Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1Cl
Solvent: ClCCl
Product: ClCc1cccnc1Cl
Temperature: 10 °C

Procedure:
To a 500 mL, round-bottom, 3-necked flask equipped with dropping funnel and magnetic stirrer and set for reflux was prepared a solution of 2-chloro-3-(hydroxymethyl)-pyridine (25.0 g, 174 mmol) in DCM (250 mL) under positive nitrogen atmosphere. The solution was cooled to 10° C. and thionyl chloride (31.0 g) was added dropwise over 25 minutes (exothermic). The reaction was then heated to reflux for 90 minutes, at which point the reaction was deemed complete by HPLC. The reaction mixture was cooled below boiling point and the equipment set for distillation. A total of 110 mL of DCM was initially removed and replenished with fresh DCM (110 mL), followed by another 80 mL of DCM before cooling the solution to 5-10° C. The acidic mixture was treated with a saturated solution of sodium bicarbonate (3 volumes) to pH 10. The lower organic phase was separated and the aqueous phase extracted with DCM (2 volumes). The organic phases were gathered, dried on sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil in excellent purity and yield (24.8 g, 88%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.10 (1H, dd), 7.50 (1H, dd), 4.85 (2H, s). LCMS (ES)+ RT 3.00 min, m/e 162.1.
Reaction SMILES: O/[C:2](/[C:10]1([CH3:13])[CH2:12][CH2:11]1)=[CH:3]\[C:4](=[O:9])/[CH:5]=[CH:6]/[O:7]C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:13][C:10]1([C:2]2[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=2)[CH2:11][CH2:12]1
Reactant: CO/C=C/C(=O)/C=C(\O)C1(C)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cc(=O)cco2)CC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of (1Z,4E)-1-hydroxy-5-methoxy-1-(1-methyl-cyclopropyl)-penta-1,4-dien-3-one one (Step 1.7) (111 mmol) and TFA (221 mmol) in toluene (175 mL) was stirred for 15.5 h at rt and then concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. LC-MS: tR=1.48 min, [M+H]+ 151; TLC: Rf=0.26 (EtOAc).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:15]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])(=O)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.COC(C)(C)C>[CH2:21]([N:28]1[CH2:6][CH2:7][C:8]2([CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCC1(COS(C)(=O)=O)CCCNC1=O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: O=C1NCCCC12CCN(Cc1ccccc1)C2

Procedure:
A solution of 1 mmol of methanesulphonic acid 3-(2-methanesulphonyloxy-ethyl)-2-oxo-piperidin-3-ylmethyl ester and 3 mmol of benzylamine in 5 ml of dioxane is heated at 60° C. for 30 hours. The reaction mixture is diluted with tert-butyl methyl ether and washed with brine. The organic phase is dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:26][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]2[C:16]=1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6]2
Reactant: CC(C)(C)c1ccc2cc3ccccc3c(-c3ccc(Cl)cc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc2c(Br)c3ccccc3c(-c3ccc(Cl)cc3)c2c1

Procedure:
A mixed solution of 6 g of the above-mentioned 2-tert-butyl-9-(4-chlorophenyl)anthracene, 3.5 g of N-bromosuccinimide and 55 g of dimethylformamide was stirred under nitrogen gas stream at room temperature for 3 hours. 50 ml of water was injected thereto to extract 100 ml of dichloromethane therefrom. The organic layer was washed twice in 50 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography to obtain 10-bromo-2-tert-butyl-9-(4-chlorophenyl)anthracene.
Reaction SMILES: [I-:1].[N:2]1([C:6]2[CH:15]=[CH:14][C:13]3[N+:12]4[CH:16]=[C:17]5[CH:26]=[CH:25][C:24]6[CH:23]=[C:22]([CH2:27][CH3:28])[CH:21]=[CH:20][C:19]=6[N:18]5[C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:29]O>>[I-:1].[N:2]1([C:6]2[CH:15]=[CH:14][C:13]3[N+:12]4[CH:16]=[C:17]5[CH:26]=[CH:25][C:24]6[CH:23]=[C:22]([CH2:27][CH2:28][CH3:29])[CH:21]=[CH:20][C:19]=6[N:18]5[C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: CCc1ccc2c(ccc3c[n+]4c5ccc(N6CCC6)cc5ccc4n32)c1
Agent: [I-]
Product: CCCc1ccc2c(ccc3c[n+]4c5ccc(N6CCC6)cc5ccc4n32)c1

