Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=[O:21])[C:19](=[O:22])[C:18]=3OC)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:25][OH:26].C(Cl)(Cl)Cl.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36]>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:32]([CH:33]2[CH2:13][CH2:14][CH2:15][CH:35]([NH:36][C:18]3[C:25](=[O:26])[C:20](=[O:21])[C:17]=3[NH:16][CH2:12][CH2:11][CH2:10][CH2:8][NH:9][C:18]3[C:19](=[O:22])[C:20](=[O:21])[C:17]=3[NH:16][CH:12]3[CH2:13][CH2:14][CH2:15][CH:10]([C:8]4[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=4)[CH2:11]3)[CH2:34]2)[N:31]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CO
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reactant: NCCCCN
Solvent: ClC(Cl)Cl
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NCCCCNc4c(NC5CCCC(c6csc(NC(=N)N)n6)C5)c(=O)c4=O)c(=O)c3=O)C2)cs1

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)-cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.35 g.) in 60 ml. of methanol/chloroform (50:50 v/v) was added 1,4-diaminobutane (0.044 g.) in methanol (1 ml.). The solution was heated under reflux for 16 hours during which time a precipitate formed. The reaction mixture was cooled and the solid precipitate collected and washed with methanol (1 ml.) and ether (2 ml.) to give, as an off-white powder, 1,4-bis{1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-3,4-dioxocyclobutenylamino}butane. The carbon-13 magnetic resonance spectrum (δ relative to tetramethylsilane) in d6 -DMSO included one carbon singlets at 182.3, 174.8, 167.7, 167.0, 156.7, 155.3, 100.3 and 52.4 together with a series of singlets from 42.9 to 24.0 p.p.m. (the latter group of signals includes the resonances due to the solvent).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:26]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:8]2[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6](=[O:25])(=[O:24])[C:7]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.4 %

Procedure:
A mixture of 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) (0.150 mg, 0.413 mmol), benzoic acid (0.055 g, 0.454 mmol), EDC (0.087 g, 0.454 mmol), HOBt (0.061 g, 0.454 mmol) and TEA (0.120 ml, 0.825 mmol) in THF (3 ml) was stirred at rt for 3.5 h. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.136 g, 71%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.42 (m, 5H), 7.42-7.35 (m, 2H), 7.32-7.29 (m, 1H), 5.21 (d, 1H), 4.48 (bs, 1H), 3.56 (bs, 1H), 3.24-3.12 (m, 1H), 2.58-2.44 (m, 2H), 1.90-1.64 (bs, 2H), 1.74 (s, 9H), 1.48-1.16 (bs, 2H); 13C NMR (125 MHz CDCl3): δ 170.6, 159.7, 135.7, 133.9, 131.8, 130.2, 130.0, 128.9, 128.7, 126.9, 125.2, 107.7, 61.9, 50.4, 27.8; Mass Spectrum: M+H+ 468.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[N:14]=[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:16]2[C:17](=[O:20])[C:18]=1Br)[CH3:12].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([C:13]1[N:14]=[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:16]2[C:17](=[O:20])[C:18]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:12]
Reactant: Cc1cccc2nc(C(C)n3cnc4c(N)ncnc43)c(Br)c(=O)n12
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc2nc(C(C)n3cnc4c(N)ncnc43)c(-c3ccccc3)c(=O)n12
Temperature: 100 °C

Procedure:
To a mixture of 2-[1-(6-amino-9H-purin-9-yl)ethyl]-3-bromo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.030 g, 0.075 mmol) and phenylboronic acid (11.0 mg, 0.0899 mmol) in 1,4-dioxane (0.6 mL) was added a 1M solution of sodium carbonate (9.53 mg, 0.0899 mmol) in water (0.089 mL) and tetrakis(triphenylphosphine)palladium (0) (4.33 mg, 0.00375 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C22H20N7O (M+H)+: m/z=398.2. Found: 398.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.37 (1H, s), 7.97 (1H, s), 7.56 (1H, dd, J=8.7 and 6.6 Hz), 7.41-7.36 (5H, m), 7.26 (1H, br d, J=9.0 Hz), 7.09 (2H, br s), 6.85 (1H, br d, J=7.2 Hz), 5.59 (1H, q, J=7.2 Hz), 2.80 (3H, s), 1.64 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:57])[C@H:41]([CH2:53][CH:54]([CH3:56])[CH3:55])[NH:42]C(OCC1C=CC=CC=1)=O)[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.CO.O1CCOCC1.[Pd]>[CH2:1]([C@H:8]([NH:39][C:40](=[O:57])[C@H:41]([CH2:53][CH:54]([CH3:55])[CH3:56])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Yield: 100.2 %

