Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[I:23])N.C([O-])([O-])=O.[K+].[K+].[NH2:30]C1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[I:23][C:22]1[CH:21]=[C:20]([NH:30][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:18]=[CH:17][C:16]=1[CH3:15]
Reactant: Nc1ccccc1
Reactant: Cc1cc(N)ccc1I
Reactant: O=C(O)c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
3-Thiophenecarboxylic acid (2.0 g, 15.6 mmol) was dissolved in methylene chloride (100 mL) and 2 drops of DMF were added. The mixture was cooled to 0° C. and oxalyl chloride (1.5 mL, 17.1 mmol) was added slowly and allowed to warm to room temperature. Gas evolution was observed during warming. 3-Methyl-4-iodoaniline (5.45 g, 23.5 mmol), 4 drops of pyridine and K2CO3 (2.58 g, 18.7 mmol) are dissolved in CH2Cl2 (10 mL) and cooled to about 0° C. After about 1 h, the acid chloride mixture is slowly added to the cooled aniline mixture and allowed to warm to room temperature and stirred for about 18 h. The resulting mixture is filtered, washed with ethyl acetate and the filtrate is concentrated to a brown oil. The crude material was purified via flash chromatography (10-30% ethyl acetate in hexanes) to afford the title compound (1.56 g, 29%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].CO[C:22]1[CH:23]=[C:24]([C:30]2[S:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.[CH3:39][O:40]C(=O)CC(=O)C(Br)C.COC1C=C(C=C(OC)C=1)C(N)=S.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:23]=[CH:22][C:27]([O:40][CH3:39])=[C:26]([O:28][CH3:29])[CH:25]=3)[S:31][C:32]=2[CH3:38])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCO)c(C)s2)c1
Reactant: COC(=O)CC(=O)C(C)Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COc1cc(OC)cc(C(N)=S)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)c(OC)c3)sc2C)c(OC)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester [example 48 a]) was reacted with 2-[2-(3,5-dimethoxy-phenyl)-5-methyl-thiazol-4-yl)-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 3,5-dimethoxy-thiobenzamide [PCT Int. Appl. (1992), WO 92/09586 A1] in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(3,4-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(3,4-dimethoxy-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1.C(OCC)C>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:24])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][S:41]([CH3:40])(=[O:43])=[O:42])=[C:13]([CH3:23])[CH:12]=2)=[C:5]2[CH2:25][CH2:26][C:27]([CH3:29])([CH3:30])[CH2:28][C:4]=12)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(OCCCO)c(C)c2)c2c1CC(C)(C)CC2
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)CCc2cc(C)c(OCCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-propan-1-one (246 mg, 0.575 mmol) in THF (10 mL) and DIPEA (0.26 mL, 1.5 mmol) is added methane sulfonylchloride (0.08 mL, 1.00 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by 10% aq. citric acid solution, dried over Na2SO4 and evaporated to give methanesulfonic acid 3-(4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenoxy}-propyl ester (290 mg) as a brown resin; LC-MS: tR=1.20 min, [M+1]+=507.39.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][C:10]([N+:11]([O-])=O)=[C:4]2[O:3]1.[H][H]>CO.[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:5]2[C:4]=1[O:3][CH:2]([CH3:1])[CH2:6]2
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c2c1CC(C)O2
Reaction time: 12 h
Yield: 91.9 %

Procedure:
Methyl 2-methyl-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 30a (100 mg, 0.42 mmol) was dissolved in 20 mL of methanol followed by the addition of palladium/carbon (10 mg, 10%), filled with hydrogen for three times. The reaction solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound methyl 7-amino-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30b (80 mg, yield: 91.0%) as a colorless oil liquid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+].CC(N(C)C)=O>C(O)(C)(C)C>[CH2:10]([O:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Yield: 38.8 %

Procedure:
A mixture of 125.0 g (0.652 mole) of 5-bromo-2-furoic acid, 210.0 g (0.978 mole) of 1-tetradecanol, 183.0 g (1.630 mole) of potassium tert-butoxide and 2500 ml of dimethylacetamide is heated with stirring. The tert-butanol formed in the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours. To the cooled mixture is added 6 liters of ice water, and the mixture is acidified with malonic acid. The resulting precipitate is collected, dried and recrystallized twice from methanol to give 82.0 g (29%) of 5-tetradecyloxy-2-furoic acid, M.P. 112°-115° C. (dec.).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>>[C:6]1([CH:4]2[N:3]=[CH:2][C:1](=[O:12])[O:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1C=NC(c2ccccc2)O1

