Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl:12][C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:13]([Cl:12])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCNc1ccccc1
Solvent: ClCCl
Product: CCCCN(C(=O)Cl)c1ccccc1
Reaction time: 27 h
Yield: 191.2 %

Procedure:
To a solution of 6.72 g (45 mmol) of butylphenylamine in 50 ml of methylene chloride cooled to 10° C. was added slowly with stirring 6.67 g (22.5 mmol) of triphosgene in 40 ml of methylene chloride. The reaction was allowed to continue at room temperature for 27 hours. The solvent was evaporated and the residue extracted twice with n-hexane. The organic solution was concentrated in vacuo to yield 9.11 g (43.03 mmol) of a yellow oil (96%). 1H-NMR (CDCl3):δ 0,9 (m, 3H), 1,3 (m, 2H), 1,6 (m, 2H), 3,7 (m, 2H), 7,2–7,4 (m, 5H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>O.C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]([C:10]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: NNC(N)=S
Agent: Cl[Fe](Cl)Cl
Solvent: CCO
Solvent: O
Product: Nc1nnc(-c2cccc(Br)c2)s1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
To a solution of thiosemicarbazide (0.493 g, 5.40 mmol, 1.0 equiv) in 6 mL of water at 70° C. is added a solution of 3-bromobenzaldehyde (0.633 ml, 5.40 mmol, 1.0 equiv) in 4.5 mL ethanol. After the precipitate formed, iron(III) chloride hexahydrate (2.92 g, 10.81 mmol, 2.0 equiv) in 6 mL water is added and the mixture is stirred for 2.5 h at 85° C. Upon completion, the mixture is allowed to cool to room temperature and the resulting precipitate is collected by filtration and taken up in 12 mL pyridine. Ice water is then added to the pyridine slurry. The mixture is cooled then filtered to give 5-(3-bromophenyl)-1,3,4-thiadiazol-2-amine (553 mg, 39.9% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-7.88 (m, 1H), 7.67 (d, J=8.22 Hz, 1H), 7.53-7.59 (m, 1H), 7.45 (s, 2H), 7.36 (t, J=8.02 Hz, 1H);
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=O)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:8][C:9]1[C:10]([C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[CH:11][CH:12]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(NC2CCCN(C(=O)OC(C)(C)C)C2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
670 mg (1.37 mmol) of tert-butyl 3-({6-[(tert-butoxycarbonyl)amino]-5-(trifluoroacetyl)pyridin-2-yl}amino)piperidine-1-carboxylate (Example 21A) were dissolved in 25 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 20 h. After the reaction had gone to completion, the reaction mixture was diluted with diethyl ether (100 ml), and the precipitate was filtered off and washed with diethyl ether (100 ml) and dried. This gave 286 mg (64% of theory) of the product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([C:25](OC)=[O:26])=[CH:23][N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C(O)(=O)C(C(C(O)=O)O)O.[Na]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][OH:26])=[CH:23][N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)s1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na]
Solvent: ClCCl
Product: O=C(Nc1ncc(CO)s1)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazole-5-carboxylate (80.8 mg, 0.2 mmol, 1 equiv) in dried CH2Cl2 (5 mL) under N2 at room temperature was then slowly added DIBAL-H (1M in CH2Cl2, 1 mL, 1 mmol, 5 equiv). The resulting mixture became a clear solution and was stirred at room temperature for 1 h. The resulting mixture was slowly poured into a vigorously stirred mixture of CH2Cl2/10 wt % sodium tartaric acid (aq.) (10 mL/10 mL). The resulting mixture was stirred for 1 h and the layers were separated. The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue purified by column using 90-100% EtOAc/hexane as the eluent to yield 4-(6-fluoroindolin-1-yl)-N-(5-(hydroxymethyl)thiazol-2-yl)piperidine-1-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC[O:33][C:34]1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl.[C]=[O:49].O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:34]([OH:33])=[O:49])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [C]=O
Reactant: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(Br)cc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)O)cc1-c1ccccc1

