Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NC(C)C)(C)C.[Cl:10][C:11]1[N:16]=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1.[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25](O)[CH:24]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:29]([C:28]1[CH:23]=[CH:24][C:25]([O:19][C:18](=[O:20])[CH2:17][C:15]2[C:14]([C:21]#[N:22])=[CH:13][CH:12]=[C:11]([Cl:10])[N:16]=2)=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#Cc1ccc(Cl)nc1CC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylcarbodiimide (3.00 mL, 19.2 mmol) was added dropwise over 2 min at 0° C. with stirring to a homogeneous dark amber solution of crude (6-chloro-3-cyano-pyridin-2-yl)-acetic acid (3.1 g, 16 mmol; mixture of regioisomers), as prepared in the previous step, p-nitrophenol (3.35 g, 24 mmol), DMAP (11 mg, 0.8 mmol) and DCM (20 mL). The ice bath was removed immediately following the completion of DIC addition, and the dark amber solution was stirred at rt overnight. The crude reaction was allowed to stand at rt for some time, and was then loaded directly onto a silica flash column (90 mm×6″). Elution with 97:3 toluene/acetone afforded the impure title compound, but as a single regioisomer (566 mg, 14% from 2,6-dichloro-nicotinonitrile).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:1]1([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CC2)cc1
Yield: 92855.4 %

Procedure:
To a solution of cyclopropyl boronic acid (0.637 g, 0.00742 mmol) in dry toluene, were added 4-bromo nitrobenzene (1.00 g, 0.00495 mmol) and tetrakis triphenylphosphine palladium (0.099 g, 0.0099 mol). Degassed the reaction mixture for 30 minutes then added potassium carbonate (1.36 g, 0.009 mmol). The reaction mass was refluxed for 48 h. The excess of solvent was removed under vacuum and the reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on silica gel eluting with 4% DCM: MeOH to afford 0.750 g of the desired product. 1HNMR (DMSO-d6): δ 0.82-0.84 (m, 2H), 1.09-1.13 (m, 2H), 2.01 (m, 1H), 7.32 (d, J=8.7 Hz, 2H), 8.09 (d, J=8.7 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O>CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:1]=[C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]3[CH:12]=2)=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ncccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccn2cc(-c3ccc(F)cc3)nc12
Yield: 36.4 %

Procedure:
To a solution of 2-amino-3-nitropyridine (1.3 g, 9.3 mmol) in N,N-dimethylformamide (20 mL) was added 2-bromo-4′-fluoroacetophenone (2 g, 9.3 mmol) and the reaction mixture was heated at reflux for 6 hours. The resulting mixture was concentrated to a solid in vacuo. This residue was dissolved in dichloromethane and the organic phase was washed with aqueous sodium bicarbonate and an aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered through a silica gel pad and concentrated to give a solid. This solid was recrystallized from methanol to give 870 mg (36%) of 2-(4-fluorophenyl)-8-nitroimidazo[1,2-α]pyridine as a brown solid. 1H NMR (d6-DMSO): δ 8.98 (d, 1H), 8.69 (s,1H), 8.32 (d, 1H), 8.10 (q, 2H), 7.36 (t, 2H), 7.15 (t, 1H); 19F NMR (DMSO-d6) δ −113.7; MS m/z 258 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:20]([C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)(=[O:22])=[O:21])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NS(=O)(=O)c2ccc3ccccc3c2)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with naphthalene-2-sulfonyl chloride
Reaction SMILES: CO[O:3][CH:4](OOC)[CH2:5][Br:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.O[C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=S)=CC=1>C(O)C>[Br:6][CH2:5][C@@H:4]([C:30]1[CH:22]=[N:28][CH:26]=[CH:25][CH:29]=1)[OH:3]
Reactant: COOC(CBr)OOC
Reactant: NC(=S)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O[C@@H](CBr)c1cccnc1
Yield: 53.8 %