Procedure:
3-(1-Azetidinyl)-10-ethylimidazo[1,2-a:3,4-a']diquinolin-15-ium Iodide; m.p. 246°-256° C., from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Solvent: ClCCl
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (150 mg, 0.69 mmol) was dissolved in 30 mL dichloromethane. Powdered molecular sieves (3 A, 200 mg), 4-chlorobenzene boronic acid (216 mg, 1.38 mmol) and [Cu(OH)TMEDA]2Cl2 (113 mg, 0.24 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 minutes and stirring was continued at room temperature overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→3:2 gradient) and by recrystallization from diisopropylether. The desired compound was obtained as a white solid (42 mg, 19%), MS: m/e=329.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH:12][S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=2)(=[O:25])=[O:24])[CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(COCC(F)(F)F)n1
Product: O=S(=O)(Nc1cccc(COCC(F)(F)F)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.104 g) as alight yellow gum (0.066 g). MS (ESI−): 413.1 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:44][CH2:45][C@H:46](O)[CH3:47])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([O:12][C@H:46]([CH3:47])[CH2:45][O:44][C:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:43])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)COC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a solution of (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoic acid (15.9 g, 33.3 mmol), (2R)-2-hydroxypropyl benzoate (5.0 g, 27.7 mmol), and 4-(dimethylamino)pyridine (340 mg) in 250 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (8.0 g, 41.6 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice, followed by the addition of brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure. Chromatography (silica gel, 1:5 then 1:4 ethyl acetate/hexane) of the residue followed by crystallization from 1:5 ethyl acetate/hexane afforded 8.0 g (45%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].C([SiH2][O:33][C:34](C)(C)[C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1)(C)(C)C.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:21]([C:12]2[CH:11]=[C:10]([O:9][C:8]3[CH:24]=[CH:25][C:5]([C:3](=[O:4])[N:2]([CH3:27])[CH3:1])=[C:6]([F:26])[CH:7]=3)[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=2)=[O:23])=[N:39][CH:40]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccc(CO)cn3)cc3c2CC(C)(C)O3)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (381 mg, 1.02 mmol), 5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (22a) (365 mg, 1.53 mmol) and triethylamine (0.284 mL, 2.04 mmol) in 5 mL of DMF was added HATU (776 mg, 2.04 mmol). The mixture was stirred at 50° C. overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried with Na2SO4, concentrated and the resulting oil was purified by Biotage column chromatography with 50-100% EtOAc in hexanes to give a yellow solid (120 mg, 25% yield). 1H NMR (400 MHz, CDCl3) δ 8.76 (br. s., 1 H) 8.29 (d, J=8.59 Hz, 1 H) 8.21 (d, J=1.77 Hz, 1 H) 7.74 (dd, J=8.59, 2.27 Hz, 1 H) 7.35 (t, J=8.08 Hz, 1 H) 7.27 (s, 1 H) 7.11 (d, J=5.81 Hz, 1 H) 6.78 (dd, J=8.46, 2.40 Hz, 1 H) 6.68 (dd, J=10.61, 2.27 Hz, 1 H) 4.66 (s, 2 H) 3.11 (s, 3 H) 2.96 (s, 3 H) 2.88 (s, 2 H) 1.48 (s, 6 H); LCMS for C26H26FN3O5 m/z 480.20 (M+H).
Reaction SMILES: [CH:1]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16](OC)=[O:17].C[O-].[Na+]>C(O)C>[CH:1]1([C:6]2[N:8]=[C:16]([OH:17])[C:11]3[S:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)C1CCCC1
Reactant: COC(=O)C1SCCCC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(C2CCCC2)nc2c1SCCC2
Temperature: 85 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a solution of cyclopentanecarboximidamide (3.2 g, 28.0 mmol) in ethanol (150 mL) was added methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (4.95 g, 28.0 mmol) and sodium methoxide (1.5 g, 28.0 mmol). The mixture was stirred at 85° C. for 16 h. The ethanol was removed under vacuum and the residue was diluted with water and extracted with methylene chloride. The organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was diluted with hexanes and the solid was filtered to afford the title compound (2.9 g, 44%) as a white solid. MW=236.33. 1H NMR (CDCl3, 500 MHz) δ 11.41 (s, 1H), 3.13-2.99 (m, 1H), 2.99-2.94 (m, 2H), 2.81-2.70 (m, 2H), 2.21-2.14 (m, 2H), 2.14-2.04 (m, 2H), 1.92-1.79 (m, 4H), 1.73-1.64 (m, 2H); APCI MS m/z 237 [M+H]+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]([F:31])([F:30])[C:6]1[CH:29]=[CH:28][C:9]([O:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH:17]([OH:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>CCOCC>[F:4][C:5]([F:30])([F:31])[C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH:17]([O:24][CH3:3])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:28][CH:29]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCOCC
Product: CCOC(=O)CC(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Diazomethane (2.8 g) in ether (100 ml) is added to ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate (1.88 g, 3.75 mmol) in ether (5 ml) under N2 and in an ice bath. Small amounts of chromatographic silica gel are added to the mixture in the ice bath until the color disappears. The mixture is then stirred overnight with cooling. The silica gel is removed by filtration and the organic phase is dried and concentrated. The crude product is purified by preparative thin layer chromatography to yield ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxypentanoate (cpd. 1 in Table A). MS m/e 412 (m+).
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:6]=1)C.[O:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:7]2[C:8]3=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:13]3[C:5]([CH2:4][O:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[CH:6]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3)c2cn1
Reactant: OC1CCOCC1
Product: COC(=O)c1cc2c(COC3CCOCC3)cn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared as in example 116, step 1, using methyl 3-[(dimethylamino) methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate and tetrahydro-2H-pyran-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (29 mg, 25%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)#N.C(O)=[O:18]>[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)=[O:18]
Reactant: O=CO
Reactant: CCC(=O)NC1CCc2cc(C#N)ccc21
Agent: [Ni]
Product: CCC(=O)NC1CCc2cc(C=O)ccc21
Yield: 80 %