Procedure:
A solution of Example 167A (40 mg, 0.051 mmol) in ethyl acetate (0.25 mL) and methanol (0.25 mL) was treated with 1N HCl in dioxane, a hydrogen balloon, and 10% Pd/C (11 mg, 0.01 mmol) at 25° C. for 16h. The mixture was filtered, rinsed with methanol, and the solvents were evaporated to give the title compound (33 mg, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:7]=1[NH2:21])=O)C.[NH4+:22].[OH-]>CO.C1COCC1>[NH2:21][C:7]1[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:9][O:10][C:6]=1[C:4]([NH2:22])=[O:3]
Reactant: [NH4+]
Reactant: CCOC(=O)c1onc(-c2ccc(S(C)(=O)=O)cc2)c1N
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2noc(C(N)=O)c2N)cc1
Reaction time: 24 h

Procedure:
To a solution of 4-amino-3-(4-methanesulfonyl-phenyl)-isoxazole-5-carboxylic acid ethyl ester (4.0 g, 12.9 mmol) in methanol (50 mL) and THF (50 mL), was added a NH4OH solution (100 mL) at room temperature. The reaction was stirred for 24 h. The precipitates were filtered and washed with H2O (100 mL). The compound was dried in vacuo to afford the crude product which was used for the next step without further purification. LCMS 282.1 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:13])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=S(O)c1cc(F)c(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
To 2,4,5-trifluoro-benzenesulfinic acid (2.0 g) in DMF (17 mL) was added 4.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (2.2 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time, water (30 mL) was poured onto the reaction mixture, and the reaction mixture was extracted with diethylether several times. The combined organic phases were dried with sodium sulfate, and the remaining mixture was distilled to yield the title compound as a light yellow oil (2.1 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.[H-].[Na+].[CH3:18]I.Cl>O1CCCC1>[CH3:18][O:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1
Reactant: CI
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1coc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A solution of 2.7 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole in 50 ml of tetrahydrofuran (dehydrated) was added dropwise to a suspension of 0.5 g NaH (purity about 60%) in 20 ml of tetrahydrofuran (dehydrated) at 0° C. After stirring the mixture at room temperature for 1 hour, a solution of 2.0 g of methyl iodide in 20 ml of tetrahydrofuran (dehydrated) was added at 0° C. and further stirred at room temperature for 1 hour. The reaction mixture was poured into a mixed solution of 200 g ice and 2N hydrochloric acid. After extraction with 100 ml of dichloromethane, the solution was washed with water and dried with anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane) to obtain 1.5 g of 4-methoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 52.5%). n20D=1.4710.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([CH3:29])[N:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([CH3:29])[N:28]=3)[N:3]=[CH:4][C:5]=2[C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)[N:10]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: OB(O)c1cncnc1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cncnc3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=335.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 5-pyrimidineboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][NH:19][C:20]3[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][N:21]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:28](O)(=O)C.[CH2:32]([NH2:34])[CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:32]([NH:34][CH2:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][CH2:18][C:8]2[N:6]3[CH:7]=[C:2]([CH3:28])[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:25]=1)[CH3:33]
Reactant: CCN
Reactant: O=Cc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCNCc1ccnc(NCc2c(-c3ccc(F)cc3)nc3ccc(C)cn23)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a suspension of 2-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methylamino)pyrimidine-4-carbaldehyde (110 mg, 0.29 mmol) in CH2Cl2 (5 mL) was added acetic acid (0.5 mL) until the reaction became clear. Ethylamine (0.87 mmol, 3.0 eq) and Na(OAc)3BH (0.58 mmol, 2.0 eq) were added and the reaction mixture was stirred for 18 h at room temperature. After this time the reaction was diluted with CH2Cl2 (20 mL) and quenched by the addition of satd. aq. NaHCO3 (10 mL). After stirring for 10 min the layers were separated and the organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse phase preparatory HPLC (silica gel, acetonitrile/water w/0.05% TFA) to afford the desired product. (0.060 g, 37% yield). M/e+ 411.1 for C21H20ClFN6 (M+H)+; 1H-NMR (500 MHz, CDCl3, δ) 8.48 (d, J=1.5 Hz, 1H), 8.29 (d, J=5.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.58 (d, J=9.5 Hz, 1H), 7.21-7.15 (m, 3H), 6.70 (d, J=5.5 Hz, 1H), 5.24 (br s, 1H), 5.05 (d, J=5.5 Hz, 2H), 3.77 (s, 2H), 2.72 (q, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(C(=O)c3ccccc3)o2)c1

