Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OC)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CNCCc2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 176.8 ml (176.8 mmol) of a 1N boron tribromide solution in methylene chloride are added dropwise to 16.03 g (53.561 mmol) of methyl 4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Example. I.1 in 100 ml of methylene chloride. After one hour of stirring at 0° C., 150 ml of methanol are added and the solution is heated at reflux for 4 hours. The solvent is distilled off under reduced pressure and the residue is taken up in a mixture of 190 ml of ethyl acetate and 10 ml of methanol. Using 10% strength sodium carbonate solution, the mixture is made alkaline and extracted with ethyl acetate/methanol 9/1. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography over silica gel (0.04-0.063 nm) using the mobile phase methylene chloride/methanol 100/2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)=[CH:7]2)([O-:3])=[O:2].Cl.Cl[CH2:27][CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH3:34][N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][CH2:27][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=1
Reactant: CN1CCCC1CCCl
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cc3ccc(OC(F)(F)F)cc3)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCC1CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C

Procedure:
compound 8 (75 mg, 0.223 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (45.2 mg, 0.245 mmol), potassium carbonate (92.4 mg, 0.669 mmol) and anhydrous dimethylformamide (5 mL) were charged to a small, argon purged flask fitted with a magnetic stirbar and resulting solution heated in an oil bath at 65° C. for 20 hours. After cooling to room temperature the mixture was diluted with H2O and ethyl acetate, transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude solid. The crude product was purified using dry silica gel column chromatography eluting with 25 mL portions of solvent system (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) to yield a yellow residue, 12 (100 mg, quantitative). 1H NMR (DMSO-d6) δ 1.35-1.45 (m, 2H), 1.58-1.64 (m, 3H), 1.72-1.88 (m, 1H), 1.97-2.05 (m, 2H), 2.08 (s, 3H), 2.86-2.95 (m, 1H), 4.15 (t, 2H, J=7.7 Hz), 4.29 (s, 2H), 6.49 (s, 1H), 7.33-7.43 (m, 4H), 7.57 (d, 1H, J=9.1 Hz), 8.00 (dd, 1H, J=9.1, 2.2 Hz), 8.50 (d, 1H, J=2.2 Hz); ESI-MS (m/z, %): 448 (MH+, 100%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(=O)CC>O>[C:1]([N:5]=[CH:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=CC=Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)N=CC=Cc1ccccc1
Reaction time: 8 h
Yield: 96 %

Procedure:
20.3 grams of t-butylamine (0.28 mol) was metered over a period of 16 minutes to 33.0 grams of cinnamaldehyde (0.25 mol) during stirring and cooling. The mixture was left to stand overnight at room temperature. 150 ml of butanone was then added to the crude reaction mixture to enable the water formed during the reaction to be evaporated azeotropically. The mixture was evaporated on a rotary evaporator. The residue consisted of 45.6 grams of product having a purity of 98%. Yield 96%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH2:16][C:17]([N:3]1[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]1[CH3:1])=[O:18]
Reactant: CC1CCC(C)N1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1CCC(C)N1C(=O)CCl
Reaction time: 0.25 h

Procedure:
A solution of 2,5-dimethylpyrrolidine (15 grams; 0.15 mol) and triethylamine (15 grams) in benzene (150 ml) was charged into a 250 ml glass reaction flask equipped with stirrer, reflux condenser and addition funnel. Chloroacetyl chloride (18 grams; 0.15 mol) was then slowly added, with vigorous stirring, over a period of several minutes. After the addition was completed stirring was continued for about 15 minutes. After this time the reaction mixture was filtered to remove the triethylamine hydrochloride which had formed. The filtered reaction mixture was then stripped of benzene under reduced pressure to yield a dark colored oil. The oil was distilled under vacuum to yield 1-(α-chloroacetyl)-2,5-dimethylpyrrolidine as a colorless oil having a boiling point of 89° to 90° C. at 0.1 mm of mercury pressure, and a refractive index at 25° C. of 1.4863.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:15]1[C:18]2([CH2:21][NH:20][CH2:19]2)[CH2:17][O:16]1.C1C=CC2C(C3C(O)=CC=C4C=3C=CC=C4)=C(O)C=CC=2C=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][C:18]3([CH2:15][O:16][CH2:17]3)[CH2:19]2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C1NCC12COC2
Agent: [Cu]I
Agent: O=C(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc(N2CC3(COC3)C2)cc1
Yield: 37.5 %