Procedure:
A solution of 4-bromo-2-phenylbenzoyl methionine methyl ester (1.0 equivalent), Pd(OAc)2 (0.05 equivalent) and DPPE (1.0 equivalent) is heated in DMF to 65° C. under 4 atm. of carbon monoxide until TLC analysis indicates that the reaction is complete. The reaction mixture is poured into water and extracted with ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1.IC.[CH3:23]N(C)C=O.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2NC1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 0.48 g (0.0016 mole) of (rac)-2-chloro-9-cyclohexyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-18), 0.2 mL (0.0032 mole) of iodomethane and 5 mL of dimethylformamide was added 0.13 g (0.0032 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at room temperature for 1 hour, then 100 mL of water was added and the mixture was extracted with twice with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (85:15), followed by recrystallization from dichloromethane-hexanes to give 0.41 g of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19) as white needles.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[OH-].[K+]>CO.O1CCCC1.O>[CH3:16][CH:9]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)C=CC=CCC(C)CCCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCCC(C)CC=CC=CC(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2.3 g of 7,11-dimethyl-2,4-dodecadienoic acid methyl ester is dissolved in 46 ml of methanol and 18 ml of tetrahydrofuran. The mixture is cooled to 0°C., and 4.9 g of potassium hydroxide in 18 ml of water is added. The mixture is stirred overnight (18 hours) at room temperature (22°C.), poured on to water, and extracted with diethyl ether. The aqueous phase is made slightly acidic with 3-N sulphuric acid and again extracted with diethyl ether. The latter, ether extract is washed to neutrality, dried and evaporated. There is obtained 7,11-dimethyl-2,4-dodecadienoic acid, obtained as a slightly-yellow, colored oil, which is uniform according to thin-layer chromatography and which can be utilized without further processing.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([CH2:37]O)[CH:35]=2)[C@H:30]([N:41]([CH2:46][C:47]2[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[C:49]([C:57]([F:60])([F:59])[F:58])[CH:48]=2)[C:42]([O:44][CH3:45])=[O:43])[CH2:29][C@@H:28]1[CH3:61])=[O:26])[CH3:23]>ClCCl.C(Cl)(Cl)Cl>[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([CH2:37][Br:20])[CH:35]=2)[C@H:30]([N:41]([CH2:46][C:47]2[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[C:49]([C:57]([F:60])([F:59])[F:58])[CH:48]=2)[C:42]([O:44][CH3:45])=[O:43])[CH2:29][C@@H:28]1[CH3:61])=[O:26])[CH3:23]
Reactant: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(CBr)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.5 %

Procedure:
To a solution of triphenylphosphine (0.457 g, 1.74 mmol) in anhydrous dichloromethane (15 mL) at 0° C. was slowly added bromine (84 μL, 1.6 mmol). After the reaction was stirred at 0° C. for 20 min, a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 85) (0.630 g, 1.09 mmol) in dichloromethane (15 ml) was added. The reaction was stirred at 0° C. for 20 min, then at room temperature for 3 h. The reaction mixture was then diluted with chloroform and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent afforded the title product (0.500 g, 72%): MS m/z 642.1 (M++1); 1H NMR (CDCl3) δ 1.15 (d, 3H), 1.3 (t, 3H), 3.8 (s, 3H), 3.85 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.7 br, 2H), 7.8 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][Cl:12].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].O>C(O)(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:16][C:13](=[O:15])[CH3:14]
Reactant: ClCCCc1ccccc1CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccccc1CCCCl

Procedure:
70 g (345 mmols) of 3-(2-Chloromethylphenyl)-propyl chloride (JACS 75, 2053 (1953)) and 50 g (0.61 mmol) of sodium acetate were heated to the boiling point while stirring in 250 ml of glacial acetic acid. It resulted from the thin layer chromatography that the reaction was finished after 41/2 hours. After cooling about 700 ml of water were added and the product was extracted with benzene. The organic phase was washed with water, dried and distilled off after evaporation of the solvent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][CH:12]=O)[CH:10]=1.Cl.NO.C([N:22](CC)CC)C.C1(=O)OC(=O)C2=CC=CC=C12>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][C:12]#[N:22])[CH:10]=1
Reactant: CCc1ncc(CC(=O)OC)cc1CC=O
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Solvent: O
Product: CCc1ncc(CC(=O)OC)cc1CC#N
Temperature: 90 °C
Yield: 79.5 %

