Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5([O:29][CH2:28][CH2:27][O:26]5)[CH2:24][CH2:23]4)[CH2:18][CH:17]=3)=[C:12]([F:32])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:17][CH2:18][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5([O:26][CH2:27][CH2:28][O:29]5)[CH2:24][CH2:23]4)[CH2:20][CH2:21]3)=[C:12]([F:32])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCOC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1

Procedure:
The compound (24) was dissolved in a mixed solvent of toluene (150 ml) and isopropyl alcohol (150 ml), and then Pd/C (2.35 g) and potassium carbonate (0.40 g) were added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and dried, giving 31.4 g of 8-(4-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)cyclohexyl)-1,4-dioxaspiro[4,5]decane (25). The yield based on the compound (24) was 66.4%.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].ClC(OCC)=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: NCCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(CC(C)C)C(=O)NCCN1CCOCC1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 51.6 %

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (2.0 g) is dissolved in 40 ml of tetrahydrofuran (THF) and 1.0 g of triethylamine. This solution is cooled to -5° C. and ethyl chloroformate in 5 ml of THF is added dropwise. The reaction mixture is stirred at -5° C. for 20 minutes and then N-(2-aminoethyl)morpholine [1.3 g] in 20 ml of THF is added dropwise. It is stirred at 20° C. for 4 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. This residue is dissolved in ether and washed once with aqueous NaHCO3 and twice with water. The ether is dried with MgSO4, filtered and concentrated in vacuo to yield 1.6 g of material. This is purified by dissolving 0.6 g in 2 ml of ether and placing it on top of a pad of alumina (activity II 10 g). The column is washed through with 250 ml of ether which is concentrated in vacuo. Product crystallizes and is washed with 1:5 ether-pentane. The remainder of the crude is seeded with a small crystal and then washed with 1:5 ether-pentane. Total yield is 1.0 g of the title compound, melting point 54°-59° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1([C:34](O)=[O:35])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1>>[C:22]1([C:34]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:35])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cn4c5c(cccc35)CCC4)CC1)O2

Procedure:
Compound 73 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid conditions outlined in procedure O. M.p.=265-267° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92 (dd, J=0.78, 7.4 Hz, 2H), 7.76-7.80 (m, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.0 Hz, 1H), 4.22 (m, 4H), 3.45 (t, J=11.4 Hz, 2H), 3.16 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 2.06-2.16 (m, 4H), 1.87 (m 2H); LCMS=485 [M+H].
Reaction SMILES: C(O[C:4]1[C:5]([NH:11][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:26])([F:25])[F:24])[CH:20]=3)[O:15][C:14]([CH3:28])([CH3:27])[C@H:13]2[OH:29])=[N:6][S:7](=[O:10])(=[O:9])[N:8]=1)C.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:27][C:14]1([CH3:28])[C@@H:13]([OH:29])[C@H:12]([NH:11][C:5]2[C:4]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:8][S:7](=[O:10])(=[O:9])[N:6]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]([F:25])([F:26])[F:24])[CH:20]=2)[O:15]1
Reactant: C1CCNC1
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H]1c2cc(OC(F)(F)F)ccc2OC(C)(C)[C@H]1O
Product: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](NC2=NS(=O)(=O)N=C2N2CCCC2)[C@@H]1O

Procedure:
In a method similar to Example 5, the product of Example 1, Step 2 (0.218 g, 0.500 mmol) was converted to the title compound with pyrrolidine (0.053 g, 0.780 mmol) in 1 hour to give 0.34 g of product which was purified by flash column (3:2 hexane/ethyl acetate) to afford 0.17 (74%) of white solid after recrystallization: mp 243°-245° C.; 1H NMR (DMSO-D6): δ 7.74 (d, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 6.89 (d, 1H), 5.81 (d, 1H), 4.94 (t, 1H), 4.00 (m, 1H), 3.87 (m, 2H), 3.57 (m, 2H), 2.10-1.90 (m, 4H), 1.41 (s, 3H), 1.17 (s, 3H); IR (KBr): 3350, 1595 cm-1 ; MS (m/z) 463 (MH +, 100%); [α]D25 =-75.5 (THF).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:25])[C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:10]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:8]=1>O.C1COCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([N:13]3[CH:17]=[N:16][N:15]=[N:14]3)[CH:10]=2)[C:6]([OH:25])=[O:5])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)nc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (440 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6˜7. The resulting precipitate was collected and dried to afford 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid as a yellow solid (390 mg, 93%). MS (M+H)=282.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH2:12][C:13]([NH2:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][CH2:12][C:13]([CH3:15])([NH2:16])[CH3:14]
Reactant: CC(C)(N)CN
Reactant: Clc1nc2ccccc2s1
Solvent: c1ccncc1
Product: CC(C)(N)CNc1nc2ccccc2s1

