Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:22][C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[N:11]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[C:5]=2[CH2:4][CH2:3]1.B>O1CCCC1>[CH3:1][CH:2]1[CH2:22][CH:6]2[CH:7]=[CH:8][C:9]3[C:10]4[N:11]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH:5]2[CH2:4][CH2:3]1
Reactant: CC1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1
Agent: B
Solvent: C1CCOC1
Product: CC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Temperature: 91 °C

Procedure:
A solution of 4.76 g. of 1,2,3,4,8,9-hexahydro-3-methylpyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine (which can be made according to the teachings of U.S. Pat. No. 3,457,271, Column 4, lines 27-54) in 50 ml. of tetrahydrofuran was added dropwise to a stirred 1N-solution of boron hydride in tetrahydrofuran (42 ml.) under a nitrogen blanket. After the addition was complete, the mixture was refluxed under nitrogen for five hours, then cooled in ice and quenched with 20 ml. of 6N hydrochloric acid. The mixture was distilled, the removed liquid being from time to time replaced by addition of dioxane. The mixture was again refluxed at 91°C. for one hour with additional 6N hydrochloric acid, then cooled to 70°C., made basic with sodium hydroxide, and evaporated in vacuum. The semisolid residue was treated with water and chloroform, and the chloroform layer was further worked up to yield 1.50 g. of a solid product, m.p. 128°-131°C. The mother liquors yielded an additional amount of material, m.p. 129.5°-130.5°C. Crystallization from ether raised the melting point to 132°-134°C.; UV spectrum: λmaxCH3OH 279.5 mμ (logε 4.13).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14][C@H:13]1[O:31][CH3:32])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:14][C@H:13]1[O:31][CH3:32]
Reactant: CO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Product: CO[C@@H]1CN(c2cccc(C(=O)OC(C)(C)C)c2)CC[C@@H]1N

Procedure:
The same operation as in Example (40e) was performed using tert-butyl cis(±)-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (42c) (115 mg, 0.26 mmol) and a 10% palladium-carbon catalyst (40 mg), to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]2[S:11][C:12]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])=[CH:13][N:14]=2)C(=O)C2=CC=CC=C12.NN>C(O)C>[NH2:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[S:11][C:12]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])=[CH:13][N:14]=1
Reactant: CN(C)C(=O)c1cnc(OCC(O)CN2C(=O)c3ccccc3C2=O)s1
Agent: NN
Solvent: CCO
Product: CN(C)C(=O)c1cnc(OCC(O)CN)s1

Procedure:
The product from Example 9 (4.0 g, 10.6 mmol) can be added to a solution of hydrazine (0.38 g, 12 mmol) in absolute ethanol (20 ml) and the suspension refluxed 4 hours under nitrogen on a steam bath. The mixture can then be cooled and filtered and the filtrate concentrated in vacuo to give the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][N:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:17])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=C(O)c2ccccc2SN1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1=C(OC)c2ccccc2SN1C
Yield: 61 %

Procedure:
This compound was prepared according to Zinnes et. al., J. Med. Chem., 1973, 16, 44-48. Thus, a solution of methyl 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate (500 mg, 1.86 mmol) (Lombardino, et. al., J. Med. Chem., 1971, 14, 1171-1177, incorporated by reference herein in its entirety) in acetone (10 ml) was treated with anhydrous potassium carbonate (2.6 g, 18.6 mmol) and iodomethane (1.32 g, 9.29 mmol) and refluxed for 40 hours. The mixture was filtered and concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 285 mg (54%) of the title compound as a yellow viscous oil, used subsequently without need for further purification; NMR (CDCl3) δ 3.03 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 7.67-7.72 (m, 2H), 7.81-7.88 (m, 2H); MS: 284 m/z (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:10])[CH3:9].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[N:27][CH:28]=2)[NH:25][CH2:24][CH2:23][CH2:22]3)O1>>[N:25]1[C:26]2[NH:27][CH2:28][CH2:19][CH2:20][C:21]=2[CH:22]=[C:23]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]([OH:10])[CH3:9])[CH:24]=1
Reactant: CC(O)c1ccncc1Br
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3)OC1(C)C
Product: CC(O)c1ccncc1-c1cnc2c(c1)CCCN2

