Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH2:9])=[CH2:7].[C:11]([O:17][CH:18]=[CH2:19])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>CO.O>[C:11]([O:17][CH:18]=[CH:19][CH2:7][CH:6]([CH:8]=[CH2:9])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1])(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C=COC(=O)C(C)(C)C
Reactant: C=CC(=C)CCC=C(C)C
Solvent: O
Solvent: CO
Product: C=CC(CC=COC(=O)C(C)(C)C)CCC=C(C)C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
23.7 mg (0.055 mmol) of (N-2-aminomethyl-p-toluene sulfonamide) (η6-benzene) ruthenium (II) chloride obtained in the Reference Example 4 and 17.5 mg (0.068 mmol) of silver triflate were mixed in 2 ml of methanol, to which were added 2 ml (purity: 78%, 1.25 g, 9.2 mmol) of myrcene and 1.73 g (13 mmol) of vinyl pivalate. The mixture was stirred at 70° C. for 6 hours. The reaction mixture was diluted with water and the organic layer was analyzed by gas chromatography to confirm that the title compound (addition product) having a purity of 76% (regioisomer: 26%) was produced at a conversion rate of 17%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:12][C:11]([Br:13])=[N:10][C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[S:12][C:11]([Br:13])=[N:10][C:9]=1[CH3:14])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(Br)sc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(Br)sc1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-bromo-4-methyl-thiazol-5-yl)-carbamic acid tert-butyl ester (2.93 g, 10 mmol) in DMF (50 mL) at 0° C. was added NaH (480 mg, 12 mmol, 60% dispersion in mineral oil) in one portion and the suspension was stirred for 1 h. Iodomethane (0.65 mL, 10.5 mmol) was added in one portion, and after 5 min the reaction mixture was warmed to ambient temperature and stirred for 5 h. Water and ethyl acetate were added and the resulting biphasic mixture was separated. The aqueous layer was extracted one time with ethyl acetate. The combined organic extracts were washed twice with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to give the desired product as a clear oil (1.66 g, 54%): IR (KBr) 1688 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.98 (s, 3H), 2.29 (s, 3H), 1.54 (s, 9H); ESIMS m/z 309 (M+2).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CN(CC1CC1)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Sodium triacetoxyborohydride (0.51 g) was added to a solution of 3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazine-2-carbaldehyde (0.37 g), N-benzylethanolamine (0.29 g) and acetic acid (0.28 mL) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20-*40% ethyl acetate/hexane) to give the title compound (0.5 g, 86%) as a pale-yellow oil.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[CH:2]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[O:1]
Reactant: CC(C)S(=O)(=O)c1cc(C#N)ccc1C1OCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)c1cc(C#N)ccc1C=O
Temperature: 165 °C
Reaction time: 0.12 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(propan-2-ylsulfonyl)benzonitrile (1090 mg, 3.7 mmol) and pyridinium 4-toluenesulfonate (696 mg, 2.8 mmol; 0.75 eq.) in acetone/water (1:1, 15 ml) were heated with stirring at 165° C. for 7 min. The reaction mixture was then added to water (150 ml) and extracted with dichloromethane (9×30 ml). The combined organic phases were subsequently washed with saturated sodium chloride solution (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 3:2). The title compound was isolated as a solid (0.764 g, 87% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:13]1[N:18]=[C:17]2[CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][C:16]2=[CH:15][CH:14]=1)#[N:2].[ClH:29]>O1CCOCC1>[ClH:29].[N:18]1[C:13]([CH:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][C:7]2=[O:12])=[CH:14][CH:15]=[C:16]2[CH2:21][NH:20][CH2:19][C:17]=12
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C3C(=O)Nc4ccc(C#N)cc43)nc2C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)C(c1ccc3c(n1)CNC3)C(=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