Procedure:
A solution of 6-ethyl-5-(2-oxo-ethyl)-pyridin-3-yl-acetic acid methyl ester (0.77 g, 3.46 mmol), hydroxylamine hydrochloride (0.26 g, 3.80 mmol) and triethylamine (0.53 mL, 3.80 mmol) in acetonitrile (9 mL, 0.4 M) is stirred under nitrogen at room temperature for 2 h. Phthalic anhydride (0.55 g, 3.71 mmol) is added and the mixture is warmed to 90° C. for 16 h. After cooling to room temperature, water (50 mL) is added and the mixture is extracted with ethyl acetate (50 mL). The organic layer is washed with saturated NaHCO3 (50 mL) and dried over Na2SO4. The product is purified by flash chromatography (20-50% ethyl acetate in n-heptane) to provide 5-cyanomethyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester as a clear oil (0.60 g, 80%): Rf 0.31 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.44 (s, 1 H), 7.67 (s, 1 H), 3.74 (s, 2 H), 3.73 (s, 3 H), 3.65 (s, 2 H), 2.83 (q, J=7.5 Hz, 2 H), 1.33 (t, J=7.5 Hz, 3 H). ESI-LCMS m/z calcd for C12H14N2O2: 218.1; found 219.0 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:9])([CH3:8])[C:6](=[O:10])[N:5](CC2C=CC(OC)=CC=2)[C:4]1=[O:20])[CH3:2].Cl>COC1C=CC=CC=1>[CH2:1]([N:3]1[C:7]([CH3:8])([CH3:9])[C:6](=[O:10])[NH:5][C:4]1=[O:20])[CH3:2]
Reactant: CCN1C(=O)N(Cc2ccc(OC)cc2)C(=O)C1(C)C
Agent: Cl
Solvent: COc1ccccc1
Product: CCN1C(=O)NC(=O)C1(C)C
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A solution of 3-ethyl-1-(4′-methoxybenzyl)-2,5-dioxo-4,4-dimethylimidazolidine (3.86 g, 14.0 mmol) in methoxybenzene (100 mL) was treated with alumiun trichloride (5.5 g, 42 mmol), stirred at 75° C. for 30 minute, then poured the reaction into HCl solution (10%) and partitioned between ethyl acetate and brine. The organic layer was dried, filtered, and concentrated. Purification by recrystalization with ethyl acetate provided 2.1 g (13.5 mmol, 96%) of title compound as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[CH3:20])=[O:8].[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=2[CH3:20])=[O:8])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)c2cc(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 98.7 %

Procedure:
A mixture of 2.50 g (7.29 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone, 1.53 g (7.29 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 3.30 g (24 mmol) of potassium carbonate in 50 mL of acetone and 5 mL of DMF was stirred and heated at reflux for 26 hours. After workup as in Example 16 the crude product was purified by HPLC using 10% ethyl acetate-hexane to give 3.40 g (98% yield) of 4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl benzoic acid methyl ester as an oil. The nmr spectrum was consistent with the structure.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1.O>[CH:33]([O:32][C:30](=[O:31])[NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)([CH3:35])[CH3:34]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 28.8 %

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.07 g, 0.25 mmol), triethylamine (0.052 mL, 0.38 mmol) and isopropyl chloroformate (1M solution in toluene) (0.281 mL, 0.28 mmol) were dissolved in toluene (3 mL) and stirred at 60° C. for 10 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL). The combined organic phases was dried over sodium sulfate, filtered and the filtrate evaporated. The residue was subjected to column chromatography (silica gel, heptane/ethyl acetate, 9:1, 4:1, 3:1) to yield the title compound (0.026 g, 41%) as a white foam; MS: m/e=361.7 (M+H+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[CH3:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[O:56][C:57]1[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[O:56][C:57]1[N:62]=[CH:61][C:60]([NH:63][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Cc1cccc(C)c1Oc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (204 mg, 1.003 mmol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.219 mL, 1.253 mmol) were dissolved in N,N-Dimethylformamide (4 mL) to give a pale yellow solution. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (381 mg, 1.003 mmol) was added. The reaction mixture became bright yellow and was stirred at room temperature for 15 minutes. 6-[(2,6-dimethylphenyl)oxy]-3-pyridinamine (Intermediate 42, 223.8 mg) was added and the reaction mixture was warmed at 60° C. After 4 hours, the reaction was complete. The solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) using as eluents a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV; then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale yellow solid (202.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([C:6]([F:9])([F:8])[F:7])=[CH2:5].O([CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:4]1([C:6]([F:9])([F:8])[F:7])[CH2:5][CH2:13][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:10]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OC)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(C(F)(F)F)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred cold solution (0° C.) of 2-trifluoromethyl-acrylic acid methyl ester (308 mg, 2 mmol) and N-(methoxylmethyl)-N-(trimethylsilylmethyl)benzylamine (529 μl, 4.8 mmol) in dichloromethane (3 ml) was added slowly trifluoroacetic acid (31 μl). The resulting solution was allowed to stir at rt overnight and directly purified by column chromatography eluting with ethyl acetate in hexane (1:4) to provide 1-benzyl-3-trifluoromethyl-pyrrolidine-3-carboxylic acid methyl ester as oil (438 mg, 76%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.[Cl:13][C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:5]2[NH:26][C:2](=[O:4])[C:1]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6]2)=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C1NC(c2ccc(Cl)cc2)Nc2ccccc21