Procedure:
The title compound was synthesized according to General Method D, utilizing 1,4-diiodobenzene (2.5 g, 7.6 mmol), 2-oxa-6-azaspiro[3.3]heptane oxalic acid salt (1.0 g, 6.9 mmol), CuI (0.26 g, 1.4 mmol), BINOL (0.40 g, 1.4 mmol), and K3PO4 (4.4 g, 21 mmol) in DMF (15 mL). The mixture was diluted with EtOAc, filtered through Celite and the filtrate was concentrated. Purification by flash chromatography (Biotage Isolera, 100 g HP-SIL, 10-50% EtOAc in hexanes) gave the title compound as a yellow solid (0.78 g, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (d, J=8.8 Hz, 2H), 6.22 (d, J=8.8 Hz, 2H), 4.82 (s, 4H), 3.98 (s, 4H); MS ESI 301.9 [M+H]+, calcd for [C11H12INO+H]+ 302.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[N:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)cn1
Yield: 79.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 6-methylpyridine-3-boronic acid (128 mg, 0.94 mmol) were reacted. After purification the title compound (119 mg, 80% yield) was obtained as a white solid. MS APCI, m/z=320.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:6]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1.C(=O)=O.CC(C)=O.CN(C)CCN(C)C.C([Li])CCC.C(P(CCCC)CCCC)CCC.I[CH2:51][C:52]1[N:53]=[C:54]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:55][C:56]=1[CH3:57]>O1CCCC1.[Cu](I)I>[CH3:12][C:9]1([CH3:13])[O:10][CH2:11][CH:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([CH2:51][C:52]3[N:53]=[C:54]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[O:55][C:56]=3[CH3:57])[CH:3]=2)[CH2:7][O:8]1
Reactant: CC1(C)OCC(Cc2cccc(Br)c2)CO1
Reactant: Cc1oc(-c2ccccc2)nc1CI
Agent: I[Cu]I
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)CCN(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC2COC(C)(C)OC2)c1
Yield: 17.7 %

Procedure:
Under argon flow, 1.45 g of 5-(3-bromobenzyl)-2,2-dimethyl-1,3-dioxane was dissolved in 7 ml of dry tetrahydrofuran, and cooled with the dry ice-acetone bath. To the mixture was added 0.9 ml of N,N,N′,N′-tetramethylethylenediamine, and then n-butyllithium (1.6 M hexane solution) was added dropwise at −60° C. or less. After 10-minute-stirring, a suspension of 1.03 g of tri-n-butylphosphine and 0.97 g of copper iodide/7 ml of dry tetrahydrofuran was added and the mixture was stirred for 10 minutes. A solution of 1.52 g of 4-iodomethyl-5-methyl-2-phenyloxazole/7 ml of dry tetrahydrofuran was added dropwise at −60° C. or less, and the mixture was stirred for 15 minutes under the same conditions. The bath was removed and the mixture was stirred for 1.5 hours. To the reaction solution was added saturated aqueous ammonium chloride solution. The mixture was diluted with water, extracted with ether, filtrated to remove insolubles, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=4:1) to provide 0.34 g of the objective compound as white crystals. M.p. 85-87° C.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:50])([F:49])[C:41]1[N:42]=[C:43]([C:46](O)=[O:47])[S:44][CH:45]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:17]2[CH:16]=[N:15][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:13][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:46]([C:43]5[S:44][CH:45]=[C:41]([C:40]([F:49])([F:39])[F:50])[N:42]=5)=[O:47])[CH2:5][CH2:6]4)[CH2:11]3)[CH:18]=2)=[N:24][CH:23]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: Cl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3nc(C(F)(F)F)cs3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 4-trifluoromethylthiazol-2-ylcarboxylic acid following the procedure described for Example 1, followed by HPLC purification (method B) provided the title compound. LC-MS: 542.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47](O)[CH2:46][CH2:45]1>>[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:46][CH2:45]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CN1CCC(O)CC1
Product: COc1cc(C(=O)OC2CCN(C)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 1-methylpiperidin-4-ol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-methyl-piperidin-4-yl ester. MS (ES+) m/z calcd. for C37H41Cl2F2N4O4: [(M+H)+]: 713. found: 713.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]1[CH:18]1[C:27]2[C:22](=[C:23]([N+:37]([O-])=O)[C:24]([O:34][CH2:35][CH3:36])=[C:25]([O:31][CH2:32][CH3:33])[C:26]=2[O:28][CH2:29][CH3:30])[C:20](=[O:21])[O:19]1.[H][H]>[Ni].C(O)C>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]1[CH:18]1[C:27]2[C:22](=[C:23]([NH2:37])[C:24]([O:34][CH2:35][CH3:36])=[C:25]([O:31][CH2:32][CH3:33])[C:26]=2[O:28][CH2:29][CH3:30])[C:20](=[O:21])[O:19]1
Reactant: [H][H]
Reactant: CCOc1c(OCC)c2c(c([N+](=O)[O-])c1OCC)C(=O)OC2C1c2c(cc(OC)c(OC)c2OC)CCN1C
Agent: [Ni]
Solvent: CCO
Product: CCOc1c(N)c2c(c(OCC)c1OCC)C(C1c3c(cc(OC)c(OC)c3OC)CCN1C)OC2=O
Yield: 76.2 %

