Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:10]([CH2:18][C:19](OCC)=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1(C)C=CC=CC=1>[OH:20][C:19]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 25 °C

Procedure:
To a solution of m-anisidine (300 g, 2.44 mole) and ethyl benzoylacetate (234.2 g, 1.22 mole) in toluene (2.0 L) was added HCl (4.0 N in dioxane, 12.2 mL, 48.8 mmole). The resulting solution was refluxed for 6.5 hr using a Dean-Stark apparatus (about 56 ml of aqueous solution was collected). The mixture was cooled to rt, partitioned multiple times with aqueous HCl (10%, 3×500 mL), aqueous NaOH (1.0 N, 2×200 mL), water (3×200 mL), and the organic layer dried (MgSO4) and concentrated in vacuo to supply an oily residue (329.5 g). The crude product was heated in an oil bath (280° C.) for 80 min using a Dean-Stark apparatus (about 85 mL liquid was collected). The reaction mixture was cooled down to rt, the solid residue triturated with CH2Cl2 (400 mL), the resulting suspension filtered, and the filter cake washed with more CH2Cl2 (2×150 mL). The resulting solid was dried in vacuo (50° C.; 1 torr; 1 day) affording analytically pure 4-hydroxy-7-methoxy-2-phenylquinoline as a light brown solid (60.7 g, 20% overall). 1H NMR δ(DMSO): 3.86 (s, 3H), 6.26 (s, 1H), 6.94 (dd, J=9.0, 2.4 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.55-7.62 (m, 3H), 7.80-7.84 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 11.54 (s, 1H); 13C NMR (DMSO-d6) δ: 55.38, 99.69, 107.07, 113.18, 119.22, 126.52, 127.17, 128.97, 130.34, 134.17, 142.27, 149.53, 161.92, 176.48. LC-MS (retention time: 1.26, method D), MS m/z 252 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23]OS(C)(=O)=O.[C-:29]#[N:30].[K+]>CN(C)C=O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:15][C@@H:14]3[C@@H:10]([N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]3)[CH2:9]2)=[CH:4][C:3]=1[CH2:23][C:29]#[N:30]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(COS(C)(=O)=O)c3)C[C@@H]21
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(c3cnc(Br)c(CC#N)c3)C[C@@H]21
Temperature: 60 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
The product of Example 66A (0.300 g, 0.630 mmol) in N,N-dimethylformamide (5 mL) was treated with KCN (61 mg, 0.945 mmol). The mixture was warmed to 60° C. and allowed to stir for 20 hours. The mixture was then concentrated under reduced pressure and the residue purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (0.100 g, 0.246 mmol, 39% yield). MS (DCI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>>[Br:19][C:20]1[CH:24]=[C:23]([Cl:25])[S:22][C:21]=1[S:26]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:27]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1sc(Cl)cc1Br
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1sc(Cl)cc1Br

