Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=3)[C:34]([O:36]C)=[O:35])=[O:30])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1.O>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=3)[C:34]([OH:36])=[O:35])=[O:30])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-((2-((2-phenylpyrimidin-5-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoate (1200 mg, 2.02 mmol, 1.00 equiv, 90%) in tetrahydrofuran/water (5:1) (30 mL) was added lithium hydroxide hydrate (420 mg, 9.97 mmol, 8.00 equiv, 95%) and the resulting solution was stirred for 3 h at 40° C. in an oil bath. The mixture was concentrated under vacuum and the residue was adjusted to pH 3-4 with hydrochloric acid. The mixture was extracted with 3×100 mL of tetrahydrofuran and the organic layers combined, washed with 1×100 mL of brine and then concentrated under vacuum to afford 1000 mg (95%) of a green to yellow solid.
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH2:14]([O:16][CH2:17]OCC)[CH3:15].[Br-].[Li+].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CC(OC)(C)C>[CH2:14]([O:16][CH2:17][O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)[CH3:15]
Reactant: OC1CCC=CCCC=CCCC1
Reactant: CCOCOCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCOCOC1CCC=CCCC=CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mechanically stirred mixture of 4,8-cyclododecadien-1-ol (5.4 g, 30 mmol; in the form of a 47% E,Z-, 48% Z,E- and 5% E,E isomer mixture), formaldehyde diethyl acetal (31.2 g, 294 mmol) and lithium bromide (0.52 g, 6 mmol) was added toluene sulphonic acid monohydrate (0.57 g, 3 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with MTBE, washed with aqueous NaHCO3, water and brine. The solvent was evaporated and the product purified by liquid chromatography (silica gel 230 g; eluent=heptane/ethyl acetate 95/5).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:14]([O:19][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCCO
Agent: [Na]
Product: CCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in 1-pentanol (20 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 3 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)[N:5]=[C:4]([NH2:21])[CH:3]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=3)[N:5]=[C:4]([NH2:21])[CH:3]=2)[CH:25]=[N:24]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(N)cc(Cl)n2)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(N)nc(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
6-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (1.00 g, 3.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.958 g, 4.60 mmol), K3PO4 (1.95 g, 9.21 mmol), and Pd(PPh3)4 (0.355 g, 0.307 mmol) were suspended in dioxane (15.3 mL) and H2O (0.829 mL). After de-gassing with nitrogen, the reaction mixture was heated to 100° C. overnight. After cooling, the reaction mixture was diluted in EtOAc and washed with water and brine. The organics were dried with MgSO4, filtered and concentrated down to an orange oil. Purification of the resulting crude material by silica chromatography using a gradient of 0-10% MeOH/EtOAc afforded 6-(1-methyl-1H-pyrazol-4-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (0.623 g, 1.68 mmol, 54.7% yield) as a thick yellow oil. MS (apci) m/z=372.4 (M+H).
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5](=[O:11])[C:4]1=[O:12].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>>[C:13]([S:15][CH2:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5](=[O:11])[C:4]1=[O:12])(=[O:16])[CH3:14]
Reactant: CCN1CCN(CCl)C(=O)C1=O
Reactant: CC([O-])=S
Agent: [K+]
Product: CCN1CCN(CSC(C)=O)C(=O)C1=O
Temperature: 0 °C
Yield: 44 %

Procedure:
To a solution of crude 1-(chloromethyl)-4-ethyl-piperazine-2,3-dione (170 mg, 0.9 mmol) in CDCl3 (1 ml) solid potassium thioacetate (123 mg, 1.08 mmol) was added with stirring at 0° C. The reaction mixxture was allowed to stir at room temperature overnight. The mixture was centifuged and the supernatant solution collected. The residual solid (KCl) was washed with CDCl3 (2 ml) and the organic solutions combined and the solvent removed in vacuo. The residue was chromatographed on silica gel (6 g, 63-200 μm) using chloroform-methanol (19:1) to give 1-(acetylthiomethyl)-4- ethyl-piperazine-2,3-dione as a white solid (overall yield 44%). NMR-specrum in CDCl3: 1.22 (t, 3H, J=7 Hz), 2.44 (s, 3H), 3.48 (q, 2H, J=7 Hz), 3.4-3.7 (m, 4H), 4.95 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[CH2:8][N:9]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(Oc1ccc(C(F)(F)F)cc1)CNCC2
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2C(Oc2ccc(C(F)(F)F)cc2)C1