Procedure:
Isatoic anhydride (163 mg, 10 003|\ was dissolved under an argon atmosphere in 5 ml of ethanol and, after addition of 4-chlorobenzaldehyde (211 mg, 15 mmol), ammonium acetate (93 mg, 12 mmol) and 4-toluenesulfonic acid (86 mg, 5 mmol), boiled at reflux for 5 hours. The product precipitated in the course of cooling. The precipitated solid was washed with a little ethanol and dried. This gave 150 mg (54.5% of theory) of 2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one as a white solid of melting point 190° C. 1H NMR (400 MHz, CDCl3 δ, ppm) 7.95 (d, 1H), 7.55 (dd, 2H), 7.42 (dd, 2H), 7.34 (t, 1H), 6.91 (t, 1H), 6.68 (d, 1H), 5.90 (s, 1H), 5.75 (br. S, 1H), 4.35 (br. S, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[N:43]1[CH:48]=[CH:47][N:46]=[CH:45][C:44]=1[C:49](Cl)=[O:50]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:49]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][N:43]=4)=[O:50])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnccn2)C3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0493 g, 0.000129 mol) in dry N,N-Dimethylformamide (0.610 mL, 0.00788 mol) was added N,N-Diisopropylethylamine (0.0684 mL, 0.000393 mol) cooled at 0° C., added Pyrazine-2-carbonyl chloride (0.0312 g, 0.000219 mol), warmed to room temperature, and stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.98-8.91 (m, 1H), 8.80 (dd, J=5.3, 2.6, 1H), 8.74 (d, J=1.4, 1H), 8.64 (d, J=12.3, 1H), 8.18 (dd, J=34.9, 8.7, 2H), 7.47 (dd, J=20.0, 8.8, 2H), 6.20-6.09 (m, 1H), 4.75 (d, J=25.1, 2H), 3.88 (t, J=5.0, 1H), 3.79-3.60 (m, 5H), 3.49 (d, J=4.0, 4H), 3.18-3.02 (m, 2H), 2.77 (s, 2H), 1.06 (dd, J=13.3, 7.0, 3H). LC/MS-m/z+489.2 (M+H)+.
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C3C=CC(C(N4CCN(C)CC4)=O)=CC=3)C=2)C=1.Br[C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[N:46]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH:44]=2)[CH:40]=[N:41][CH:42]=1.[CH:60]([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][C:70]2[CH:75]=[CH:74][C:73](B(O)O)=[CH:72][CH:71]=2)[CH2:65][CH2:64]1)([CH3:62])[CH3:61]>>[CH:60]([N:63]1[CH2:64][CH2:65][N:66]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:37]3[CH:38]=[C:39]([C:43]4[CH:48]=[C:47]([N:49]5[CH2:53][CH2:52][CH2:51][CH2:50]5)[N:46]=[C:45]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=5)[CH:44]=4)[CH:40]=[N:41][CH:42]=3)=[CH:72][CH:71]=2)[CH2:67][CH2:68]1)([CH3:62])[CH3:61]
Reactant: Brc1cncc(-c2cc(-c3ccccn3)nc(N3CCCC3)c2)c1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Agent: CNc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)c2)cc(-c2ccccn2)n1
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(-c5ccccn5)nc(N5CCCC5)c4)c3)cc2)CC1

Procedure:
is prepared analogously to [4-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone (Example 2.1) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1, step1) with 5″-Bromo-6′-pyrrolidin-1-yl-[2,2′;4′,3″]terpyridine and by replacing (4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 4-(4-Isopropyl-piperazin-1-ylmethyl)-phenyl boronic acid (Intermediate B3).