Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]([OH:13])=[O:12].[C:14]([O-])(O)=O.[Na+]>CO.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(Br)ccc2c1OCO2
Yield: 55 %

Procedure:
5-Bromo-1,3-benzodioxole-4-carboxylic acid (0.34 g, 1.39 mmol) was dissolved in methanol (25 mL). A few drops of concentrated sulfuric acid were added and the solution was heated to reflux for 60 h at which time TLC analysis indicated the reaction complete. The reaction was cooled and poured into a solution of 5% NaHCO3 (25 mL) and extracted with ethyl acetate. The organic layers were dried with magnesium sulfate and concentrated by rotary evaporation to afford 0.20 g of product (0.77 mmol, 55% yield) as an off-white solid. 1H NMR (CDCl3) δ 7.11 (d, J=8.3 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.09 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: O[CH:2]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([SH:21])[CH:18]([SH:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:3]([C:2]1[S:21][CH2:17][CH:18]([CH3:19])[S:20][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(=O)C(O)CCCCCC
Reactant: CC(S)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCC1=C(CCCCCC)SC(C)CS1
Yield: 63 %

Procedure:
The method of Example 4 was used, using 7-hydroxytetradecan-8-one (22.8 g), propane-1,2-dithiol (10.8 g) and p-toluenesulphonic acid (0.5 g) to give 2,3-dihexyl-5,6-dihydro-5-methyl-1,4-dithiin as a greenish oil, bp 148°-155°/0.2 mm, yield 63%. NMR, 0.7-1.8 δ (multiplets), 2.05-2.35 δ (broad triplet), 2.45-3.6 δ (multiplets), 2.95 δ (doublet).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Br:22][C:23]1[CH:24]=[C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[S:26][CH:27]=1.BrC1C=C(C=O)SC=1.C(N(CC)CC)C>CN(C=O)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:30](=[O:31])[CH:29]=[CH:28][C:25]4[S:26][CH:27]=[C:23]([Br:22])[CH:24]=4)[C@@H:16]([CH3:20])[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)/C=C/c1cc(Br)cs1
Reactant: C[C@@H]1NCCN(Cc2ccc3c(Cl)ccnc3c2)C1=O
Agent: Cl
Agent: O=Cc1cc(Br)cs1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1C(=O)C=Cc1cc(Br)cs1
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
(S)-1-(4-chloroquinolin-7-ylmethyl)-3-methylpiperazin-2-one hydrochloride (0.35 g, 1.4 mmol), EXAMPLE 91, is treated with DMF (20 mL), 3-(4-bromothiophen-2-yl)-(E)-acrylic acid (0.32 g, 1.4 mmol), prepared according to EXAMPLE 26, using 4-bromothiophene-2-carboxaldehyde, triethyl amine (0.21 ml, 1.4 mmol) and 2-(1H-benzotriazol-1-yl)1,1,3,3-tertamethyluronium tetrafluoroborate (0.45 g, 1.4 mmol) and heated to 50° C. for 5 minutes. The reaction mixture is stirred at ambient temperature for 16 h then partitioned between ethyl acetate and water. The organic layer is concentrated and the residue is chromatographed (5% methanol/methylene chloride) to give crude title compound (0.5 g, 0.9 mmol). MS m/z: [M+H]+=504. 1H NMR (CDCl3, 300 MHz) δ8.9 (d, 1H), 8.2-8.3 (m, 2H), 8.0 (s, 1H), 7.7-7.8 (m, 1H), 7.4 (s, 1H), 7.3-7.4 (m, 1H), 6.7-6.8 (m, 1H), 6.6 (d, 1H), 5.1-5.2 (m, 1H), 4.6-4.7 (m, 2H), 3.4-3.6 (m, 2H), 3.0-3.3 (m, 2H), 1.5 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Br)c(N3CCN(C)CC3)cc21
Yield: 33 %