Procedure:
A solution of 2-chlorobenzothiazole (5.0 g) in 1,2-diamino-2-methylpropane (20 ml) and pyridine (2.3 ml) was stirred 2 h at RT. The solvent was evaporated. Flash chromatography (silica gel; CH2Cl2/MeOH) provided 6.2 g of a colorless oil, which crystallized upon standing.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:19][CH:20]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:21]([OH:27])[CH:22]([CH:24]1[CH2:26][CH2:25]1)[OH:23]>>[CH:29]1([CH2:28][C@H:20]([NH:19][C:16]([CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:18])[C@@H:21]([OH:27])[C@H:22]([CH:24]2[CH2:25][CH2:26]2)[OH:23])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Reactant: NC(CC1CCCCC1)C(O)C(O)C1CC1
Product: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In a manner analogous to the procedure described in Example 16(c), by condensing (RS)-Boc-3-(4-thiazolyl)alanine, prepared according to the synthesis described in EPA 0274259, and 3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol there is obtained tert-butyl [(RS)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(4-thiazolyl)ethyl]carbamate (1:1 epimer mixture) as a colourless solid; MS: 482 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:16])[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].F[C:18]1[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>CS(C)=O>[CH3:16][N:5]([CH3:4])[CH2:6][CH2:7][CH:8]([O:9][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CN(C)CCC(O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
57 ml of dimethylsulfoxide were added at 60°-65° C. to 5.7 g of a 50% oil-sodium hydride suspension and after cooling the mixture to 25° C., 10.55 g of N,N-dimethyl-3-phenyl-3-hydroxy-propanamine hydrochloride were added thereto under an inert atmosphere. The mixture stood at room temperature and 10.6 ml of 3-fluoro-nitrobenzene were added thereto. After standing at 25° C. for 18 hours, the mixture was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure to obtain 25 g of raw product. The latter was extracted twice with 50 ml of N hydrochloric acid and the neutral fraction was extracted twice with 100 ml of ether. The aqueous phase was made alkaline with an excess of sodium hydroxide solution and was extracted with methylene chloride. The organic phase was washed with water and evaporated to dryness under reduced pressure to obtain 11 g of N,N-dimethyl-γ-(3-nitrophenoxy)-benzene-propanamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[OH:21])#[N:15]>C(#N)C>[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: COP(=S)(Cl)OC
Reactant: CCCCOc1cc(O)c(C#N)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=S)(OC)OC)c(C#N)s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
7 g of potassium carbonate and 8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 9.8 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with benzene yielded 11 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 = 1.5375.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](Cl)(Cl)=[O:19]>C(Cl)Cl.C1C=CC=CC=1>[C:1]([N:5]1[CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[O:17][C:18]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)N1CC(c2ccc([N+](=O)[O-])cc2)OC1=O
Temperature: -5 °C
Reaction time: 3.5 h

Procedure:
In 270 ml of CH2Cl2, 12.97 g of α-[(tert-butylamino)methyl]-p-nitrobenzyl alcohol is dissolved. The solution is cooled to -5° C. and 54 ml of 12.5% phosgene in benzene is added slowly. After the addition is completed, the mixture is stirred for 3.5 hours and poured on ice. The organic phase is separated, and the aqueous layer is extracted with CH2Cl2 (2×100 ml). The combined organic layers are washed with saturated NaHCO3 solution (2×250 ml), 100 ml of H2O and dried over MgSO4. The solution is evaporated to dryness to give 16.3 g, which is recrystallized from MeOH twice to afford 12.58 g of 3-tert-butyl-5-(p-nitrophenyl)-2-oxazolidinone, mp 123°-125° C. This product (10 g) is dissolved in 200 ml of MeOH and hydrogenated over 6 g of Raney nicke at 51 p.s.i.g at 40° C. to give, after filtration and evaporation, 8.21 g of 5-(p-aminophenyl)-3-tert-butyl-2-oxazolidinone, mp 125°-129° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:20])[NH:24][C:23]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:22]=1[Cl:21])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To the solution of (S)-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (100 mg, 361 μmol, Eq: 1) and 2-chloro-6-fluoroaniline (63.0 mg, 433 μmol, Eq: 1.2) in pyridine (2.00 mL) at 0° C. was added POCL3 (82.9 mg, 50.4 μL, 541 μmol, Eq: 1.5). Reaction was warmed to RT and stirred for 2 h. The mixture was evaporated and water was added to the residue. The mixture was extracted with EtOAc, the combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (79 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([NH:7][NH2:8])=O)[CH3:3].Cl.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][N:17]=[C:18]=[S:19]>CCO>[CH3:1][N:2]([CH2:4][C:5]1[N:17]([CH3:16])[C:18]([SH:19])=[N:8][N:7]=1)[CH3:3]
Reactant: CN=C=S
Reactant: CN(C)CC(=O)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CN(C)Cc1nnc(S)n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
N,N-dimethylglycine hydrazide hydrochloride (50 g, 0.263 mol) was stirred for 5 min in EtOH (525 mL). To this suspension was added Cs2CO3 (62.5 g, 0.192 mol) and the mixture was stirred at room temperature for 15 min. Methyl isothiocyanate (19.25 g, 0.263 mol) in EtOH (270 mL) was added to the pot and the reaction mixture was brought to reflux. The reflux condenser was removed and the EtOH was allowed to evaporate under atmospheric pressure (oil bath temperature 105-110° C.) over 3H to give a purple paste. The reaction was removed from heat and allowed to sit at room temperature overnight (18H), during which time the paste became a solid. The solid was mixed with CH2Cl2 (1.5 L) and filtered. The organic filtrate was concentrated under reduced pressure to give 31 g of a crude yellow oil. The oil was purified by column chromatography through silica gel, eluting with 4:1 CH2Cl2/MeOH to afford 15.3 g (34.9%) of the desired product. 1H NMR (DMSO-d6) d 2.17 (s, 6H) 3.46 (s, 5H) 13.57 (s, 1H). MS (APCI) calcd for C6H12N4S: 172.25; found (M−H+) 171.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:24])=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]>O1CCCC1>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([NH:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:24])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid methyl ester (158) (91 mg, 0.283 mmoles) in dry tetrahydrofuran (5 ml) was treated with potassium trimethylsilanoate (182 mg, 1.42 mmoles) and the mixture stirred under an argon atmosphere for 3 hours. After evaporation of the solvent, the residue was purified by HPLC (gradient: 15% acetonitrile/85% water containing 0.1% trifluoroacetic acid to 55% acetonitrile/45% water at a rate of 1%/min) to afford compound 160 (35 mg) as a white solid. LC/MS System D; Rt=7.64 mins, m/z (ES+)=308 (M+H for C19H17NO3).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[N:34]=[CH:35][C:36]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]2)=[O:23])=[CH:37][CH:38]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(Cl)nc1)N1CCN(C2CCC2)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (54%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[CH2:9][CH:8]([CH2:13][CH2:14]Cl)[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[N:18]1([CH2:14][CH2:13][CH:8]2[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:12]=[N:11][C:10]=3[CH2:9]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CN1CC(CCCl)Cc2ncc(Cl)cc2C1=O
Reactant: C1CNC1
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC2)Cc2ncc(Cl)cc2C1=O