Procedure:
270 g of the nitro derivative (a) is added to 1.570 liters of ethanol and 21 g of Raney nickel in an autoclave. Hydrogen is added under a pressure of 10 atmospheres and the reactants are heated at a temperature of 65° while stirring. After 1 hour 45 minutes the theoretical volume of hydrogen has been absorbed. The solution is cooled and filtered. The ethanol is distilled in vacuo, the residue is dissolved in 0.6 l of methanol, 60 g of potassium hydroxide tablets are added, and the mixture is heated under reflux for 1 hour while stirring. The mixture is cooled and allowed to crystallise. 194.5 g (yield=76%) of 2-methyl-6,7,8-trimethoxy-1-(4,5,6-triethoxy-7-amino-3-phthalidyl)-1,2,3,4-tetrahydro-isoquinoline is obtained in the form of white crystals having a melting point of 144° and exhibiting only a single spot when analysed by thin layer chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C:19]([F:25])([CH3:24])[C:18](=O)[NH:17]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C@@:19]([F:25])([CH3:24])[C:18](=[S:37])[NH:17]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([C@@]2(C)NC(=O)C(C)(F)CC2(F)F)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c([C@@]2(C)NC(=S)[C@@](C)(F)CC2(F)F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Tert-butyl (4-fluoro-3-((2R)-3,3,5-trifluoro-2,5-dimethyl-6-oxopiperidin-2-yl)phenyl)carbamate (2.1 g, 5.38 mmol) (1:1.7 mixture of diastereomers) was placed in a round bottom flask and dissolved in toluene (60 ml) (dried over 4 Å MS). Argon was bubbled through the reaction for 10 min followed by addition of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) (2.18 g, 5.38 mmol). The reaction was carefully evacuated and backfilled with argon (×3). The suspension was heated to 80° C. The reaction was stirred at this temperature for 3 h 30 min. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The crude material was suspended in CHCl3 and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified using a CombiFlash system (120 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→80:20) to afford tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (1.15 g, 52.6% yield) (fast eluting isomer) LC-MS (m/z) 407.4 (MH+) tR=0.83 minutes (Method B) and tert-butyl (4-fluoro-3-((2R,5R)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (0.816 g (60% purity), 22.4% yield) (slow eluting isomer) LC-MS (m/z) 407.4 (MH+) tR=0.82 minutes (Method B).
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][NH:9][C:10]([NH:33][C:34]1[C:35]([CH3:41])=[CH:36][CH:37]=[CH:38][C:39]=1[CH3:40])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)([OH:7])=[O:5]
Reactant: COc1cc2c(N=C(NCC(=O)OC(C)(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(N=C(NCC(=O)O)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of N-(tert-butoxycarbonylmethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]guanidine (0.09 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixture of methylene chloride and a 2M solution of ammonia gas in methanol as eluent. There was thus obtained the title compound in 67% yield: NMR Spectrum: (DMSOd6, 100° C.) 1.2–1.5 (m, 3H), 1.7–1.9 (m, 2H), 2.0–2.1 (m, 2H), 2.14 (s, 3H), 2.19 (s, 6H), 2.84 (d, 2H), 3.82 (s, 3H), 3.95–4.05 (m, 4H), 7.08 (s, 1H), 7.17 (s, 3H), 7.71 (s, 1H), 8.43 (s, 1H); Mass Spectrum: M+H+ 507.
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(N)C=CC1=2.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.S(Cl)(Cl)=[O:27]>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:27])=[O:22])=[CH:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC1(C)CCC(C)(C)c2cc(N)ccc21
Product: O=C(O)c1ccc(F)cc1

Procedure:
In a manner analogous to Example 9, by reacting 5.9 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine with 4-fluorobenzoyl chloride, obtained from 4 g of 4-fluorobenzoic acid and 15 ml of thionyl chloride, there were obtained, after recrystallization from hexane/ethyl acetate, 6.3 g of p-fluoro-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide, m.p. 160°-162° C.
Reaction SMILES: [O:1]1[CH2:4][C:3](=[O:5])[CH2:2]1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].CCCCCC>C1COCC1>[CH2:6]([C:3]1([OH:5])[CH2:4][O:1][CH2:2]1)[CH2:7][CH2:8][CH3:9]
Reactant: O=C1COC1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1(O)COC1