To a suspension of tert-butyl 2-(5-cyano-2-oxoindolin-3-yl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (70 mg, 0.186 mmol) in dioxane (2 mL) was added dropwise 4N HCl in dioxane (2.5 mL). After stirring the resulting mixture at RT for 3 d all volatiles were removed under reduced pressure. The residue was suspended in diethylether and stirred at RT for 2 h. The suspension was filtered, the remaining solid was washed with diethylether and dried under reduced pressure. Amount 55 mg. Yield 95%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH3:15][O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34]O)[CH2:26][CH2:25]2)=[N:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:34][CH2:33][C@@H:31]2[CH2:32][C@@H:30]2[CH:27]2[CH2:28][CH2:29][N:24]([C:21]3[N:20]=[CH:19][C:18]([CH2:17][O:16][CH3:15])=[CH:23][N:22]=3)[CH2:25][CH2:26]2)=[CH:5][C:4]=1[F:9]
Reactant: COC(=O)Cc1c(F)cc(O)cc1F
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl (2,6-difluoro-4-hydroxyphenyl)acetate (1.46 g, 7.22 mmol) in 10 ml anhydrous dichloromethane at RT was added a solution of 2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethanol (2.10 g, 7.22 mmol) in 20 ml anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 3.79 g, 11.4 mmol), and di-tert-butyl azodicarboxylate (1.83 g, 7.94 mmol). The reaction mixture was stirred at RT for 3 hours. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-40% ethyl acetate in hexanes (900 ml) to afford the title compound. LC/MS (m/z) 476.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.I[CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), iodoethane (31 uL, 0.39 mmol, Sigma-Aldrich, Cat. No. 17780), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 h. After cooling it was quenched with water. The product was extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 34 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: CSC(=NC#N)SC
Reactant: COc1cccnc1CSCCN
Solvent: CCO
Product: COc1cccnc1CSCCN=C(NC#N)SC
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3-methoxypyridine (2.1 g) in ethanol (15 ml) was added over one hour to a stirred solution of dimethyl N-cyanodithioimidocarbonate (1.5 g) in ethanol (15 ml). The mixture was allowed to stand overnight and nitrogen was bubbled through for one hour. The crystalline precipitate was recrystallised from ethanol/ether to yield N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (2.2 g), m.p. 102°-103°.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[ClH:43].[ClH:1].[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118, see example 76) and amine 21 analogously to the method described in example 1.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:36]([Cl:37])=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=2)[CH2:24][CH:23]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:37].[Cl:37][C:36]1[C:28]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:23]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])[CH2:24]2)=[N:29][CH:30]=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2ncc(C(=O)O)cc2Cl)CC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](NCC1CCN(c2ncc(C(=O)O)cc2Cl)CC1c1ccccc1F)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(2-fluorophenyl)piperidin-1-yl]-5-chloronicotinic acid obtained in the aforementioned reaction in 2.0 mL of ethyl acetate was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase silica gel column chromatography (acetonitrile-0.01 M hydrochloric acid) to obtain 56 mg of 5-chloro-6-[3-(2-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]nicotinic acid hydrochloride as a white solid.
Reaction SMILES: N[C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=CNN=1.[CH3:14][N:15](C)[CH:16]=CC(C1C=C(N(C)C(=O)C)C=CC=1)=O>C(O)(=O)C>[CH3:14][N:15]([CH3:16])[C:6](=[CH2:2])[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8]
Reactant: Nc1n[nH]cc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: C=C(C(=O)c1cccs1)N(C)C
Yield: 70 %

Procedure:
A mixture of (3-amino-1H-pyrazol-4-yl)-2-thienylmethanone (4) (1.93 g, 10 mmol) and N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]-N-methylacetamide (6) (2.46 g, 10 mmol) in glacial acetic acid (100 mL) is refluxed for 8 hrs. Evaporation of all volatiles on a rotary evaporator gives a residue which is partitioned between aqueous saturated sodium bicarbonate and methylene chloride. The methylene chloride layer is dried over sodium sulfate and filtered. Two additional volumes of methylene chloride are added and the solution is warmed to reflux. Hexane is added until crystallization is observed. The mixture is cooled and filtered to give Compound 1 as a yellow solid (2.57 g, 7 mmol, 70%).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([NH:14][NH:15]C(=O)CC2C=CC=CC=2)=[O:13])[C:9]([O:25][CH3:26])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.BrC1N=[C:36]([C:38]([OH:40])=O)[C:35](OC)=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=N2.C1(CC(NN)=O)C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O.ON1C2C=CC=CC=2N=N1>[Br:1][C:2]1[N:11]=[C:10]([C:12]([N:14]([C:38](=[O:40])[CH2:36][C:35]2[CH:34]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH2:15])=[O:13])[C:9]([O:25][CH3:26])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(C(=O)O)nc(Br)c2cccnc12
Reactant: COc1c(C(=O)NNC(=O)Cc2ccccc2)nc(Br)c2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNC(=O)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COc1c(C(=O)N(N)C(=O)Cc2ccccc2)nc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
5-Bromo-8-methoxy-N′-(phenylacetyl)[1,6]naphthyridine-7-carbohydrazide. To a solution of 5-bromo-8-methoxy[1,6]naphthyridine-7-carboxylic acid (284 mg, 1.00 mmol) in dichloromethane (25 mL) was added phenylacetic hydrazide (137 mg, 1.00 mmol), 1-hydroxybenzotriazole hydrate (4 mg, 0.0301 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 3 hours, during which time a large amount of white solids formed. The reaction mixture was then partitioned between water and dichloromethane (a large excess of dichloromethane was needed to solubilize product). The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0% to 10% methanol in dichloromethane) to provide 5-bromo-8-methoxy-N-(phenylacetyl)[1,6]naphthyridine-7-carbohydrazide (328 mg, 79%) as a white solid. 1H NMR (DMSO-d6) δ 10.50 (d, J=1.6 Hz, 1H), 10.44 (d, J=1.6 Hz, 1 H), 9.27 (dd, J=4.0, 1.6 Hz, 1H), 8.63 (dd, J=8.8, 1.6 Hz, 1H), 7.94 (dd, J=8.8, 4.0 Hz, 1H), 7.36-7.26 (m, 5 H), 4.16 (s, 3H), 3.57 (s, 2 H); MS m/z 415 (M+1).
Reaction SMILES: C(SC1C=C2C(C(Cl)=CC=N2)=CC=1F)C1C=CC=CC=1.ClN1C(C)(C)C(=O)N(Cl)C1=O.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([F:43])[CH:41]=2)[N:36]=[CH:35][CH:34]=1.[F:48][C:49]1[C:54]([F:55])=[C:53]([F:56])[C:52]([F:57])=[C:51]([F:58])[C:50]=1[OH:59].C(N(CC)CC)C>CCOC(C)=O.O.C(O)(=O)C.C(#N)C>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([S:44]([O:59][C:50]3[C:49]([F:48])=[C:54]([F:55])[C:53]([F:56])=[C:52]([F:57])[C:51]=3[F:58])(=[O:46])=[O:45])=[C:40]([F:43])[CH:41]=2)[N:36]=[CH:35][CH:34]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(Cl)c1cc2nccc(Cl)c2cc1F
Agent: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: Fc1cc2c(Cl)ccnc2cc1SCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2nccc(Cl)c2cc1F
Reaction time: 1 h

Procedure:
A round-bottom flask was charged with 7-(benzylthio)-4-chloro-6-fluoroquinoline (0.148 g, 0.487 mmol), acetonitrile (4.59 ml), acetic acid (0.172 ml), and water (0.115 ml), and after cooling the suspension in an ice bath for 10 minutes (material fell out of solution), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.192 g, 0.974 mmol) was added in one portion (mixture became homogeneous). After 1 h, conversion to 4-chloro-6-fluoroquinoline-7-sulfonyl chloride was observed (light yellow solution), and 2,3,4,5,6-pentafluorophenol (0.179 g, 0.974 mmol) was added, followed by drop wise addition of triethylamine (0.170 ml, 1.218 mmol). After 25 minutes, the mixture was diluted with EtOAc and washed with water and brine, and then dried over sodium sulfate. After filtration and concentration in vacuo, the material was purified via silica gel chromatography (12-g RediSep Gold column, eluting with 0-50% ethyl acetate in heptane) to yield perfluorophenyl 4-chloro-6-fluoroquinoline-7-sulfonate as a white solid. m/z (ESI) 428.1 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:36]([CH:26]1[C:25](=[O:30])[CH2:24][C:23]([CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([Cl:12])[CH:14]=2)([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[O:28][C:27]1=[O:29])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (60.6 mg, 0.172 mmol) in benzene (2.0 ml), under an atmosphere of argon. Benzyl bromide (20.5 ul, 0.172 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (11.1 mg).