Procedure:
3.3 g of 6-bromo-7-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.01 mol) and 4.5 cm3 of 1-methylpiperazine (0.04 mol) in solution in 30 cm3 of dimethylsulphoxide, were heated at 110° C. for 4 hours. After cooling, the solution was diluted with 250 cm3 of water. The precipitate formed was filtered off, washed with water and recrystallised from 50 cm3 of methyl cellosolve. 1.3 g of 6-bromo-1-ethyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 209C (decomposition), were obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:37][CH3:38])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=1[CH:35]=O)=[O:28])[CH3:22]>C(O)C.N1CCCCC1>[CH2:37]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18])=[O:28])[CH3:38]
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (28 mg, 22%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C@@H:17]3[CH2:21][C@H:20]([CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)[CH2:19][N:18]3[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:4].[Cl:39]N1C(=O)CCC1=O>C(#N)C.CN(C)C=O>[Cl:39][C:13]1[N:14]=[C:15]([C@@H:17]2[CH2:21][C@H:20]([CH:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)[CH2:19][N:18]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:16][C:12]=1[C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)OC(C)(C)C)[nH]2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)OC(C)(C)C)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of the compound prepared in Example 64 (2.41 g, 4.4 mmol) in acetonitrile (50 mL) and N,N-dimethylformamide (20 mL) at 0° C. was added N-chlorosuccinimide (0.62 g, 4.6 mmol). The reaction was warmed to room temperature, stirred under nitrogen overnight then heated between 50-70° C. for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue washed with aqueous sodium bicarbonate solution (1×50 mL). The solid residue was suspended in a mixture of ethyl acetate (100 mL) and dichloromethane (100 mL) and sonicated. The solids were collected by filtration to give the title compound (1.39 g) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: C1CNCCN1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Solvent: CC#N
Product: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Yield: 87.8 %

Procedure:
A solution of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (2.52 g, 11.0 mmol) and piperazine (2.83 g, 32.8 mmol) in acetonitrile (30 mL) was heated to refluxed for 2 hours. The solvent was removed by evaporation, the residue was dissolved in water (50 ml) and extracted with dichloromethane (3×100 mL). The organic extract was dried over anhydrous Na2SO4 and then evaporated. The residue was passed through a pad of silica gel and concentrated to give 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (2.68 g, 88% yield). MS (ES+) m/z 278 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CC(C)(C)C(Cl)=O.[CH2:43]([C@@H:50]1[CH2:54][O:53][C:52](=[O:55])[NH:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Li]CCCC>C1COCC1>[CH2:43]([CH:50]1[CH2:54][O:53][C:52](=[O:55])[N:51]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minute and 0° C. at 1 h. The white solid was filtered off to receive the anhydride in the filtrate which was cooled back to −78° C. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred at −78° C. for 45 min. This metalated chiral auxiliary was cannulated to the anhydride at −78° C. and warmed to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minute and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([C:10]1[S:11][C:12]([S:28][CH3:29])=[C:13]([S:15]([C:18]2[CH:26]=[C:25]([Br:27])[C:21]3[N:22]=[CH:23][NH:24][C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:33]=1[CH2:34]Br.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([C:10]1[S:11][C:12]([S:28][CH3:29])=[C:13]([S:15]([C:18]2[CH:26]=[C:25]([Br:27])[C:21]3[N:22]([CH2:34][C:33]4[CH:36]=[C:37]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:39][C:32]=4[F:31])[CH:23]=[N:24][C:20]=3[CH:19]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([C:10]1[S:11][C:12]([S:28][CH3:29])=[C:13]([S:15]([C:18]2[CH:26]=[C:25]([Br:27])[C:21]3[N:22]=[CH:23][N:24]([CH2:34][C:33]4[CH:36]=[C:37]([N+:40]([O-:42])=[O:41])[CH:38]=[CH:39][C:32]=4[F:31])[C:20]=3[CH:19]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2nc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2c(c1)ncn2Cc1cc([N+](=O)[O-])ccc1F
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3cc([N+](=O)[O-])ccc3F)c2c1
Temperature: 40 °C
Yield: 17.7 %