Procedure:
In a round-bottomed flask, bromoacetaldehyde dimethoxyacetal (123 μl, 1.04 mmol), p-toluenesulfonic acid (199 mg, 1.04 mmol), and 4-hydroxy-thiobenzamide (160 mg, 1.04 mmol) were dissolved in ethanol (10 ml) and the resulting solution was heated to reflux for about twenty-four hours. The reaction mixture was then concentrated to an oil which was redissolved in ethyl acetate, and extracted with saturated aqueous sodium carbonate. The combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. The crude product was purified by column chromatography (hexanes to 10% ethyl acetate/hexanes) to furnish the title compound as a white solid (113 mg, 61% yield). LRMS ([M+H+])=177.8. Preparation of Intermediate 1-(4-Methoxy-phenyl)-1H-pyrazole:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[CH:22][C:21]1[NH:20][CH:19]=[C:18]2[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=12
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cccc(Cl)c2N1
Product: O=C1Nc2c(Cl)cccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
7-Chloro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:20]([CH:24]([CH3:26])C)[CH:21]([CH3:23])C.N1CCCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH3:17])([C:14]([N:20]2[CH2:21][CH2:23][CH2:26][CH2:24]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 4-methylpiperidine-1,4-dicarboxylic acid mono-tert-butyl ester (229 mg, 0.94 mmol) in DMF (10 mL) were added DIPEA (0.493 mL, 2.83 mmol), pyrrolidine (0.118 mL, 1.41 mmol) and HATU (537 mg, 1.41 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and EtOAc. The organic layer was separated and washed with a 0.1N aqueous HCl solution and brine, dried over Na2SO4, filtered and concentrated to give 4-Methyl-4-(pyrrolidine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid (279 mg, 100%). LCMS (Method H): RT 4.00 min; [M+Na]+ 319
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:33])[NH2:32])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:33])[NH:32][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:5]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:8]([CH:10]4[CH2:11][CH2:12]4)=[CH:7][N:6]=3)[CH2:18][CH2:17]2)=[O:20])=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOC(N)=O
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CCOC(=O)Nc1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cc1
Yield: 48.1 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 186 and carbamic acid ethyl ester (137 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (209 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O)(=O)C.[F:12][C:13]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:14]=1[CH2:15][S:16][C:17]1[N:22]=[C:21]([NH:23][S:24]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:20]=[C:19]([O:34][CH3:35])[N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:12][C:13]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:14]=1[CH2:15][S:16][C:17]1[N:22]=[C:21]([NH:23][S:24]([N:27]2[CH2:28][CH2:29][CH:30]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:31][CH2:32]2)(=[O:25])=[O:26])[CH:20]=[C:19]([O:34][CH3:35])[N:18]=1
Reactant: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCC(N3CCN(C)CC3)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-piperazine (0.13 mL) in DCM (2 mL) was added to a solution of acetic acid (0.03 mL) and N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of example 148, step iii) (0.10 g) in DCM (2 mL). The solution was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.24 g) was added in portions. The mixture was stirred at room temperature overnight then the DCM was evaporated and 3M aqueous sodium hydroxide (6 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water, saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by reverse phase HPLC (gradient 25-95% acetonitrile in 0.1% aqueous ammonium acetate) to afford the title compound as a white powder. Yield: 22 mg
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=3)[C:9]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:16][CH:15]=3)[C:9]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(OCCO)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Yield: 88.9 %

Procedure:
A suspension of 11.4 g (30 mmol) of 5,7-di-tert-butyl-3-[4-(2-hydroxyethoxy)phenyl]ben-zofuran-2-one (compound (105), Example 3) and 9.4 g (31 mmol) of stearoyl chloride in 60 ml of toluene is refluxed for 4 hours. The reaction mixture is then concentrated on a vacuum rotary evaporator, and the residue is recrystallized from methanol to give 17.3 g (89%) of 5,7-di-tert-butyl-3-[4-(2-stearoyloxyethoxy)phenyl]benzofuran-2-one, m.p. 54°-60° C. (compound (107), Table 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:12](=[O:23])[CH:11]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:30][CH:31](Br)[CH3:32].CN(C=O)C>C(Cl)(Cl)Cl>[Br:30][CH2:31][CH2:32][O:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[CH:11][C:12]2=[O:23])=[CH:21][CH:20]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(O)cc1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 14.5 h
Yield: 89 %

Procedure:
A mixture of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-hydroxyphenyl)-1H-pyridin-2-one (1.0 g, 3.1 mmols), cesium carbonate (5.0 g, 15 mmols), dibromoethane (5 mL) and DMF (10 mL) was stirred at 80° C. for 14.5 hours. Chloroform was added to the reaction liquid, followed by filtration. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil FLASH 25+ M, chloroform:methanol=1:0→100:2) to provide the title compound (1.2 g, 89%).
Reaction SMILES: Br.Br[CH:3]([C:5]1[O:6][C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[S:16][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].C(OC([N:35](C(OC(C)(C)C)=O)[C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[NH:38][CH:39]=[N:40]2)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:35][C:36]1[N:44]=[CH:43][N:42]=[C:41]2[C:37]=1[N:38]=[CH:39][N:40]2[CH:3]([C:5]1[O:6][C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[S:16][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4]
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2nc[nH]c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1)n1cnc2c(N)ncnc21
Yield: 45.3 %

Procedure:
3-(1-Bromoethyl)-4-(5-(morpholinomethyl)thiophen-2-yl)-1H-isochromen-1-one hydrobromide (intermediate C16, 52 mg, 0.113 mmol), N6,N6-bis(tert-Butoxycarbonyl)-adenine (74.1 mg, 0.221 mmol), K2CO3 (30.5 mg, 0.221 mmol) were reacted in DMF (0.5 ml) at 80° C. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) and recovered material was then treated with HCl 37% before evaporation to give a crude that was further purified via reverse phase chromatography with a Biotage C18 12 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (25 mg, 69%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1

Procedure:
2-Chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine was prepared by allowing to react 1 eq of cyanuric chloride with 1.9 eq of m-xylene in the presence of 3 eq of aluminum chloride and concentrated HCl in chlorobenzene as discussed above.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].CS(C)=O>CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][N:30]=[N+:31]=[N-:32])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 88.7 %