Procedure:
To a cooled solution of 7,8-dimethoxy-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine (5.5 g, 0.015 mole) and triethylamine (1.7 g, 0.017 mole) in chloroform (70 ml) was slowly dropped a solution of ethyl chloroformate (1.0 g, 0.017 mole) in chloroform (20 ml). After stirring twenty hours at ambient temperatures the reaction mixture was concentrated to an oil which was dissolved in ether, washed with water, dilute HCl, again twice with water, then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered then concentrated to a solid (5.0 g, 76%, m.p. 120° C.) of which a sample was twice recrystallized from hexanes to yield 7,8-dimethoxy-3-ethoxycarbonyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.[NH4+].[Cl-].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH2:35])=[O:22])[CH2:17][CH2:18]3)[CH:12]=2)=[CH:4][C:3]=1[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: Nc1ncc(-c2cnn(C3CCN(CC(=O)O)CC3)c2)cc1-c1nc2ccccc2s1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of {4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidin-1-yl}-acetic acid (10.0 mg, 0.0184 mmol), NH4Cl (2.0 mg, 0.037 mmol), TBTU (8.86 mg, 0.0276 mmol) and DMF (1 mL) was charged with DIPEA (0.03 mL, 0.2 mmol) and allowed to stir at rt for 10 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.17-2.35 (m, 4H), 2.69 (td, J=11.9, 2.5 Hz, 2H), 3.28 (d, J=12.4 Hz, 2H), 3.37 (s, 2H), 4.29-4.40 (m, 1H), 7.41-7.47 (m, 1H), 7.53 (td, J=7.6, 1.3 Hz, 1H), 7.89 (s, 1H), 8.01 (dd, J=12.3, 8.0 Hz, 2H), 8.11 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.3 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33]>>[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH:33][CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: NCCC(F)(F)F
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCC(F)(F)F)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3,3,3-trifluoropropan-1-amine via General Procedure E to give 8 mg of 293 following reverse phase purification. MS (Q1) 475.2 (M)+
Reaction SMILES: C(O)(=O)C.Cl.[CH3:6][CH:7]1[CH:12]=[C:11]([C:13]([O:15]CC(Cl)(Cl)Cl)=[O:14])[N:10]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:9]2[S:8]1>CN(C)C=O.[Zn]>[CH3:6][CH:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]2[C:21](=[O:24])[CH:22]([NH2:23])[C@H:9]2[S:8]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
Acetic acid (1 ml) and zinc powder (2.0 g) were added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (1.53 g) in dimethylformamide (10 ml) and the mixture was stirred for 1 hour at -5° to 0° C., after which the reaction mixture was filtered. The filtered zinc powder was washed with dimethylformamide and the filtrate and the washings were combined, after which a few mls. of water was added to the solution. The precipitated crystals were collected by filtration and dissolved in a small amount of a sodium bicarbonate aqueous solution and then the insoluble material was filtered off. The filtrate was adjusted to pH4 with 10% hydrochloric acid and the precipitated crystals were collected by filtration, washed with water and acetone and dried to give 2-methyl-7-amino-3-cephem-4-carboxylic acid (0.38 g), mp 222° C. (dec.).
Reaction SMILES: Cl.[CH3:2][C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[CH3:2][C:3](=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH:18][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)=Cc1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=C(C)C(=O)O)cc1