Procedure:
1-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol is synthesized according to the procedure of Suzuki Coupling Method VI using 1-(3-bromo-pyridin-4-yl)-ethanol and crude 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (which is prepared according to Step 4 of Example 105).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[NH2:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[C:47]#[N:48]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:44][C:45]4[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=4[C:47]#[N:48])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4C#N)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 50 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]amine (intermediate C4.1) with 2-aminobenzonitrile yielded the title compound (50% yield) as an off-white foam. MS (ISP): m/z=691.3 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[NH:36]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][S:46][CH2:47][CH2:48][NH2:49])[N:44]=1)[C:37]([NH2:39])=[NH:38]>>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:24]([NH:49][CH2:48][CH2:47][S:46][CH2:45][C:43]2[N:44]=[C:40]([NH:36][C:37]([NH2:39])=[NH:38])[S:41][CH:42]=2)=[O:25])[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CN(CCCCN)CCOC(c1ccccc1)c1ccccc1
Product: CN(CCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCOC(c1ccccc1)c1ccccc1

Procedure:
Preparation is effected analogously to Example 63, using 0.37 g (1.2 mmol) of N-[2-(diphenylmethoxy)ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=570 ([M+H]+, 11), 167 (100); IR (KBr): 1644 cm-1 (C=O). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from acetonitrile/isopropanol/petroleum ether; m.p.: 101° C. (acetonitrile/isopropanol/petroleum ether).
Reaction SMILES: [CH3:1][S:2][CH3:3].[CH3:4][S:5]([O:8]C)(=[O:7])=[O:6]>>[CH3:4][S:5]([O-:8])(=[O:7])=[O:6].[CH3:1][S+:2]([CH3:4])[CH3:3]
Reactant: CSC
Reactant: COS(C)(=O)=O
Product: CS(=O)(=O)[O-]
Product: C[S+](C)C
Reaction time: 72 h