Procedure:
The title compound was prepared by the dehydration of hippuric acid with acetic anhydride according to the procedure of Bullerwell and Lawson, [J. Chem. Soc. (1952), 1350], mp 91.5°-93.5° C. (lit. 91° C).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11].C1C=CC=CC=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]3[C:46]4[C:41](=[CH:42][C:43]([O:47][CH3:48])=[CH:44][N:45]=4)[N:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[N:21][N:20]=1>>[CH3:48][O:47][C:43]1[CH:42]=[C:41]2[C:46]([C:37]([S:36][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:22]4[C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:19]([O:11][CH2:10][CH2:9][CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][NH:3]5)=[N:20][N:21]=4)=[CH:31][CH:32]=3)=[CH:38][CH:39]=[N:40]2)=[N:45][CH:44]=1
Reactant: OCCC1CCCCN1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OCCC5CCCCN5)c5ccccc45)cc3)ccnc2c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Sodium Hydride (11 mg, 449 μmol), 2-(piperidin-2-yl)ethanol (58 mg, 449 μmol), and benzene (2243 μl, 449 μmol) were combined in a resealable tube capped with a septum and heated to 40° C. for 30 minutes. 4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (200 mg, 449 μmol) was added, and the reaction mixture was allowed to stir at 80° C. for 18 hours. The mixture was concentrated in vacuo and the crude material was partitioned between methylene chloride and water. The organic layers were combined and over Na2SO4 and concentrated. The crude material was purified via ISCO, 12 g RediSep column eluting with a 20-100% gradient of 90:10:1 (DCM:MeOH:NH4OH) in DCM. The product fractions were combined and concentrated in vacuo to afford N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(2-(piperidin-2-yl)ethoxy)phthalazin-1-amine MS: [M+H]=539.
Reaction SMILES: B(F)(F)[F:2].CCOCC.N[C:11]1[C:12]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:13][C:14]2[CH2:15][CH2:16][C@@H:17]3[C@@H:26]([C:27]=2[CH:28]=1)[CH2:25][CH2:24][C@@:22]1([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]1=[O:29].N(OC(C)(C)C)=O.CCCCC>C(Cl)Cl>[F:2][C:11]1[C:12]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:13][C:14]2[CH2:15][CH2:16][C@@H:17]3[C@@H:26]([C:27]=2[CH:28]=1)[CH2:25][CH2:24][C@@:22]1([CH3:23])[C@H:18]3[CH2:19][CH2:20][C:21]1=[O:29]
Reactant: COCCOc1cc2c(cc1N)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCC
Product: COCCOc1cc2c(cc1F)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To neat BF3-Et2O (126 μL, 141 mg, 1.00 mmol) at −15° C. under Ar (g) was added a solution of compound 95 (228 mg, 0.66 mmol) in dry CH2Cl2 (4 mL) followed by the dropwise addition t-butyl nitrite (95 μL, 82 mg, 0.80 mmol). This solution was stirred at −15° C. for 10 min then at 0° C. for 1.5 h. Pentane (16 mL) was added to the cold solution and a red gummy solid precipitated. The solvent was decanted and the residue was rinced with cold Et2O (5 mL). The residue was dried under vacuum to give a foamy orange-red solid. This solid was heated under vacuum with a heatgum for 5 min. The residue was purified by flash chromatography (SiO2) using 3:7 to 1:1 EtOAc/Hexanes as eluent to give compound 96 (32 mg, 14%) as a solid. 1H NMR (CDCl3) δ 0.90 (3H, s), 1.25-1.64 (m, 6H), 1.92-2.29 (6H, m), 2.50 (1H, dd, J=18.9 Hz, 8.9 Hz), 2.82 (2H, dd, J=8.4 Hz, J′=3.5 Hz), 3.45 (3H, s), 3.75 (2H, t, J=4.7 Hz), 4.15 (2H, t, J=4.5 Hz), 6.71 (1H, d, J=8.7 Hz), 6.98 (1H, d, J=13.2 Hz); 13C NMR(CDCl3) δ 13.8, 21.5, 25.9, 26.5, 29.0, 29.7, 31.5, 35.8, 38.0, 43.9, 47.9, 50.3, 59.2, 69.2, 71.0, 113.1 (d, J=18.7 Hz), 116.1, 132.6 (d, J=87.0 Hz), 144.5, 149.5, 152.7, 220.6.
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[Cl:34][C:35]1[C:40]([C:41]2[NH:22][C:20]3[CH:21]=[C:16]([N:14]4[CH2:13][CH2:12][CH2:11][C:10]5([CH2:27][CH2:28][CH2:29][NH:8][CH2:9]5)[CH2:15]4)[CH:17]=[C:18]([CH3:26])[C:19]=3[N:25]=2)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (100:9:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (288 mg, 55%). 1H NMR (CDCl3) δ 1.28-1.72 (8H), 2.57 (s, 3H), 2.57-3.12 (8H), 6.82 (s, 1H), 6.92 (s, 1H), 6.73 (d, J=6 Hz, 1H), 7.98 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:29]3[CH2:28][CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCc1ccccc1
Reaction time: 10 h
Yield: 78.6 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.29 ml (0.016 mol) of 3-phenylpropylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 70° and 80 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. There were obtained 4.02 g (76%) of oily rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-phenyl-propyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: C([C:3]1([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4]1)C.[CH3:15][NH:16][NH2:17]>C(O)CC>[CH:3]1([C:10]2[CH2:11][C:12](=[O:14])[N:16]([CH3:15])[N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCC1(CCC(=O)O)CCCC(=O)C1
Reactant: CNN
Solvent: CCCO
Product: CN1N=C(C2CCCCC2)CC1=O