Procedure:
Acid (9) (48 mg, 0.22 mmol) was coupled to aniline (2) (43 mg, 0.22 mmol) using Method B, except that DIPEA (57 mg, 0.44 mmol) and DMF (0.5 mL) were used. The crude product was purified by preparative HPLC to give the title compound. Yield: 28 mg; LC-MS tr 41.54 min; MS (ES+) m/z 389 (M+H)
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([O:62][C:63]([F:66])([F:65])[F:64])=[CH:58][C:54]=1[C:55](Cl)=[O:56]>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([O:62][C:63]([F:64])([F:65])[F:66])=[CH:58][C:54]=1[C:55]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:56]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)Cl
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(OC(F)(F)F)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Reaction time: 14 h

Procedure:
Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (1.7 g, 2.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in ethyl acetate/water (1/1) (20 mL). Add a solution of 2-methoxy-5-trifluoromethoxybenzoyl chloride (0.64 g, 2.5 mmol) in ethyl acetate (10 mL). After 14 hours, separate the organic layer. Extract the aqueous layer four times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.32 (silica gel, ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33]>>[CH2:31]([N:35]([CH3:36])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH:32]([CH3:34])[CH3:33]
Reactant: CNCC(C)C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CC(C)CN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and Isobutyl-methyl-amine. MS (ESI): 428.4 (MH+).
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:3][CH2:4][C@@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: OC[C@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 59.3 %

Procedure:
A mixture of 2.5 g (10.3 mmol) of (7S,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihydrochloride, 7.62 g (51.5 mmol) of 2,5-dichloropyridine, 5.45 g (51.5 mmol) of sodium carbonate and 100 mL of isoamyl alcohol was heated at reflux for 72 h. The mixture was cooled, the mixture filtered to remove solids and the solvent evaporated in vacuo. Purification by flash silica gel chromatography using 95:5 chloroform:methanol gave 1.72 g (59%) of the title compound. mp (base) 61-62° C. 13C NMR (base, CDCl3): δ26.6, 27.2, 34.3, 45.4, 50.9, 54.6, 58.4, 60.5, 68.0, 107.7, 120.1, 137.1, 146.2, 157.5. HRMS calcd for C14H20ClN3O: 281.1295, found: 281.1298.
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:25]C1(C2C=CC(C=O)=CC=2)CC1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC1(c2ccc(C=O)cc2)CC1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1-methyl-cyclo-propyl)-benzaldehyde (150 mg, 0.94 mmol), 2-(3-trifluoromethylphenyl)-ethylamine (177 mg, 0.94 mmol) and sodium borohydride (53 mg, 1.40 mmol). The isolated residue was purified by flash column chromatography (2%-5% MeOH in EtOAc) to give the desired product (195 mg, 62%) as a colorless oil. MS (ISP) 334.3 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCCCCC.CCOC(C)=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1C1CCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of 1.94 g of 4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzyl alcohol in 70 mL of anhydrous CH2Cl2 was treated with 2.05 g of pyridinium chlorochromate (Aldrich) and was stirred at RT under nitrogen. After 30 min, tlc (SiO2, 85:15 hexane:EtOAc) indicated no remaining starting material and a major new component at Rf =0.80. The mixture was filtered to remove solids and the filtrate was washed with 5% aqueous citric acid (4×50 mL) followed by 5% aqueous NaHCO3 (4×50 mL). The CH2Cl2 solution was dried over anhydrous MgSO4 and concentrated in vacuo to give a brown oil. This material was purified by flash chromatography on silica gel (9:1 hexane:EtOAc) to afford 1.52 g (79%) of 4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzaldehyde as a clear oil.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[C:17]([CH3:19])[C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([N:16]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:17]([CH3:19])[CH:18]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: BrCCCCBr
Reactant: Cc1cc(OC23CC4CC(CC(C4)C2)C3)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(OC23CC4CC(CC(C4)C2)C3)cc(C)c1N1CCCC1
Yield: 111.2 %