Procedure:
To a stirred solution of 3-oxetanone (0.5 g, 6.93 mmol) in dry THF (6 mL), at −78° C., under argon atmosphere, 2.5M solution of butyl lithium (BuLi) in hexane (3.05 mL, 7.62 mmol) was added dropwise over 10 min. The reaction was left to react 3 h at −78° C., then quenched with water and concentrated to dryness. The crude mixture was dissolved in CH2Cl2 and dried over Na2SO4. The organic solution was filtered and concentrated to dryness to afford a pale yellow oil (0.505 g). The crude product was purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy/TBME (from 100:0 to 70:30) affording the title compound (0.45 g, 50%) as transparent oil. 1H NMR (CDCl3): δ 0.90-1.04 (m, 3H), 1.36-1.47 (m, 4H), 1.79-1.93 (m, 2H), 4.53 (d, J=7.1, 2H), 4.59 (d, J=6.9, 2H).
Reaction SMILES: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.C(=O)(O)[O-].[Na+].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43].[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.CC1CCCO1>O>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])=[O:50])=[CH:47][CH:46]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: O=C(Nc1ccccc1O)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
To a 500 ml 4 necked round bottom flask equipped with a thermometer, a mechanic stirrer, a drop funnel, a nitrogen in-let, was added sodium bicarbonate (29.6 g, 0.354 mol, 1.1 eq), 2-aminophenol (34.88 g, 0.32 mol, 1 eq) and 2-Methyl THF (250 ml). The temperature of the mixture was controlled under 20° C. by ice-bath. Under vigorously stirring, 4-fluorobenzoyl chloride (50.72 g, 0.32 mol, 1 eq) was added drop wise within 10 min. Then the reaction was allowed to be stirred for another 1.5 hrs. When HPLC data showed that less than 0.3% of 2-aminophenol remained, 100 ml of water and 50 ml of 2-methyl tetrahydrofuran was added to quench the reaction and then the mixture was heated to 60° C. with stirring. The mixture was partitioned into two phases and the organic phase was washed with 100 ml of 1N H2SO4 and subsequently with 100 ml of water. Then the solvent was evaporated to almost dryness with stirring.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([OH:11])[CH2:9][OH:10].[CH:12](O)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>S(=O)(=O)(O)O.CCOCC>[CH:12]([O:10][CH2:9][CH2:8][OH:11])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCO
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OCCOC(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
8 ml of toluene and 2 drops of concentrated sulfuric acid were added to 621 mg (10.0 mmol) of ethylene glycol, and they were heated to 90° C. 737 mg (4.0 mmol) of benzhydrol was added dropwise to the obtained mixture for the duration of 50 minutes. 30 minutes after, 621 mg (10.0 mmol) of ethylene glycol was added thereto and they were stirred under heating for 40 minutes. Ether was added to the reaction mixture, and the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate solution, water and finally saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][O:17][CH3:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].CN(C=O)C.C1(S(NN)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5]
Reactant: COCC=Cc1ccc(Cl)c(C(=O)NC2CC2)c1
Agent: NNS(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCCCc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 110 °C
Yield: 78.5 %

Procedure:
2-Chloro-N-cyclopropyl-5-(3-methoxy-propenyl)-benzamide (12.6 g, 47.6 mmol) was dissolved in dry toluene (650 mL). Dry DMF (70 mL) was added, and the mixture was heated to 110° C. Benzensulfonyl hydrazine (24.5 g, 143 mmol) was added in three portions over 3 h. The mixture was heated for a total time of 3 h, and allowed to cool to rt. The solvents were removed under reduced pressure, and the residue was diluted with Et2O. The mixture was washed with water, and the aq. phase was extracted back with Et2O (3×). The combined org. extracts were washed with water, and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→1:4→1:3→1:1) yielded the title compound (10.0 g, 78%). LC-MS: tR=0.83 min; ES+: 268.19.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22](=O)[CH3:23]>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH3:23])[C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ncccc1OCc1ccccc1
Reactant: CC(=O)CCl
Product: COC(=O)c1c(C)cn2cccc(OCc3ccccc3)c12

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation III using the Tschitschibabin reaction, starting with 25.82 g of methyl 2-[3-(benzyloxy)pyridin-2-yl]acetate [according to J. Med. Chem.; (1996), 39(19), 3636-3658] and chloroacetone.