Reaction SMILES: O[CH2:2][N:3]1[C:15](=[O:16])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>CCOCC>[Cl:19][CH2:2][N:3]1[C:15](=[O:16])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:17]
Reactant: COC(=O)C1C=CCn2c(=O)n(CO)c(=O)n21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)C1C=CCn2c(=O)n(CCl)c(=O)n21
Temperature: 25 °C
Reaction time: 22 h
Yield: 73.4 %

Procedure:
3.97 g (0.017 mol) of methyl 2-hydroxymethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate were suspended at 0° C. in 300 ml of dry ether. 3.49 g (0.017 mol) of phosphorus pentachloride were added portionwise and the mixture was stirred at room temperature for 22 hours. The resulting clear solution was evaporated in vacuo and the residue was chromatographed on silica gel using chloroform/ethyl acetate (1:1) for the elution. There were obtained 3.24 g (76%) of methyl 2-chloromethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 164°-165° C.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[C:17](=O)([O:20]C)[O:18][CH3:19]>>[CH3:19][O:18][C:17]([CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:14]1=[O:15])=[O:20]
Reactant: O=C1CCCCCc2ccccc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCCc2ccccc2C1=O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Dimethyl carbonate (20 mL) was treated with NaH (60% dispersed in oil, 660 mg, 46 mmol), heated at 85° C., treated dropwise with a solution of 7,8,9,10-tetrahydro-6H-benzocycloocten-5-one (prepared according to Richard W. Thies, J. Org. Chem. 42(2), 280-281, 1977) (950 mg, 5.5 mmol) in dimethyl carbonate (10 mL), stirred at 85-90° C. for three hours, cooled to 0° C., acidified by the slow addition of 1 M HCl (50 mL) and extracted with ether (150 mL). The organic was isolated, washed with brine, dried (MgSO4) and concentrated to provide the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:5]2[CH2:6][CH2:7][NH:8][C:9](=[O:10])[C@@H:4]2[CH2:3]1.CC(C)([O-])C.[Na+].Br[C:19]1[CH:24]=[N:23][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:21][N:20]=1.O>CS(C)=O>[CH:25]1([C:22]2[N:23]=[CH:24][C:19]([O:1][CH:2]3[CH2:11][N:5]4[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]4[CH2:3]3)=[N:20][CH:21]=2)[CH2:27][CH2:26]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: O=C1NCCN2C[C@H](O)C[C@@H]12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Temperature: 25 °C
Reaction time: 0.4 h
Yield: 23.7 %

Procedure:
In a 4 mL vial were combined (7R,8aS)-7-hydroxyhexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one (180 mg, 1.152 mmol) from Step 2 and sodium tert-butoxide (188 mg, 1.959 mmol) in dimethyl sulfoxide (1 mL). The mixture was stirred at room temperature for 0.4 hours followed by the addition of 2-bromo-5-cyclopropyl-pyrazine (229 mg, 1.152 mmol). After stirring at room temperature for 8 hours, water was added, and the solution was extracted with ethyl acetate. The extract was concentrated in vacuo, and the resulting solid was purified using an Agilent Technologies SuperFlash SF-15-12 g cartridge eluted with a gradient of 0-8% methanol/dichloromethane over 20 minutes to give 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (75 mg, 0.273 mmol, 23.72% yield) as an oil in a 3:1 (7R,8aS: 7R,8aR) diastereomer ratio. 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=32.4 Hz, 1H), 8.19 (dd, J=14.4, 0.9 Hz, 1H), 8.12-8.05 (m, 1H), 5.54-5.41 (m, 1H), 3.77 (t, J=8.0 Hz, 0.5H), 3.54 (dddd, J=12.4, 10.1, 8.1, 4.0 Hz, 1H), 3.49-3.35 (m, 1H), 3.30-3.19 (m, 1.5H), 3.02 (ddd, J=16.9, 9.2, 4.7 Hz, 1H), 2.91 (dt, J=7.7, 4.2 Hz, 1H), 2.89-2.80 (m, 1H), 2.80-2.66 (m, 1H), 2.60-2.51 (m, 1H), 2.00 (qt, J=9.5, 4.8 Hz, 1H), 1.12-1.02 (m, 2H), 0.96-0.86 (m, 2H); MS (ESI+) m/z 275 (M+H)+.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37]>>[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:41][NH:42][CH:43]=1)=[O:37]
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Reactant: COc1cc(F)c(C(=O)Nc2c[nH]nc2C(=O)O)c(F)c1
Product: COc1cc(F)c(C(=O)Nc2c[nH]nc2-c2nc3cc(CN4CCOCC4)ccc3[nH]2)c(F)c1

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2,6-difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid to give 2,6-difluoro-4-methoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (32 mg) as a pink solid. (LC/MS: Rt 1.99, [M+H]+ 469.21).