Procedure:
A mixture of 1.8 g (6.63 mmoles) of 4-(1-adamantyloxy)-2,6-dimethylaniline, 1.43 g (6.63 mmoles) of 1,4-dibromobutane, and 2.01 g (14.6 mmoles) of K2CO3 in 25 deaerated absolute ethanol is refluxed for 45 hours, cooled, and evaporated. The residue is taken up in CH2Cl2 (125 ml) and water (125 ml). The CH2Cl2 layer is washed with water, and the combined aqueous layers are extracted with CH2Cl2 (50 ml.). The combined organic layers are dried and concentrated to give 2.4 g of a brown oil, which is chromatographed by HPLC on a 2.54 cm×109 cm column at 40 psi eluting with 0.5% acetone in CH2Cl2 and then 0.75% acetone in CH2Cl2 to give 0.45 g in the first liter eluted from the column. This solid in 1 ml of CH2Cl2 and 5 ml of ether is treated with 3.5 N HCl in ether. The hydrochloride is filtered, washed with ether, and dried to give 0.38 g of white solid, m.p. 184.4-185.6 (dec.).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]([C:14](=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:33])[NH:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.O1CCOCC1.[OH-].[Na+]>C(O)C>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([CH2:23][NH:22][C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:14]([N:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:34])=[O:33])=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN(Cc1ccccc1)C(=O)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of N-benzo[1,3]dioxol-5-ylmethyl-isophthalamic acid (3.0 g, 10 mmol) in methylene chloride was added 1-hydroxy-benzotriazole monohydrate (“HOBt”) (1.35 g, 10 mmol) and ethyl N-benzylglycine (1.94 g, 10 mmol). To this was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (“EDAC”) (1.92 g, 10 mmol) and the mix stirred at room temperature for 24 hours. The solution treated with water (150 mL) and the organic phase separated, washed with 10% citric acid (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL). The organic phase dried over magnesium sulfate and evaporated at reduced pressure to give ({3-[(1,3-benzodioxol-5-ylmethyl)-carbamoyl]-benzoyl}-benzyl-amino)-acetic acid ethyl ester as a solid, 3.69 g. To a solution of this ester (3.6 g, 7.6 mmol) in a mix of water (15 mL), dioxane (60 mL) and ethanol (20 mL) was added sodium hydroxide (0.72 g, 18 mmol). The mixture stirred at 50° C. for 24 hours. The solution cooled to room temperature and evaporated at reduced pressure free of solvents. The residue was diluted with water (100 mL) and washed with ether (2×50 mL). The ether discarded and the aqueous phase made acidic with 6N HCl. This was extracted with ethyl acetate (2×100 mL). The organic phases washed with brine (100 mL) and dried over magnesium sulfate. The solvent was evaporated at reduced pressure to give the title compound, 3.41 g. Microanalysis (C25H22N2O6.0.3H2O): Calc'd: C=66.45; H=5.05; N=6.20. Found: C=66.25; H=5.15; N=5.99.