Procedure:
A mixture of 1.24 g of dimethylsulfide and 2.20 g of methyl methanesulfonate was allowed to stand for three days at room temperature. The crystals which deposited were collected by filtration, washed with diethyl ether and dried. By this procedure crystals of S,S,S-trimethylsulfonium methanesulfonate were obtained. When this product was recrystallized, it had a melting point of 193.0° to 195.0°C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4.[CH:24]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:24]1([CH2:28][N:20]2[CH2:19][CH2:18][C@@:15]34[C:16]5[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=5[CH2:8][C@@H:9]2[C@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13](=[O:21])[CH2:14]4)[CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3
Reactant: BrCC1CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A mixture of 3,14-dimethoxymorphinan-6-one hydrochloride (6b) (1.0 g, 2.96 mmol), cyclobutylmethyl bromide (0.662 g, 4.44 mmol) and NaHCO3 (1.492 g, 17.76 mmol) in 25 ml of dimethylformamide (DMF) was refluxed at an oil bath temperature of 110° under nitrogen for 16 hours. The mixture was filtered and the residue washed with DMF whereupon the filtrate was distilled under reduced pressure (oil bath temperature 30°-40° C.) and the residual material was taken up in methylene chloride (50 ml) and water (50 ml). The two layers were separated and the aqueous layer re-extracted with methylene chloride (2×50 ml). The organic layers were combined, washed with water (20 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting solid was chromatographed on Florisil, and eluted with graded methanol/chloroform mixtures to give 17-cyclobutylmethyl-3,14-dimethoxymorphinan-6-one as a yellow oil. This material was converted to its HCl salt (7) by treatment with ethereal hydrogen chloride to give 0.507 g of a light-colored solid (42% theory), m.p. 230° C. (decomposed).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:33][N:32]=[C:31]2[C:7]=1[CH2:8][CH:9]1[CH:22]3[CH:13]([C:14]4[CH:15]=[CH:16][C:17]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:18][C:19]=4[CH2:20][CH2:21]3)[CH2:12][CH2:11][C:10]12[CH3:34])=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH2:24]([O:23][C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH:22]([CH2:21][CH2:20][C:19]=2[CH:18]=1)[CH:9]1[CH2:8][C:7]2[C:31]([C:10]1([CH3:34])[CH2:11][CH2:12]3)=[N:32][NH:33][C:6]=2[CH2:4][OH:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1[nH]nc2c1CC1C3CCc4cc(OCc5ccccc5)ccc4C3CCC21C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC12CCC3c4ccc(OCc5ccccc5)cc4CCC3C1Cc1c2n[nH]c1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Benzyloxy-6a-methyl-4b,5,6,6a,8,10,10a,10b,11,12-decahydro-7,8diaza-pentaleno[2,1-a]phenanthrene-9-carboxylic acid ethyl ester (457 mg, 1.0 mmol, CAB03049) was added to a suspension of LiAlH4 (100 mg) in THF (20 mL). The mixture was stirred for 30 minutes at room temperature, then water (1 mL) was added (to destroy the excess of LiAlH4). Stirring was continued for 1 hour (light yellowgreen suspension), acetic acid (0.5 mL) was added, the inorganic solids were filtered of and washed carefully with THF (ca. 50 mL).The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was crystallised from ethyl acetate/diethyl ether. Yield: 215 mg (52%) colorless crystals. 1H-NMR (CDCl3, 400 MHz), δ: 1.01 (s, 3H, —CH3), 1.40-2.46 (m, 10 H), 2.60 (dd, J=13.7, 6.3 Hz, 1H), 2.82-3.00 (m, 2H), 4.69 (s, 2H, —CH2OH), 5.04 (s, 2H, —CH2Ph), 6.28 (bs, 2H, —OH and NH), 6.73 (d, J=2.3 Hz, 1H), 6.80 (dd, J=8.6, 2.3 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.30-7.45, (m, 5H). LRMS (FAB+): 91.1 (100), 415.3 (60, [M+H]+). HRMS (FAB+): 415.238434 C27H31N2O2 requires 415.238554
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)COc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N=Nc2ccc(OCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
1.95 g (0.006 mol) of ethyl 2-[4(4-cyanophenylazo)phenoxy]-ethanoate was dissolved in a mixture of 100 mL of dimethylformamide and 20 mL of water in a 250 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 1.3 g (0.033 mol) of NaOH was added. Stirring and heating were continued for ½ h. After cooling on an ice-water bath 6 mL of 6 N HCl was added. The precipitated crude product was recovered by filtration. The precipitate was suspended in a mixture of 10 mL of ethanol and 3 mL of water for 15 min. and filtered. The filtercake was washed with 10 mL of cold ethanol. After drying under vacuum overnight 1.17 g (yield 69%) of 2-[4-(4-cyanophenylazo)phenoxy]-ethanoic acid was obtained
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([CH2:13][CH2:14][C:15](O)=[O:16])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].B.Cl>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][C:8]12[CH2:9][CH2:10][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:12][CH2:11]1)[CH2:6][CH2:7]2
Reactant: COC(=O)C12CCC(CCC(=O)O)(CC1)CC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C12CCC(CCCO)(CC1)CC2

Procedure:
Carboxylic acid 2-3 (400 mg, 1.67 mmol) was dissolved in tetrahydrofuran (5 mL) and borane (1 M solution in THF, 2.17 mL, 1.3 eq.) was added dropwise at room temperature. After 2 h the reaction was added to 50 mL of 1 N HCl and then extracted three times with 50 mL of methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to afford crude methyl 4-(3-hydroxypropyl)bicyclo[2.2.2]octane-1-carboxylate (2-4) which was used without purification in the next step. 1H NMR (500 MHz, CD3OD): δ 3.66 (3H, s), 3.62 (2H, t, J=6.5 Hz), 1.78 (6H, m), 1.50 (2H, m), 1.41 (2H, m), 1.17 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]>CO.[Pd]>[CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(=Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccccc1)C(=O)O

Procedure:
A solution of α-methyl cinnamic acid (10.0 g., 61.7 mmol.) in dry methanol (250 ml.) was treated with 10% palladium on carbon and hydrogenated (balloon used) at room temperature for 16 hours. The reaction mixture was diluted with methanol (250 ml.), filtered through a Celite pad in a millipore unit, washing the pad well with methanol (2×100 ml.). The clear filtrate was evaporated to dryness to give 10.225 g. of title product as a thick syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:19][C:20]1[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:22][O:23][C:24]=1[CH3:25]>C1COCC1.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[CH2:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CNc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of 2-aminopyridine (109 mg, 1.2 mmol) in THF (2 mL) was added potassium bis(trimethylsilyl)amide (0.9 M in THF, 1.2 mL, 1.1 mmol) at 0° C. under argon. After 10 min, a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (200 mg, 1.0 mmol) in THF (1 mL) was added and the resulting mixture stirred at 0° C. for 1 h. The mixture was then diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous phase was extracted with ethyl acetate and the combined extracts dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1: to 1:1) afforded the title compound (45 mg, 18%) as an off white solid. MS: m/e=266.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7](B(O)O)[CH:8]=1)#[N:2].Br[C:14]1[CH:15]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[C@@H:23]([CH3:37])[CH2:22]2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([C:18]2[CH:19]=[CH:14][CH:15]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[C@@H:23]([CH3:37])[CH2:22]3)[CH:17]=2)[CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(C#N)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Yield: 39.9 %

