Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS(O[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]([O:34][C@@H:35]3[O:52][C@H:51]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@H:36]3[O:37][C:38](=[O:40])[CH3:39])=[N:28][NH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])=[C:21]([CH3:58])[CH:20]=1)(=O)=O.[CH2:59]1[C:62]2([CH2:67][CH2:66][CH2:65][N:64]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:63]2)[CH2:61][NH:60]1>C(#N)C>[CH3:58][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[CH2:16][CH2:15][N:60]2[CH2:61][C:62]3([CH2:67][CH2:66][CH2:65][N:64]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:63]3)[CH2:59]2)[CH:24]=[CH:23][C:22]=1[CH2:25][C:26]1[C:27]([O:34][C@@H:35]2[O:52][C@H:51]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@H:36]2[O:37][C:38](=[O:40])[CH3:39])=[N:28][NH:29][C:30]=1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCCC2(CNC2)C1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CC4(CCCN(C(=O)OC(C)(C)C)C4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 53.6 %

Procedure:
Add diisopropylethylamine (0.2 mL, 1.1 mmol) to a solution of (3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl methanesulfonate (200 mg, 0.28 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (77 mg, 0.34 mmol) in acetonitrile (3 mL). Heat the mixture at 80° C. for overnight. Concentrate under reduced pressure and purify residue by flash chromatography to yield the title compound (127 mg, 0.15 mmol). MS (m/z): 838.8, 839.6 (M+1), 836.8, 837.6 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])[CH:12]=1)[C:6](OC)=[O:7].Cl.[CH3:20][NH:21][O:22][CH3:23].C([Mg]Br)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([F:16])([F:18])([F:17])([F:14])[F:15])[CH:12]=1)[C:6]([N:21]([O:22][CH3:23])[CH3:20])=[O:7]
Reactant: COC(=O)c1cc(OC)cc(S(F)(F)(F)(F)F)c1
Reactant: CNOC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
Methyl 3-methoxy-5-(pentafluorosulfanyl)benzoate (O4.007; 2.5 g) was dissolved in absolute THF (65 ml), and N,O-dimethylhydroxylamine hydrochloride (1.2 g) was added. Then the mixture was cooled to −15° C. and isopropylmagnesium bromide solution (13.59 ml, 2 M in THF) was added dropwise. After 20 min, the cooling bath was removed and the mixture was stirred at RT for 1 h. Then ammonium chloride solution was added and the aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude product thus obtained still contained significant reactant, and was therefore converted and worked up again as described above. No reactant was present any longer in the residue which was then obtained. Purification was effected by means of preparative HPLC (met. A). The product-containing fractions were combined and freed of the acetonitrile, and the aqueous phase was extracted three times with EA. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.78 g of the desired compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis (triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white needles. mp: 235–237° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8–7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0–1.9 (m, 8H); MS (EI) M+ @ m/z 306.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)C.C(=O)=O.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:38])([F:37])[F:36])[C:29]#[N:30]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]2[N:30]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:37])([F:38])[F:36]
Reactant: N#Cc1ccc(OC(F)(F)F)c(F)c1
Reactant: Cc1ncccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
300 mg 2-methyl-nicotinic acid was suspended in 10 mL of tetrahydrofuran, and cooled to −70° C. with a bath of ethanol/dry ice. 3.3 mL lithium diisopropylamide (2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise over 10 min and the mixture was stirred for 1.5 h at 0° C. After this time, it was cooled again to -70° C. and 0.9 g 3-fluoro-4-trifluoromethoxy-benzonitrile (4.1) was added quickly. Then the reaction mixture was stirred for 2 h at −70° C. and then warmed overnight to ambient temperature. The solvent was distilled off, diluted with ethyl acetate, 10 mL phosphate buffer and 5 mL 2N aqueous hydrochloric acid solution (pH 6-7). The formed precipitate was collected and dried. The resulting liquid phase was separated and the water phase extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated and the residue suspended in ether and ethyl acetate. The precipitate was collected, dried and combined with the first precipitate.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH:23]=[CH2:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+]>CS(C)=O.O>[CH2:28]([O:30][N:31]=[C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH:23]=[CH2:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:29]
Reactant: C=CCN1C(=O)COc2ccc(C3CC(=O)C(C(=O)CC)=C(O)C3)cc21
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCN1C(=O)COc2ccc(C3CC(=O)C(C(CC)=NOCC)=C(O)C3)cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.3 g (3.7 mmol) of 2-propionyl-3-hydroxy-5-(N-(2-propenyl)-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one in 20 mL of methyl sulfoxide was treated with 0.43 g (4.5 mmol) of ethoxyamine hydrochloride and 0.36 g (4.4 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 6 hours. The reaction mixture was diluted with 200 mL of water and extracted thrice with 20 mL portions of diethylether. The extracts were combined, washed with water, then aqueous sodium chloride, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as a yellow oil which solidified upon standing. The resulting glassy solid was dissolved in a warm 1:1 ether-hexane solution. On cooling, the compound oiled out of the solution and again solidified and was isolated by filtration as a light tan solid. The product was recovered in a yield of 1.1 g (75 percent of theoretical) and melted at 79°-83° C.; 1H NMR(CDCl3): d1.12 (t, J=7 Hz, 3H,--CCH2CH3), 1.32 (t, J=7 Hz, 3H,--OCH2CH3), 2.55-3.55 (m, 7H), 4.16 (q, J=7 Hz, 2H,--OCH2CH3), 4.50-4.70 (m including s at 4.60 for OCH2C=O, 4H, --N--CH2), 5.10-5.42 (m, 2H,--OCH=CH3), 4.70 (s, 2H, --OCH2C=O), 4.88 (s, 2H, --NCH2CN), 6.92-7.20 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 5).
Reaction SMILES: Br[CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1.C(C(C(C(O)=O)O)O)(O)=O.[CH2:28]([O:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)=[O:32])[CH3:29].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:28]([O:30][C:31]([C@@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:2][CH:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[S:4]2)[CH2:34]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: BrCC1Sc2ccccc2Oc2ccccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CC2Sc3ccccc3Oc3ccccc32)C1
Yield: 53 %