Procedure:
Following the procedure of Example 21, 3-chloro-8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one and azetidine are reacted and the free base of the title is isolated and reacted with oxalic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH:29][CH3:30]>>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH3:30])[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:5]=1
Reactant: CNCCOC
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COCCN(C)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(OC)n1
Yield: 51 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and N-(2-methoxyethyl)methylamine in analogy to example 1c. It was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent to give the title compound as a slightly yellowish solid in 51% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CCN(C(C)C)C(C)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>C1COCC1>[O:4]=[C:3]1[N:5]([CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8])[C:21](=[S:22])[NH:1][CH2:2]1
Reactant: CCC(NC(=O)CN)C(=O)O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)O)N1C(=O)CNC1=S
Yield: 38 %

Procedure:
To a mixture of 2-(2-aminoacetamido)butanoic acid (0.5 g, 3.12 mmol) and DIPEA (1.812 g, 14.05 mmol) in anhydrous THF 10 mL is added 1,1′-thiocarbonyldiimidazole (0.834 g, 4.68 mmol) and heated to reflux overnight. The resulting reaction mixture is concentrated to dry and the pure product 2-(5-oxo-2-thioxoimidazolidin-1-yl)butanoic acid (0.24 g, 1.187 mmol, yellow solid) is obtained by column chromatography using acetic acid/DCM, 0-5% ration solvent system. 1H-NMR (CD3OD/300 MHz): 5.21 (dd, J=10.5, 5.1 Hz, 1H), 4.09 (d, J=5.4 Hz, 2H), 2.25 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). MS (ES+, m/z): 200.9 (M−, 100.0).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=O)=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>C1(C)C=CC=CC=1>[S:16]=[C:11]1[CH2:12][CH2:13][CH2:14][N:9]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)CC(=O)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN1CCCC(=S)C1
Reaction time: 96 h

Procedure:
A mixture of 1-[(ethoxycarbonyl)acetyl]piperidine, 131 g of phosphorus pentasulfide and one liter of toluene was stirred for 96 hours. The solvent was decanted and saved. The gum was washed with 250 ml of toluene. The toluene solutions were combined and concentrated in vacuo. The residue was dissolved in dichloromethane and percolated through a bed of hydrous magnesium silicate, washing with the same solvent. The filtrate and wash were combined and concentrated in vacuo, giving 92 g of ethyl 3-thioxo-N-piperidinepropionate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[CH:16]=1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cccnc2)C1
Yield: 67.2 %

Procedure:
tert-Butyl 3-pyrrolidinylcarbamate (0.099 g, 0.53 mmol; TCI) and 3-bromopyridine (0.050 mL, 0.52 mmol; Aldrich) were processed according to the procedure of Example 1A to provide the title compound (0.092 g, 66%). MS (CI/NH3) m/z 264 (M+H)+.