Procedure:
Compound 159 (3.01 g, 7.05 mmol), sodium azide (1.26 g, 19.40 mmol) and DMSO (12 mL) were combined and heated to 60° C. for 3 hours. EtOAc (100 mL) was added to the reaction and filtered. The solids were washed with EtOAc (20 mL), and the filtrated evaporated. The crude material was chromatographed on silica eluting with 5% EtOAc/hexanes to give 160 as an oil (1.86 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:38]([N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][N:45]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH2:47]2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCCN2CCN(Cc3ccccc3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 2-(4-benzylpiperazino)ethan-1-amine (41.3 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulforxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (t, 3H) 2.19-2.51 (m, 9H) 3.14-3.20 (m, 1H) 3.35 (t, 2H) 3.42-3.49 (m, 2H) 4.41-4.49 (m, 2H) 6.97-7.11 (m, 1H) 7.19-7.44 (m, 5H); MS (ESI) positive ion 409 (M+H).
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10](=[O:35])[CH:11]([OH:34])[C@@H:12]([NH:22][C:23](=[O:33])[C@@H:24]([NH2:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.[N:43]1([C:49](Cl)=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C=O)C>[CH2:15]([O:14][CH2:13][C@H:12]([NH:22][C:23](=[O:33])[C@@H:24]([NH:32][C:49]([N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:50])[CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH:11]([OH:34])[C:10](=[O:35])[NH:9][C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)NC(=O)C(O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
N1-(1,1,3,3-tetramethylbutyl)-(3S)-3-[(2S)-2-amino-3-cyclohexylpropanoyl]amino-4-(benzyloxy)-2-hydroxybutanamide (360 mg, 0.7 mmole) was dissolved in DMF (7 mL), followed by addition of addition of triethylamine (205 ul, 1.5 mmole) and stirring under N2 for 15 min. 4-Morpholinecarbonyl chloride (93 ul, 0.8 mmole) was added. Stirring was continued overnight and DMF was removed under reduced pressure. The solution was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, Hexane/EtOAc with 10% MeOH, Rf=0.5) afforded N4-[(1S)-2-((1S)-1-[(benzyloxy)methyl]-2-hydroxy-3-oxo-3-[(1,1,3,3-tetramethylbutyl)amino]propylamino)-1-(cyclohexylmethyl)-2-oxoethyl]-4-Morpholinecarboxamide as a white solid (280 mg, 63%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.O>CN(C=O)C>[Cl:12][C:13]1[N:18]=[C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc(Cl)nc1-n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Indole (1.0 g, 8.54 mmol) was added in portions to a suspension of NaH (0.358 g, 8.96 mmol) in DMF (10 mL) at 0° C. under N2 and stirred for 15 minutes at RT. 2,4-Dichloro-5-fluoro-pyrimidine (1.49 g, 8.96 mmol) was then added in portions and allowed to stir at RT overnight. The reaction mixture was poured into cold water, extracted into DCM, washed in brine, dried with Na2SO4, filtered, and dried in vacuo to obtain an oil. The residue was purified using flash chromatography on a silica column eluting with hexane:EtOAc (1000:25) to (1000:50), to yield 1-(2-chloro-5-fluoro-pyrimidin-4-yl)-1H-indole after drying the collected fraction (0.11 g, 5%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: Cc1cccc(C#N)c1N
Reactant: O=C=NC(=O)c1ccccc1
Product: Cc1cccc(C#N)c1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-amino-3-methylbenzonitrile (Example 15b) and benzoyl isocyanate as a white powder (186 mg, 67%). MS 280 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.C[O-].[Na+]>CO>[Cl:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:2][C:3]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])[CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COc1ccc(C(=O)O)c(CBr)c1
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1ccc(C(=O)O)c(C=Cc2cccc(Cl)c2)c1

Procedure:
For the synthesis of the title compound, 45.6 g (0.186 mol) of 2-bromomethyl-4-methoxybenzoic acid, 48.8 g (0.186 mol) of triphenylphosphine, 26.1 g (0.186 mol) of 3-chlorobenzaldehyde and 84.0 g (0.435 mol) of NaOMe (28%) in 150 ml of methanol are reacted by method I. Purification is carried out by recrystallization from methanol at 4° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:14]([CH:38]([OH:40])[CH3:39])[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:53][C:54](OC(C)=O)=[O:55]>CN(C1C=CN=CC=1)C.CCOCC>[C:54]([O:40][CH:38]([C:14]1[C:15]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][C:17]2[C:12]([C:13]=1[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)[CH3:39])(=[O:55])[CH3:53]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reaction time: 2 h

Procedure:
To a solution alcohol (300 mg) from Step 4 in Ac2O (2 mL) was added pyridine (300 mL) and DMAP (2 mg). After 2 hr, the reaction mixture was diluted with Et2O, washed with H2O, a solution of CuSO4, and the solvent evaporated to give the title product which was used as such for the next step.