Procedure:
1.46 g of N-(5-cyanoindan-1-yl)propionic acid amide were dissolved in 20 ml of a 75% aqueous formic acid solution. 1.1 g of Rainey nickel were added to this solution followed by heating and refluxing for 2 hours. After returning the reaction solution to room temperature and filtering with CELITE, the solvent was distilled off under reduced pressure. The resulting residue was added to water, and extracted with ethyl acetate. After washing the organic layer with saturated aqueous sodium bicarbonate and saturated brine, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.18 g of the target compound. Yield: 80%
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([NH:8][C:9]1[CH:10]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:13][C:14]=1[NH2:15])[CH:5]([CH3:7])[CH3:6]>C(O)(C)C.C(OCC)(=O)C>[CH2:4]([N:8]1[C:9]2[CH:10]=[C:11]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:13][C:14]=2[N:15]=[C:2]1[NH2:1])[CH:5]([CH3:7])[CH3:6]
Reactant: N#CBr
Reactant: CC(C)CNc1cc(-n2ccnc2-c2ccccc2)ccc1N
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(N)nc2ccc(-n3ccnc3-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Add cyanogen bromide (177 mg, 1.67 mmol) to a solution of 1-(3-(isobutylamino)-4-aminophenyl)-2-phenyl-1H-imidazole (410 mg, 1.34 mmol) in 10 mL isopropanol cooled to 0° C. Stir for one hour at this temperature and then stir at room temperature over night. Dilute with ethyl acetate and wash with 1N sodium hydroxide. Dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to radial silica gel chromatography, eluting with methanol containing 4% methanol to provide the title compound as a tan solid (220 mg, 50%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:57][CH2:56][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[CH:47]=[CH:48][C:49]5[S:53][C:52]([CH3:54])=[N:51][C:50]=5[CH:55]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:57][CH2:56][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[CH:47]=[CH:48][C:49]5[S:53][C:52]([CH3:54])=[N:51][C:50]=5[CH:55]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1
Reactant: Cc1nc2cc(C(=O)N3CCOC4(CCN(Cc5cc(CCO[Si](C)(C)C(C)(C)C)cs5)CC4)C3)ccc2s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(C(=O)N3CCOC4(CCN(Cc5cc(CCO)cs5)CC4)C3)ccc2s1
Reaction time: 1 h