Procedure:
A mixture of 11-bromomethyl-11H-dibenz[b,f][1,4]oxathiepine (6.15 g, 20 mmol, prepared similarly as described in Coll. Czech. Chem. Commun. 50, 1484, 1985), (R)-3-piperidinecarboxylic acid ethyl ester tartrate (4.7 g, 30 mmol) and chloroform (10 ml) was warmed to achieve dissolution. The solution was then allowed to stand for 1 week at room temperature, and was subsequently heated at reflux temperature for 7 h. After cooling, the mixture was diluted with benzene and washed with 5% ammonia. The organic phase was dried (potassium carbonate) and evaporated. The residue was purified by column chromatography on silica gel (55 g) using first benzene and then diethyl ether as eluents to give 4.1 g (53%) of (R)-1-(11H-dibenz[b,f][1,4]oxathiepin-11-ylmethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [C:1]1([CH2:7]C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC=O)C=CC=CC=1.C1([CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=CC=CC=1>>[C:1]1([CH2:7][CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Agent: O=CCCc1ccccc1
Product: O=C(Cc1ccccc1)NC(CCc1ccccc1)NC(=O)Cc1ccccc1
Yield: 92 %

Procedure:
Compound 45 was prepared from 2-phenylacetamide and 3-phenylpropanal using the procedure for compound 44. Yield: 92%. 1HNMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.6 Hz, 2H), 7.10-7.31 (m, 15H), 5.26 (t, J=7.6 Hz, 1H), 3.38-3.46 (m, 4H), 2.47-2.53 (m, 2H), 1.88-1.94 (m, 2H). LC-MS (ESI): m/z 387.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33]Cl.O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][CH2:32][CH2:31][O:30][CH3:29])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCCCl
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCOC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.1 g (15.2 mmol) of potassium carbonate were added to a hot solution of 3 g (10.0 mmol) of 7-benzyl-3-butylxanthine from stage a) in 90 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. 1.3 g (12.0 mol) of 3-methoxypropyl chloride were then added dropwise and the mixture was stirred at 100° C. for 3 hours. It was then allowed to cool to room temperature, and was treated with water and extracted using dichloromethane. The organic phase was washed with water and 1 N sodium hydroxide solution, dried using sodium sulfate and concentrated under reduced pressure. The oily residue was purified by flash chromatography on a silica gel column, toluene/ethanol (39/1)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.Cl.N>>[N:13]1[CH:12]=[CH:11][N:9]2[CH:10]=[C:5]([C:3]3[N:4]=[C:14]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[O:1][N:2]=3)[CH:6]=[CH:7][C:8]=12
Reactant: NC(=NO)c1ccc2nccn2c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: N
Product: c1cncc(-c2nc(-c3ccc4nccn4c3)no2)c1

Procedure:
The title compound was prepared according to Method D using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and nicotinoyl chloride, hydrochloric Acid (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.91 (m, 4 H), 8.20 (s, 1 H), 8.56 (dt, J=8.1, 1.9 Hz, 1 H), 8.92 (dd, J=4.7, 1.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([OH:20])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>CN(C=O)C.O>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[C:12]([O:20][CH2:30][C:29]([O:28][CH3:27])=[O:32])[C:13]([CH3:19])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)CBr
Reactant: Cc1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[(trans-4-hydroxycyclohexyl)amino]-7-methylquinazolin-8-ol (20 g, 0.073 mol) in DMF (160 mL) was added K2CO3 (10.6 g, 0.077 mol) in one portion at room temperature. Then a solution of bromoacetic acid methyl ester (11.5 g, 0.075 mol) in DMF (40 mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (150 mL), dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product. The crude product was re-crystallized from EtOH (150 mL) to give the title compound (13 g, 51.4%) as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([CH2:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[CH2:19][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:38]([NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[CH:30][CH:29]=1)[CH:9]1[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:12][CH2:11][CH2:10]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)Nc1ccccc1
Yield: 72.3 %