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 3-bromo-5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J=2.1 & 10.5 Hz, 1H), 7.35 (br m, 2H), 7.31 (dd, J=2.1 & 4.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.08 (dd, J=9.0 & 17.4 Hz, 1H), 6.02 (dt, J=2.1, 8.4 & 17.1 Hz, 1H), 5.59 (br s, 1H).
Reaction SMILES: II.Br[C:4]1[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1.[CH3:21][C:22](Cl)=[O:23].[NH4+].[Cl-]>C1COCC1>[CH2:10]1[O:9][C:8]2[C:7](=[CH:6][C:5]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]([C:22](=[O:23])[CH3:21])[CH:12]=2)[O:11]1
Reactant: CC(=O)Cl
Reactant: Brc1cc2c(cc1OCc1ccccc1)OCO2
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(cc1OCc1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
In a flame-dried flask was added under argon Mg (0.58 g, 0.024 mol), a few crystals of I2 and dry THF (10 ml). A solution of 6-bromo-5-(phenylmethoxy)-1,3-benzodioxole (6.14 g, 0.02 mol) in dry THF (15 ml) was added dropwise under reflux. Heating was continued for 3 hours. The Grignard reagent was added over 1.5 h to a solution of freshly distilled CH3COCl (7 ml) in dry THF (20 ml) held at -78° C. The stirred reaction mixture was allowed to warm to room temperature overnight, poured into 2N-NH4Cl (100 ml) solution and extracted with chloroform (3×50 ml). The organic layer was washed with 10% NaOH and brine, and dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to flash chromatography (silica gel) using petroleum ether--CHCl3 (2:1) as eluent affording 3.87 g (71.6%) of 1-[4,5-(methylenedioxy)-2-(phenylmethoxy)phenyl]ethanone mp (EtOH) 116.5°-117° C.; IR(KBr) 1652 (carbonyl) cm-1 ; NMR (CDCl3, 90 MHz) δ 2.55 (S, 3H, CH3), 5.11 (S, 2H, CH2Ph), 5.98 (S, 2H, OCH2O), 6.58 (S, 1H, ArH), 7.34 (S, 1H, ArH), 7.40 (S, 5H, CH2Ph). Anal. calcd. for C16H14O4 : C, 71.10; H, 5.22. Found: C, 70.96; H, 5.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:27]([CH:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:31]1C(O)=O)(O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:27]([CH:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)=[O:28])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)[C@H]1C(=O)O
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
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: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)piperazine-1-carboxamide (2.00 g, 7.30 mmol) in DMF (150 ml) was added DIPEA (3.8 ml, 21.9 mmol), 3-carboxy-N-boc-proline (Arch Corporation) (1.727 g, 8.02 mmol) and HATU (3.051 g, 8.02 mmol) and the reaction stirred at ambient temperature for overnight (convenience). The solvents were then removed under reduced pressure. The resulting gum was then partitioned between EtOAc and water, extracted, the organic phase washed with saturated sodium bicarbonate solution and evaporated to dryness. The resulting foam was then purified on Isco™ Companion (40 g column:EtOAc) to give the product tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate as a pale yellow foam (3.396 g, 7.20 mmol, 99%).
Reaction SMILES: [CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:5][CH:6]=[C:7]([CH:9]=O)[CH:8]=1)[CH3:2].C1(P(=[CH:34][CH:35]=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:5][CH:6]=[C:7]([CH:9]=[CH:34][CH:35]=[O:36])[CH:8]=1)[CH3:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Product: CC[Si](CC)(CC)c1cc(C=CC=O)co1

Procedure:
Reacting 2-triethylsilyl-4-furaldehyde (Compound 5) with (triphenylphosphoranylidene)acetaldehyde gives 3-(2-triethylsilyl-4-furyl)-2-propen-1-al (Compound 45). Conjugate addition of dodecylCu(CN)ZnI (Compound 30) to this aldehyde (Compound 45) gives 4-[1-(2-oxoethyl)tridecyl]-2-triethylsilylfuran (Compound 46). Treatment of this intermediate with manganese dioxide, sodium cyanide and ammonia in tert-butanol, followed by singlet oxygen oxidation gives 4-[1-(2-carboxyamido)methyl]tridecyl-5-hydroxy-2(5H)-furanone (Compound 16).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[N:6][C:7]=1[N+:8]([O-])=O.[NH4+].[Cl-]>CO.[Zn]>[Br:1][C:2]1[C:7]([NH2:8])=[N:6][CH:5]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ncc(N2CCOCC2)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ncc(N2CCOCC2)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of 4-(5-Bromo-6-nitropyridin-3-yl)morpholine (2 g, 6.9 mmol) in MeOH (150 mL) in a round bottom flask was added Zn dust (4.54 g, 69.4 mmol). The reaction mixture was cooled to 0° C. Solid NH4Cl (3.71 g, 69.4 mmol) was added in portions, over 5 min. The heterogeneous reaction mixture was stirred at room temperature for 2 h, filtered through a plug of Celite washing the filter cake with methanol and ethanol. The filtrate was concentrated to a brownish solid which was purified by flash column chromatography on silica gel (ISCO, 80 g column, 0-70% EtOAc/heptane in 15 min and 70% EtOAc to 25 min), obtaining 3-bromo-5-morpholinopyridin-2-amine (936 mg, 52.2%) as a slightly off white solid. LCMS (m/z): 258.2 (MH+), 0.35 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=2.3 Hz, 1H) 7.40-7.30 (m, 1H) 4.66 (br. s., 2H) 3.91-3.74 (m, 4H) 3.07-2.90 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Reactant: c1c[nH]cn1
Product: Cc1csc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:4][CH2:5][OH:6].C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:4][CH:5]=[O:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
A solution of (E,E)-4,8,12-trimethyl-3,7,11-tridecatrienol (400 mg, 1.59 mmol) in acetonitrile (5 ml) was added to a slurry of N-methymorpholine N-oxide (280 mg, 2.38 mmol) and powdered 4A molecular sieves in acetonitrile (10 ml) and the mixture stirred at r.t. for 10 min. Tetrapropylammonium perruthenate (28 mg, 0.00795 mmol) was added in one portion and the resulting dark green slurry stirred at r.t for 1 hr. The reaction mixture was filtered through a plug of silica gel eluting with ethylacetate and the filtrate evaporated in vacuo. The resulting oil was chromatographed over silica gel eluting with diethylether: hexanes (1:10, v:v) to afford the title compound (200 mg, 50%) as a clear colorless oil.
Reaction SMILES: C([Li])CCC.[N:6]([CH2:9][CH2:10][C:11]#[CH:12])=[N+:7]=[N-:8].[CH2:13]=[O:14].[Cl-].[NH4+]>C1COCC1>[N:6]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][OH:14])=[N+:7]=[N-:8]
Reactant: C=O
Reactant: C#CCCN=[N+]=[N-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC#CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6M in hexane, 18.8 mmol, 11.7 ml) was added dropwise at -78° C. to a solution of 4-azido-1-butyne II-32 (1.28 g, 17.3 mmol) in THF (35 ml). After stirring the resulting green solution for 1 h, paraformaldehyde was added in one portion, the solution was stirred for 5 min, and then warmed to room temperature for 2 h (an orange suspension gradually formed). The reaction mixture was poured into saturated aqueous ammonium chloride (100 ml) and extracted with ether (3×50 ml). The combined extracts were washed with brine (50 ml), dried over sodium sulphate and evaporated to give a yellow oil. This was purified by flash chromatography eluting with pentane/ether 1:1 to afford the title compound II-33 as a pale yellow oil (930 mg, 70.7%): IR (CHCl3) 3600 (m), 3000 (m), 2940 (m), 2880 (m), 2100 (s), 1550 (w), 1380 (m), 1270 (m), 1220 (br), 1140 (m), 1000 (s) cm-1 ; 1H NMR (500 MHz, CDCl3) δ4.24-4.22 (m, 2 H), 3.37 (t, J=6.8 Hz, 2 H), 2.51-2.48 (m, 2 H), 1.84 (t, J=6.0 Hz, 1 H); 13C NMR (62.9 MHz, CDCl3) δ77.42, 70.47, 49.68, 19.45.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 59.1 %