Procedure:
TBAF (1M solution in THF, 1.5 mL) was added to stirred solution of (9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-methylbenzo[d]thiazol-5-yl)methanone (example 49, step a) (0.36 g) in THF (2 mL). After 1 h, the reaction was evaporated to a gum. Purification by silica gel chromatography eluting with ethyl acetate:triethylamine, 20:1 gave the subtitled compound as a gum. Yield 0.2 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:52][CH2:53][CH:54]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:55]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C=O)C>ClCCCl>[CH:39]([O:38][C:36]([C:33]1([O:32]/[N:31]=[C:14](/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH:11]=2)\[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][NH:52][CH2:53][CH:54]3[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:55]3)[CH:26]=[N:25]2)=[O:16])[CH2:35][CH2:34]1)=[O:37])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(C=O)n2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CNCC3CN(C(=O)OC(C)(C)C)C3)n2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.21 mmol) in DCE (4 ml) at 0° C. was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (78 mg, 0.420 mmol), sodium triacetoxyborohydride (66.7 mg, 0.315 mmol), and DMF (0.4 mL). After stirring at rt for 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and diluted with 10% EtOH/DCM (40 mL). The organic layer was separated, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.55 min, m/z=885.5 (M+1). Method 2m_acidic.
Reaction SMILES: C([CH:8]([CH2:10][NH2:11])O)(OC(C)(C)C)=O.[C:12]([OH:18])([C:14]([F:17])([F:16])[F:15])=[O:13]>C(Cl)Cl>[OH:18][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[C:12]([O:18][CH2:8][CH2:10][NH2:11])(=[O:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)C(O)CN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCCN
Reaction time: 1 h

Procedure:
A solution was made containing ethanolamine (36.5 ml, 0.6 mol) in chloroform (1000 ml). The Boc2O (13.1 g, 60 mmol) dissolved in chloroform (600 ml) was slowly added dropwise at 0° C. over a 6-hours period (the temperature was maintained all over this period). The reaction was allowed to reach room temperature and was stirred overnight. The organic layer was washed with water (2×500 ml), brine and dried over magnesium sulfate before being concentrated in vacuo. The desired product (9.5 g,>95%) was isolated as a colourless oil and was used without further purification. A solution was made containing the Boc-ethanolamine (1.92 g, 12 mmol) with potassium carbonate (5 g, 36 mmol) in DCM (40 ml). Acetyl chloride (30 ml, 0.42 mol) was added and the reaction stirred for 6 hours at room temperature. The excess of acetyl chloride was removed in vacuo and the crude dissolved in DCM (100 ml). The organic layer was washed with water (50 ml), brine and dried over magnesium sulfate before being concentrated in vacuo. The desired product (1.86 g, 77%) was isolated as a colourless oil and was used without further purification. A solution was made containing the O-acyl, Boc-ethanolamine (1.65 g, 8.1 mmol) in DCM (20 ml) and TFA (20 ml) was added. After one hour at room temperature, the solvent was removed in vacuo. The crude was concentrated from methanol (2–3 times) and from DCM (2–3 times) to give the expected compound (1.75 g, quant.) as an oil used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[C:6]([Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: Oc1c(Cl)ccnc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)ccnc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
2-bromo-4-chloropyridin-3-ol (8.15 g, 39.1 mmol), potassium carbonate (10.5 g, 76 mmol) and iodomethane (3.65 ml, 58.6 mmol) were added to acetone (300 ml) and stirred for 18 h at room temperature under inert conditions. The reaction mixture was evaporated to dryness, dissolved in ethyl acetate (100 mL), filtered over silica gel and the filter washed with ethyl acetate (3×100 mL). The filtrate was evaporated to dryness to obtain crude product which was purified over silica gel using 0:1 to 1:0 ethyl acetate in heptane to obtain 2-bromo-4-chloro-3-methoxypyridine as a white crystalline solid (6.8 g, 78%).