Procedure:
By the reaction of ethyl α-methyl-4-(2-aminoethyl)-cinnamate hydrochloride (m.p. 270° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained α-methyl-4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid; m.p. 188°-191° C., after recrystallization from ethanol.
Reaction SMILES: C([OH:23])CCCCCCCCCCCCCCCCCCCCC.[CH3:24][CH:25]([CH2:27][CH2:28][CH2:29][C@H:30]([CH2:32][CH2:33][CH2:34][C@H:35]([CH2:37][CH2:38][CH2:39]/[C:40](=[CH:42]/[CH2:43]O)/[CH3:41])[CH3:36])[CH3:31])[CH3:26]>>[CH3:41][C:40]([OH:23])([CH2:39][CH2:38][CH:37]=[C:35]([CH3:36])[CH2:34][CH2:33][CH:32]=[C:30]([CH3:31])[CH2:29][CH2:28][CH:27]=[C:25]([CH3:26])[CH3:24])[CH:42]=[CH2:43]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
Compound U ##STR47## docosanol Compound V ##STR48## phytol Control compound: -MDP (AcMur-L-Ala-D-Glu)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][OH:14].ClCCl.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[CH3:18][S:19]([O:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:21])=[O:20]
Reactant: OCCOc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc2ccccc2c1

Procedure:
As described in Example 2, 13.5 g. of 2-(2-naphthyloxy)ethanol in 400 ml. of dichloromethane is reacted with 9.5 g. of methanesulfonyl chloride in the presence of 11.4 g. of triethylamine to give the product as tan crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:14]2=[CH:15][N:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(-c3cc4ccncc4s3)n2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5ccncc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.174 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (25 mg, 0.174 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.870 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 42 mg of the yellow solid, 67%.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][NH:9][CH2:10][CH:2]12.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:14]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31](Cl)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C:23]([CH3:44])([CH3:43])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][NH:9][CH2:10][CH:2]4[CH2:1]3)=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:14]=[C:13]([C:12]([F:46])([F:11])[F:45])[CH:18]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CN2CCNCC2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
To a solution of octahydro-2H-pyrazino[1,2-a]pyrazine (D79, 197 mg, 1.395 mmol) in 6 mL of DMSO was added 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (372 mg, 0.698 mmol) and potassium carbonate (289 mg, 2.09 mmol) and the reaction was heated at 130° C. for 22 h. The product was isolated by SCX, and the obtained crude (451 mg) was used in the following reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([NH2:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([NH:20][CH2:18][CH3:19])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: CCNC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 28 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (280 mg, 1.03 mmol) and ethylamine using General Procedure G and was isolated in 28% yield as a white solid. HPLC Rt=10.61 min; 1H NMR (400 mHz, CDCl3) 7.44 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.43 Hz, 1H), 7.21 (dd, J=2.2, 8.4 Hz, 1H), 5.4 (bs, 1H), 3.21-3.14 (m, 2H), 2.25-2.20 (m, 2H), 1.86-1.79 (m, 2H), 1.58-1.52 (m, 5H), 1.35-1.32 (m, 1H), 1.00 (at, 3H); 13C NMR (100 mHz, CDCl3) 174.3, 144.8, 132.8, 130.9, 130.7, 128.7, 126.2, 50.5, 34.8, 34.7, 25.7, 23.0, 14.8; GC-MS (SCOUT) 12.9 min, M+ 299.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[OH:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:16]([CH3:18])[CH3:17])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)=[O:11]
Reactant: O=C(CO)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CO)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
Then 2-hydroxy-1-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-ethanone 28 was prepared as follows. To a solution of compound 27 (0.4 g, 1.8 mmole) and o-isopropylthiophenol (0.31 ml, 1.8 mmole) in DMF (10 ml) was added Cs2CO3 (0.59 g, 1.8 mmole). The mixture was stirred for 10 minutes and EtOAc (30 ml) was added. The mixture was filtered, concentrated and chromatographed on a silica gel column eluting with 30% EtOAc in hexane. The desired product 28 was obtained as an oil, 0.22 g, 34.8%. 1H-NMR (CDCl3, 300 MHz) δ1.17 (d, J=7.0 Hz, 6H), 3.40–3.46 (m, 2H), 4.80 (s, 2H), 6.82 (d, J=8.4 Hz, 1H), 7.27–7.31 (m, 1H), 7.51–7.55 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 8.17 (s, 1H); MS (DCI/NH3) m/z 355 (M+H)+, 372 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:23])=[CH:13]/[C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(Cl)(Cl)Cl.C(OCC)C.[OH-].[Na+]>[CH2:25]([NH:28][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14](/[CH:13]=[C:12](/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH2:4][CH2:3][C:2]3([CH3:24])[CH3:1])\[CH3:23])=[CH:15][CH:16]=1)[CH2:26][CH3:27]
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCNC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1