Procedure:
Beginning with 11.6 gm (86.0 mMol) 6-fluoro-1H-indole and 26.5 gm (172 mMol) 4-piperidone hydrochloride monohydrate, 11.0 gm (59%) of the title compound were recovered as a light tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-])=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O.[C:33](O)(=[O:35])[CH3:34]>C(OC(=O)C)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:33](=[O:35])[CH3:34])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2nc(Sc3ccccc3[N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2nc(Sc3ccccc3NC(C)=O)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
At room temperature, 2.5 g of iron filings is added to a solution of 4.34 g of 4,5-bis(4-methoxyphenyl)-2-(2-nitrophenylthio)imidazole in 50 ml of glacial acetic acid and 3 ml of acetic anhydride. The mixture is stirred overnight, poured into 500 ml of water, the precipitated product is vacuum-filtered, taken up in ethyl acetate, and the solution washed with sodium bicarbonate solution. The solution is then dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/ether. Recrystallization from ethyl acetate yields 3.67 g of 4,5-bis(4-methoxyphenyl)-2-(2-acetamidophenylthio)imidazole, mp 183°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][N:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:6][CH2:5][C:4]2[N:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:3]1=2.C1C(=O)N([I:27])C(=O)C1>C(O)(C(F)(F)F)=O.CC(O)=O>[I:27][C:17]1[C:16]([OH:19])=[N:15][C:4]2[CH2:5][CH2:6][N:7]([C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])[CH2:8][CH:2]([CH3:1])[C:3]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)ccc21
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol hydrobromide (1.76 g, 6.79 mmol) in DCM (50 ml) and DMF (10 ml) was added Et3N (2.90 ml, 20.7 mmol) and TFAA (1.00 ml, 6.90 mmol). The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and parted between sat. aq. NaHCO3 and EtOAc. The organic phase was dried, concentrated in vacuo and purified by column chromatography to yield 1.46 g (77%) of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (DMSO-d6) δ 11.43 (br s, 1H), 7.30 (m, 1H), 6.18 (m, 1H), 3.95-3.42 (m, 4H), 3.06-2.96 (m, 2H), 2.95-2.87 (m, 1H), 1.12 (2× d, 3H) ppm. A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (1.36 g, 4.96 mmol) and NIS (1.12 g, 4.96 mmol) in TFA (2 ml) and AcOH (36 ml) was stirred at room temperature for 16 h. Evaporation of TFA and AcOH followed by chromatographic purification of the resulting residue gave 1.95 g (98%) of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 4.17-3.41 (m, 4H), 3.20-2.94 (m, 3H), 1.26 (2× d, 3H) ppm. A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (50.0 mg, 125 μmol) and K2CO3 (17.3 mg, 125 μmol) in MeOH (10 ml) was heated at reflux for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 20.2 mg (53%) of 3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol. 1H-NMR (CDCl3) δ 7.90 (s, 1H), 3.09-2.80 (m, 7H), 1.28 (d, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].C(O)(C)C>CC(C)=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([C:8]([OH:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1cc(Cl)c(Br)cn1
Agent: [Mn+4]
Agent: [K+]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(O)c1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.50 g (2.3 mmol) (5-bromo-4-chloro-pyridin-2-yl)-methanol in 8 mL acetone were added dropwise at RT to 0.71 g (4.5 mmol) potassium permanganate in 10 mL acetone and then the mixture was stirred for 17 h at RT. Then 10 mL isopropanol were added and the mixture was stirred for a further 5 h at RT. The precipitated manganese dioxide was suction filtered and washed with water. The filtrate was partially evaporated down and the aqueous phase was adjusted to a pH of 3 with 1N aqueous hydrochloric acid solution. The precipitate formed was suction filtered.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=4)[NH2:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=4)[NH:19][C:23](=[O:25])[CH3:24])=[N:14][N:15]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine-3-yl]aniline (180 mg) and acetic anhydride (3 ml) was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the resultant crude crystals were washed with diethyl ether to obtain 3′-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]acetoanilide (190 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].C([Mg]Cl)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Mg]Br>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:3]=1[C:4]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=1)=[O:5]
Reactant: Br[Mg]c1ccccn1
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ccc(F)cc1C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a −78° C. solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide (9.40 g, 47.4 mmol) in THF (39.5 mL) was added isopropylmagnesium chloride 2.0M in THF (47.4 mL, 94.8 mmol) at −40° C. The solution was allowed to rise to −10° C. over 40 min then was lowered back to −40° C. in an acetonitrile/dry ice bath. To the cooled mixture was added 2-pyridylmagnesium bromide, 0.25M in THF (209 mL, 52.2 mmol) and the mixture was allowed to warm to rt. After 22 h, the reaction was diluted with DCM (200 mL) and quenched with satd ammonium chloride solution (200 mL). The aq layer was extracted with DCM (2×100 mL). The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (2-amino-5-fluorophenyl)(pyridin-2-yl)methanone as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65-8.72 (1H, m), 8.02 (1H, td, J=7.7, 1.8 Hz), 7.79 (1H, dt, J=7.8, 1.0 Hz), 7.60 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.29-7.36 (1H, m), 7.18-7.29 (3H, m), 6.88 (1H, dd, J=9.2, 4.7 Hz); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [CH:1]([C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][O:6][CH2:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:3])[CH3:2].[CH3:25][C:26]([CH3:28])=O>>[CH:1]([C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:26]([CH3:28])[CH3:25])[CH2:10][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](COCC1CCNCC1)NC(=O)OCc1ccccc1
Reactant: CC(C)=O
Product: CC(C)[C@H](COCC1CCN(C(C)C)CC1)NC(=O)OCc1ccccc1
Yield: 91.3 %

Procedure:
Using alkylation method A, benzyl N-[(R)-1-(isopropyl)-2-(piperidin-4-ylmethoxy)ethyl]carbamate (1.1 g, 3.2 mmol) and acetone (5 mL, 68 mmol) afforded 1.1 g (92%) of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11]([O:14][C:15]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:16]=1[C:17](O)=[O:18])([CH3:13])[CH3:12]>>[N:1]1([C:17]([C:16]2[CH:20]=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:23][C:15]=2[O:14][CH:11]([CH3:13])[CH3:12])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2c(c1)CCCN2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCCc2ccccc21

Procedure:
Prepared in analogy to example 1.1 from 1,2,3,4-tetrahydro-quinoline (CA [635-46-1]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 373.3 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([C@H:14]3[CH2:13][CH2:12][CH:11]4[CH:9]([CH2:10]4)[N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1C2CC2CC[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCC4CC4N3C(=O)OC(C)(C)C)CC2)cc1
Yield: 16.3 %

Procedure:
The title compound (D70) (28 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (3R)-2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-3-carboxylic acid (D22) (100 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (103 mg). Reaction time: 1 h