Procedure:
A solution of {[4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((from above step c) 0.132 g, 0.248 mmol) in dry DMF (3 mL) was treated with 2-fluoro-5-nitrobenzylbromide (0.087 g, 0.373 mmol) and diisopropylamine (0.070 mL, 0.497 mmol) and heated to 40° C. 24 h. The solution was diluted with EtOAc and washed well with water (4×35 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the products ({4-[7-bromo-1-(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester and ({4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (0.015 g, 9%) as a brown solid. C25H23BrFN5O6S3: 684.00 (M+1) found 684.60.
Reaction SMILES: Cl.[CH2:2]([NH:5][O:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH3:4].N1C=CC=CC=1.[Br:16][CH2:17][C:18](Br)=[O:19]>C(#N)C>[CH2:2]([N:5]([O:6][CH2:7][CH2:8][CH3:9])[C:18](=[O:19])[CH2:17][Br:16])[CH2:3][CH3:4]
Reactant: CCCNOCCC
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCON(CCC)C(=O)CBr
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 197.8 %

Procedure:
N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to −20° C. Pyridine (0.2 mL) was added. Bromoacetyl bromide (0.15 g) was added dropwise over 5 min. The solution was stirred at −20° C. for 30 min. The bath was removed and the solution was stirred for 6 hours at room temperature. The solvent was removed in vocuo and the residue taken up in EtOAc (50 mL) and washed with water (1×25 mL), 1N phosphoric acid (3×25 mL), and brine (1×25 mL). The organic layer was dried with sodium sulfate and evaporated to give a dark orange oil (0.35 g). The product is a mixture of chloro- and bromoacetamides in a ratio of ˜3:1.
Reaction SMILES: N([CH2:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:17]=3)=[CH:12][CH:11]=2)=[N:7][N:6]=1)=[N+]=[N-].C(N(CC)CC)C.Cl.[CH:37]1(CC(=N)OCC)[CH2:39][CH2:38]1>C(O)C>[CH:26]1([NH:25][C:23]([C:18]2[CH:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:8]4[O:9][C:5]([CH2:4][CH:37]5[CH2:39][CH2:38]5)=[N:6][N:7]=4)=[CH:15][CH:14]=3)[C:21]([CH3:22])=[CH:20][CH:19]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Reactant: CCOC(=N)CC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CC3CC3)o2)cc1

