 (d, 1H, J=3.6 Hz), 6.81 (dd, 1H, J=3.6, 2.8 Hz), 4.22 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 1.28 (t, 3H, J=7.2 Hz); 1H NMR (DMSO-d6) δ 13.07 (br s, 1H), 7.88 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.66 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.27 (dd, 1H, J=5.0, 2.9 Hz), 7.09 (dd, 1H, J=2.9, 1.2 Hz), 6.63 (dd, 1H, J=5.0, 1.2 Hz), 4.11 (q, 2H, J=7.1 Hz), 2.36 (s, 3H), 1.14 (t, 3H, J=7.1 Hz). Elemental Analysis calculated for C25H19Cl2NO6S2 : C, 53.20; H, 3.39; N, 2.48. Found: C, 52.80; H, 3.19; N, 2.29.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M44) (0.79 g, 1.24 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (350 mg, 65%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][S:16]([CH3:15])(=[O:18])=[O:17])[C@H:10]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CN(Cc2ccccc2)C[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To an ice-cold (0-5° C.) solution of the product from Step 2 (5.27 g, 27.3 mmol) and TEA (8.27 g, 81.9 mmol) in dichloromethane (50 mL), was added methanesulfonyl chloride (6.87 g, 60.0 mmol) over a period of 30 minutes. After stirring at RT overnight, the reaction mixture was washed with water. The organic layer was dried (sodium sulfate), filtered, and concentrated to give the crude product which was purified over a silica column (5:95 EtOAc/hexane) to obtain pure product (6.44 g, 67.6%). 1H NMR (400 MHz, CDCl3) δ 7.32-7.26 (5H, m), 5.14 (2H, m), 3.65 (2H, s), 3.15-3.08 (2H, m), 3.08 (6H, s), 2.76 (2H, dd). MS m/z 350 (MH+).