Procedure:
To ethyl 3-oxo-cyclohexanepropionic acid (4.4 g, 0.234 mole) in n-propanol (500 ml) is added dropwise with stirring under nitrogen at 80° C. methylhydrazine (13.8 g, 0.3 mole). After heating at reflux during 5 hours, the reaction is cooled and evaporated to a residual oil. Crystallization from ethylacetate gives a white powder mp 170.5° C. to 172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].C(N(CC)CC)C.C[CH:19]([C:23](Cl)=[O:24])[C:20](Cl)=[O:21].CN([CH:29]=[O:30])C>CN(C1C=CN=CC=1)C>[CH3:29][O:30][C:23](=[O:24])[CH2:19][C:20]([NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: CN(C)C=O
Reactant: CSc1ccc(N)c(F)c1
Reactant: CC(C(=O)Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)Nc1ccc(SC)cc1F
Temperature: 60 °C
Yield: 72 %

Procedure:
To a solution of 2-fluoro-4-methylsulfanylphenylamine (13 g, 82.7 mmol), triethylamine (9.3 mL, 86.8 mmol) and DMAP (100 mg, 0.8 mmol) in DMF (50 mL) was added methyl malonyl chloride (11.5 mL, 82.7 mmol). The reaction was heated at 60° C. for 2 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10-30% ethylacetate in cyclohexane) to yield the title compound as a white solid (15.4 g, 72%). LCMS (Method B): RT=2.94 min, M+H+=258.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[CH3:19].C1(C)C=CC=CC=1>C(O)C>[CH2:18]([N:20]([CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCNCC1(C)OCCO1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC1(C)OCCO1)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 54.4 %

Procedure:
4-t-butyl-2,6-dinitro chlorobenzene (2.5 grams; 0.01 mole), 2-(ethylamino)methyl-2-methyl-1,3-dioxolane (2.9 grams; 0.02 mole) and toluene (50 ml) were placed into a glass reaction vessel equipped with a stirrer, oil bath and thermometer and heated to 70° C. with stirrer for 30 hours. Ethanol (50 ml) was added to the cooled mixture and the solid filtered therefrom. The filtrate was evaporated to a volume of approximately 10 ml. It was then chromatographed on silica gel to yield the desired product (2.0 grams). The product was analyzed for C17H25N3O6 :
Reaction SMILES: [F:1][C:2]([F:23])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[OH:14].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[F:23][C:2]([F:1])([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1
Reactant: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C

Procedure:
(3aR,4R,5R,6aS)-4-(3,3-Difluoro-4-phenoxybutyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one, prepared in Step D, is dissolved in DCM (0.1 M) under a nitrogen atmosphere. Dihydropyran (1.1 molar equivalents) is added, followed by a catalytic amount of p-toluenesulfonic acid. The reaction is stirred at room temperature under a nitrogen atmosphere and the reaction progress is monitored by TLC. Upon completion, brine is added to the reaction mixture and the layers are separated. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes to afford the title intermediate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:44][CH:43]([NH2:59])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:61])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([C:53](=[O:58])[C:54]([CH3:55])([CH3:56])[CH3:57])[CH2:44][CH:43]([NH:59][C:14]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=3)=[O:16])[C:42]2=[O:60])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Methyl 5-amino-2-methylbenzoate (223 mg) was dissolved in tetrahydrofuran (30 ml), under ice-cooling triphosgene (135 mg) was added, triethylamine (116 μl) was added thereto five times every 3 minutes, the mixture was stirred for 10 minutes at same temperature. Subsequently, a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (500 mg) in tetrahydrofuran (20 ml) was added dropwise, stirred for 30 minutes at same temperature, and then stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 271 mg of the titled compound.
Reaction SMILES: [O:1]=[C:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].Br[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=1[F:39].C(OCC)(=O)C.O>C(N(CC)CC)C.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>[O:1]=[C:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=2[F:39])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: C#CCN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
A mixture of 17.28 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)-piperidine-3-carboxylate in 173 cm3 of triethylamine is stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 4.05 g of tetrakis(triphenylphosphine)palladium, 0.834 g of cuprous iodide and 7.9 g of 1-bromo-2,3,5-trifluorobenzene are added. The mixture is stirred for 2 hours at a temperature in the region of 80° C. After cooling to approximately 20° C., 150 cm3 of ethyl acetate and 150 cm3 of water are added to the reaction mixture, which is then separated after settling out. The aqueous phase is extracted with 3 times 150 cm3 of ethyl acetate. The organic phases are pooled, washed with 5 times 150 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20–45μ; diameter 7 cm; 600 g), eluting with pure ethyl acetate and collecting first a fraction of 2.5 1, and then fractions of 250 cm3. Fractions 2 to 29 are pooled and then concentrated as above. 18.4 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-piperidine-3-carboxylate, in the form of a yellow oil, are obtained.