Procedure:
4′-[5-(Azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 44) (40 mg), triethylamine (0.051 ml) and ethyl 2-cyclopropylethanimidate hydrochloride (23 mg) in ethanol (3 ml) were heated at 80° C. for 16 hours. The ethanol was removed under vacuum, the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient. Evaporation of the solvent from the product fractions gave N-cyclopropyl-4′-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]1[C:12]([O:14]CC)=O.C(=O)([O-])O.[Na+].[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[CH2:22]([N:28]1[CH2:2][CH:3]2[CH:4]([CH:5]2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]1=[O:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CBr)C1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1CC2C(C1=O)C2c1ccccc1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-3-phenylcyclopropanecarboxylate (Preparation 26, 65 mg, 0.22 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (30 mg, 0.36 mmol) and hexylamine (33 μl, 26 mg, 0.26 mmol), and the mixture was heated to 150° C. for 3 h. The mixture was cooled, water (30 ml) was added, and the mixture was extracted with diethyl ether (2×30 ml). The extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was purified by silica column (5 g) chromatography eluting with 4:1 dichloromethane:ethyl acetate. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (45 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[CH2:23][CH2:24][NH:25][CH:26]4[CH2:35][CH2:34][CH2:33][C:32]5[N:31]=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:28][C:27]4=5)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:43]=1.I[CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=4[CH2:23][CH2:24][N:25]([CH2:45][CH2:46][C:47]4[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=4)[CH:26]4[CH2:35][CH2:34][CH2:33][C:32]5[N:31]=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[CH:28][C:27]4=5)=[CH:41][CH:42]=3)=[N:7][C:6]=2[CH:43]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 375 mg (0.63 mmol) of ethyl 5-{[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]-oxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 117A), 272 mg (0.94 mmol) of methyl 4-(2-iodoethyl)benzoate and 99 mg (0.94 mmol) of anhydrous sodium carbonate in 10 ml of dry acetonitrile was stirred overnight at a bath temperature of 110° C. A further 272 mg of methyl 4-(2-iodoethyl)benzoate and 99 mg of sodium carbonate were then added, and the mixture was once more heated under reflux overnight. Another 272 mg of methyl 4-(2-iodoethyl)benzoate and 99 mg of sodium carbonate were then added, and the mixture was again heated under reflux overnight. After cooling of the reaction mixture, ethyl acetate and water were added, the organic phase was separated off and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1→2:1). This gave 324 mg (0.42 mmol, 68% of theory) of the target compound.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].Cl.[CH2:6]([C:13]1([OH:42])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[CH2:22][NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[ClH:4].[CH2:6]([C:13]1([O:42][C:1](=[O:3])[CH3:2])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[CH2:22][NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NCC(CCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1(Cc2ccccc2)CCN(CCC(CNC(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
0.12 g of acetyl chloride is added to 0.4 g of N-[4-(4-benzyl-4-hydroxypiperidyl)-2-(3,4-dichlorophenyl)butyl]-2,4-dichlorobenzamide hydrochloride (Compound 7), obtained according to Example 1, dissolved in 10 ml of dichloromethane in the presence of two equivalents of triethylamine.
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH3:10])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([CH2:12][CH2:13][C:14]1([CH3:16])[O:8][CH2:7][C:4]([N+:1]([O-:3])=[O:2])([CH2:9][CH3:10])[CH2:5][O:6]1)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCC(CO)(CO)[N+](=O)[O-]
Reactant: CCCCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)CCC1(C)OCC(CC)([N+](=O)[O-])CO1
Yield: 90 %

Procedure:
7.46 g of 2-nitro-2-ethyl-1,3-propanediol, 8.61 g of butyl levulinate, 50 mg of p-toluenesulfonic acid in 50 ml of toluene was refluxed until no more water separated. The reaction mixture was cooled, washed with 2% sodium bicarbonate and water, dried and concentrated to give 13.65 g of 2-carbobutoxyethyl-2-methyl-5-nitro-5-ethyl-1,3-dioxane as a light yellow oil. This was dissolved in 50 ml of ethanol and hydrogenated over 1 g Raney Nickel catalyst at 60 under pressure. Distillation of the crude material at 160° C./3mm gave 11 g of the product.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:26])([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]([O-:16])=[O:15].[CH2:27](N(CC)CC)C>C(Cl)Cl>[CH3:12][C:13]([CH3:26])([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:22][CH2:21]1)[C:14]([O:16][CH3:27])=[O:15]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(CCCN1CCNCC1)C(=O)[O-]
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CCCN1CCN(C(=O)C=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cinnamoyl chloride (3.32 g) in methylene chloride (25 ml) is added dropwise to a solution of methyl, α,α-dimethyl-1-piperazinepentanoate (4.56 g) in methylene chloride (25 ml) containing triethylamine (2.0 g) and the mixture is stirred overnight at room temperature. The solution is washed with water, dried, and distilled to yield the product methyl α,α-dimethyl-4-(1-oxo-3-phenyl-2-propenyl)-1-piperazine pentanoate, mp 76° following crystallization from isopropyl ether.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([OH:23])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH3:11])=[CH:14][C:15]=1[O:23][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]

Procedure:
A solution of 2-fluoronitrobenzene (3.978 g, 28.19 mmol), methyl 4-methoxysalicylate (5.131 g, 28.15 mmol), and potassium carbonate (7.800 g, 56.43 mmol) in DMF (30 mL) was warmed to 50° C. overnight. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The water was extracted twice more with dichloromethane and the combined organic extracts washed with brine and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound 1-1 as a pale yellow oil.