Procedure:
A 15 ml aliquot of the chloroform solution of the mixed anhydride of 4-[(E)-2-(4,4-dimethyl-6-chromanyl)-2-methylvinyl]benzoic acid from Preparation 13 was added to a solution of 0.1 g (1.71 mmole) of n-propylamine in ca. 25 ml of chloroform at 0° C. The reaction mixture was filtered and then it was extracted twice with 1N hydrochloric acid. The resulting chloroform solution was dried (MgSO4) and evaporated in vacuo to give an oily solid. This solid was dissolved in diethyl ether and 2N sodium hydroxide. The layers were separated and the ether layer was filtered, dried (MgSO4) and evaporated in vacuo. The residue was recrystallized from diethyl ether-hexane, to give 0.127 g of the title compound, mp 138°-139° C.
Reaction SMILES: [Na].Cl.C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1=O)=O)C.C(O)(=O)C.[CH:26]([NH2:28])=[NH:27]>C(O)C>[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:6](=[O:5])[NH:28][CH:26]=[N:27][C:9]=2[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N=CN
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Sodium metal (10.1 g, 0.44 mol) was added to ethanol (520 mL) and stirred at room temperature under nitrogen gas until a clear solution had formed. Ethyl-3-oxo-N-benzylpiperidine-4-carboxylate hydrochloride (56.5 g, 0.19 mol) and formamidine acetate (22.9 g, 0.22 mol) were then added and the reaction mixture heated under reflux for 40 hours. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between water (400 mL) and dichloromethane (400 mL). The aqueous phase was re-extracted with dichloromethane (2×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether (100 mL) and the product collected by filtration to give the title compound as a light brown solid (32.0 g, 70%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:25])([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH3:17][C:16]([O:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])([CH3:25])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: CC(C)(Cn1cnc2c(Cl)nc3ccccc3c21)OCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)OCCS(C)(=O)=O
Temperature: 150 °C

Procedure:
A suspension of 4-chloro-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline (4.30 g, 11.3 mmol) in a solution of ammonia in methanol (7 M, 43 mL) in a high pressure vessel was heated at 150° C. for 12 hours. The vessel was allowed to cool to room temperature. The mixture was concentrated under reduced pressure to afford a solid that was slurried in water (50 mL), saturated aqueous sodium carbonate, and methanol. The solid was isolated by filtration, washed with water, and purified by flash chromatography (silica gel, eluted with 10% methanol in dichloromethane) to provide a white solid. The solid was heated in methanol (200 mL) at reflux, isolated by filtration, washed with methanol, and dried to yield 2.2 g of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 261-264° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].N1C=CC=CC=1.Cl[C:24](OCC)=[O:25]>O1CCOCC1>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[CH:11][C:12]=2[N:13]=[C:24]1[OH:25])[CH3:16]
Reactant: CCN(CC)CCNc1nc(Cl)ccc1N
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCN(CC)CCn1c(O)nc2ccc(Cl)nc21
Reaction time: 1 h

Procedure:
The solution of 80 grams of 2-(2-diethylaminoethylamino)-3-amino-6-chloropyridine in 900 ml of dioxane was treated with stirring with 32 ml of pyridine and 36.6 ml of ethyl chloroformate and stirred for one hour. The product precipitating thereby was washed with water and dried (2-(2-diethylaminoethylamino)-3-carbethoxy-amino-6-chloropyridine, M.P. 205°-206° C.) and subsequently melted with occasional stirring and held for 3 hours at 190°-210° C. After cooling the solidified melt was recrystallized from methanol under the addition of activated carbon and isopropanolic H Cl. M.P. of the hydrochloride 252°-254° C.; Yield 52.8 grams.