Procedure:
To the solution of (5-cyano-2-fluorophenyl)boronic acid (660 mg, 4 mmol) in dioxane/H2O (40 mL/13.3 mL) was added phenylmethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazinecarboxylate (1.2 g, 4 mmol), K2CO3 (2.2 g mg, 16 mmol) and Pd(PPh3)4 (230 mg, 0.2 mmol). The resulting solution was irradiated in a microwave reactor at 150° C. for 20 minutes then diluted with EtOAc (5 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by Gilson HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 90/10, v/v, over 12 min), to give the title compound (708 mg, 92%). LC/MS: m/z, 444 (M+H), 1.93 min.
Reaction SMILES: C(OC(=O)[N:7]([C:15](=[O:26])[CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:15](=[O:26])[CH2:16][CH2:17][C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccc(F)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCC#Cc1ccccn1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
tert-Butyl-5-(pyridin-2-yl)pent-4-ynoyl-4-fluorophenylcarbamate (299 mg, 0.81 mmol) was dissolved in DCM (4 mL) with 0.01% w/w of water. 4 mL of trifluoroacetic acid was added at room temperature to the solution. The resulting mixture was stirred at R.T. for 2 h. The solvent was removed under reduced pressure. The brown oil was dissolved in saturated NaHCO3 until pH=8. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The brownish solid was triturated in a mixture Et2O/Pentane: 50/50. The solid was collected by filtration and washed with a mixture Et2O/Pentane: 50/50. The solid was dried by lyophilisation to afford 181 mg of N-(4-fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide (Yield: 83%) as a colorless solid (M.P.=189.9-190.2° C.).
Reaction SMILES: C[O:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[C:5](O)=[O:6].OC1C(Cl)=CC(Br)=C(Cl)C=1CO>>[OH:2][C:3]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:4]=1[CH2:5][OH:6]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)O
Agent: OCc1c(O)c(Cl)cc(Br)c1Cl
Product: OCc1c(Cl)ccc(Cl)c1O

Procedure:
A process for the preparation of 2-methoxy-3,6-dichloro-benzoic acid comprising the steps of catalytically debrominating 2-hydroxy-5-bromo-3,6-dichloro-benzyl alcohol to produce 2-hydroxy-3,6-dichloro-benzyl alcohol, methylating said 2-hydroxy-3,6 -dichloro-benzyl alcohol at the 2-hydroxy group to produce 2-methoxy-3,6-dichloro-benzyl alcohol, oxidizing said 2-methoxy-3,6-dichloro-benzyl alcohol to produce 2-methoxy-3,6-dichloro-benzoic acid, and recovering said 2-methoxy-3,6-dichloro-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.CI.[C:30](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:27])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH3:30])=[CH:7][CH:6]=2)[CH:9]=[CH:10]3)[CH2:21][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC)cc3)ccn2c1=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 30.8 %

Procedure:
50 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in 2 ml of DMF. 20 mg of methyl iodide and 29 mg of potassium carbonate were added to the obtained solution, and they were stirred at 70° C. for 17 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=9/1) to obtain 16 mg of ethyl 1-cyclopropyl-9-methyl-8-(4-methylaminophenyl)-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([F:16])[F:15])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(F)(F)c1ccccc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Heat at 60° C. a solution of 2,2-difluoro-2-phenyl-ethyl trifluoromethanesulfonate (759 mg, 2.617 mmol) and sodium azide (357 mg, 5.496 mmol) in anhydrous DMF (10 mL) under nitrogen for 3 h. Cool the reaction mixture to room temperature. Dilute with water and extract the aqueous phase twice with diethyl ether. Wash the combined organic extracts twice with ice-cold water, dry over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as an oil (475 mg, 99%) that was used without any further purification.