Procedure:
To a cold (0° C.) solution of (4-aminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.136 g, 0.34 mmol) in CH2Cl2 (3.5 mL) was added phenyl isocyanate (41 μL, 0.38 mmol) and the resultant solution was stirred for 50 minutes. The cooling bath was removed and the mixture was concentrated under reduced pressure. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2—CH3OH—NH4OH) provided the free base of the title compound (0.127 g, 72%) as a white solid.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Cl:14]Cl>C1(C)C=CC=CC=1.O>[Cl:14][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: ClCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(Cl)C(=O)Nc1ccccc1
Temperature: 6 °C
Yield: 63.9 %

Procedure:
A suspension of 177 g (1.0 mole) of acetoacetanilide in 1440 ml of toluene and 167 ml of water, in a chlorinator (2000 ml 3-neck flask), was cooled to approximately 6° C. and chlorine gas was added at about the rate of 1.5 g/minute, while maintaining the temperature at 6° C. until 82.6 g (1.16 moles) of chlorine had been added (about 56 minutes). The resultant mixture was stirred for an additional 36 minutes and then heated to 70° C. for 15 minutes. The mixture was then cooled and the product was precipitated. The precipitate was filtered from the toluene/aqueous HCl mixture to give 134.8 g (63.9%) of α-chloroacetoacetanilide, mp 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[C:5]([CH3:8])=[N:6][CH:7]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:25]([CH2:9][C:4]1[C:5]([CH3:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ncc(Cl)cc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ncc(Cl)cc1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 399 mg (2.55 mmol) of (5-chloro-2-methylpyridin-3-yl)methanol in 10 mL of toluene at r.t. was added 660 μL (3.06 mmol) of DPPA (diphenylphosphoryl azide). The solution was cooled to 0° C. and 450 μL of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) was added. The ice bath was removed and stirring was continued with warming to r.t. After 16 h, 1 N HCl was added to a pH=8. Water was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (45% EtOAc/hexanes) provided 3-(azidomethyl)-5-chloro-2-methylpyridine as a yellow oil in quantitative yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:43]([NH:50][CH:51]([CH3:53])[CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([N:50]([CH:51]([CH3:53])[CH3:52])[C:18](=[O:19])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:12][CH2:13]1)=[O:21])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)NCc1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)N(Cc1ccccc1)C(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1

Procedure:
To a stirred solution of 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-acetic acid (0.091 g, 0.31 mmol) in methylene chloride (5.0 mL) was added EDCI (0.078 g, 0.41 mmol) and HOBt (0.055 g, 0.41 mmol) at room temperature. After 40 min N-benzylpropan-2-amine (0.054 g, 0.36 mmol) was added at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 80:20 to 70:30 heptane/ethyl acetate, gradient elution) to provide N-benzyl-2-(4-(2-tert-butylphenyl)-piperazin-1-yl)-N-isopropyl-2-oxoacetamide as a mixture of cis and trans isomers (0.041 g, 32%) as a white solid, mp 65-68° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:39][O:40][C:41]1[C:42]2[N:55]=[C:54]([NH2:56])[S:53][C:43]=2[C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[N:45][CH:46]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:56][C:54]1[S:53][C:43]2[C:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[N:45][CH:46]=[C:41]([O:40][CH3:39])[C:42]=2[N:55]=1)=[O:7]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCC(=O)Nc1nc2c(OC)cnc(N3CCOCC3)c2s1

Procedure:
From 3-methoxypropionic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 353 (M+H+, 100).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:16](O)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CS(O)(=O)=O>>[C:16]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: OCCOc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOc1ccccc1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 994.13 g (2.24 moles) of the Alkoxylate from example 27 and 605.87 g (2.13 moles) of Stearic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](O)[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[C:5]1=[O:28])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:30]>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccccc32)cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of 11.4 g of 1-acetyl-3-(1-hydroxy-1-(4-acetylamino-3-nitrophenyl)-methylene)-2-indolinone and 9.37 g phosphorus pentachloride in 200 ml dioxane is stirred for 4 hours at 100° C. After the addition of another 2.0 g of phosphorus pentachloride the mixture is stirred for a further 3 hours at 10° C. Then the solvent is distilled off, the residue is stirred with 100 ml of ethyl acetate, suction filtered, washed with ethyl acetate and dried at 60° C.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([CH2:18][CH2:19][NH2:20])[CH2:10]C(OC(C)(C)C)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>C1COCC1>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:20][CH2:19][CH2:18][N:9]([CH3:10])[CH2:8][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CC(C)(C)OC(=O)CCN(CCN)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(CCN)CCC(=O)O

Procedure:
3-(Boc-aminoethyl-methyl-amino)-propionic acid tert-butyl ester (630 mg, 2.1 mmol) was treated with trifluoroacetic acid (6 mL) for 2 hours. 3-(Aminoethyl-methyl-amino)-propionic acid trifluoroacetic acid salt was isolated by recrystallisation from THF to give a white powder, 974 mg (quantitative).