Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:9](=O)[CH2:10][CH2:11][C:12]([O-:14])=[O:13])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16]([NH2:19])(=[S:18])[CH3:17].[CH2:20](O)[CH3:21]>>[CH3:17][C:16]1[S:18][C:10]([CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13])=[C:9]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:19]=1
Reactant: CCO
Reactant: CC(N)=S
Reactant: CCOC(=O)CC(Br)C(=O)CCC(=O)[O-]
Product: CCOC(=O)CCc1nc(C)sc1CC(=O)OCC
Temperature: 25 °C
Reaction time: 70 h
Yield: 54 %

Procedure:
The crude product obtained in step (a) is dissolved in anhydrous ethanol (150 ml) with thioacetamide (37.5 g; 0.5 mole). The mixture is stirred for 70 hours at room temperature, after which the ethanol is distilled off and the residue is taken up into water and ethyl ether. The ether phase is repeatedly extracted with 2 N sulfuric acid, and is then combined with the aqueous phase. The latter is adjusted to pH 7: the oil which separates is extracted with ether and distilled under reduced pressure: b.p.0.2 =135°-140° C.; Weight: 78.5 g. Overall yield: 54%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[CH:33]=[CH:32][C:29]([C:30]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2ccnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 28.9 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-morpholin-4-yl-benzaldehyde (36.9 mg, 0.193 mmol) were reacted to produce 24 mg (29%) of the title compound. mp: 240-244° C., 1H NMR (300 MHz, DMSO-d6): 12.83 (s, 1H), 8.00 (d, J=8 Hz, 2H), 7.86 (d, J=8 Hz, 1H), 7.66 (s, 1H), 7.16 (s, 1H), 7.06 (d, J=8 Hz, 2H), 6.77 (d, J=8 Hz, 1H), 6.38 (d, J=8 Hz, 1H), 6.33 (s, 2H), 3.88 (br s, 1H), 3.76 (s, 4H), 3.31 (s, 3H), 2.87 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 431 (M+H), HPLC: 1.99 min (G method).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
116.3 g (0.61 mol) of decanoyl chloride were heated to 125° C. in 300 ml of xylene, and 69.1 g (0.5 mol) of 4-hydroxybenzoic acid were introduced in portions over the course of six hours. The batch was subsequently stirred at 125° C. for one hour, cooled to room temperature, and filtered with suction, and the solid product was washed three times with 45 ml of xylene. The yield after drying under reduced pressure at 100° C. was 108.4 g (74% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid, but contained 0.4% by weight of byproducts such as dimers and trimers of the para-hydroxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]3[CH2:26][CH2:25][CH2:24][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]=[C:19](N(C)C)[CH3:20])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][NH2:30]>C(O)(=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]3[CH2:26][CH2:25][CH2:24][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:29]([CH3:28])[N:30]=[C:19]([CH3:20])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CC(=NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2)N(C)C
Solvent: CC(=O)O
Product: Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n(C)n1
Reaction time: 1.75 h

Procedure:
A mixture of 3.96 g (10.3 mmol) of (S)-8-chloro-N-[1-(dimethylamino)ethylidene]-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide, 25 ml of glacial acetic acid and 0.65 ml (12.4 mmol) of methylhydrazine is stirred at 90° for 1.75 hours. The solution is then evaporated in vacuo and the residue is chromatographed on silica gel while eluting with ethyl acetate/methanol (19:1). After recrystallization from methylene chloride/ethyl acetate there is obtained (S)-8-chloro-1-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 221°-222°.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:10]1[C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1])([O-:14])=[O:13]
Reactant: COc1ccc(C=O)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1c(O)cc(C=O)cc1[N+](=O)[O-]
Temperature: 27.5 °C
Yield: 65 %

Procedure:
Isovanillin (500 gm) and acetic acid (1750 ml) were cooled to −5 to 0° C. To this solution, nitric acid (750 ml) was charged slowly at −5 to 0° C. with stirring. The temperature of the reaction mass was slowly raised to 25-30° C. and maintained for 12 hours. The reaction mass was quenched into ice water (4 kg), the solids filtered and washed with water (2 lt). The solids were stirred with a 1% sodium bicarbonate solution (1 lt), filtered and dried at 45-50° C. The solid was dissolved in 6 volumes of ethyl acetate, ethyl acetate was distilled off up to half the volume and 3 volumes of n-Hexane were charged slowly at 45-50° C. The reaction mass was cooled slowly to 0-5° C., maintained for 1 hour, the solids filtered, washed with 0.5 volumes of 1:1 mixture of ethyl acetate:n-Hexane and dried at 45-50° C. to yield the title compound (423 gm, 65% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13]CC=C)[CH:9]=[CH:8]2)[CH3:2].[C:18]1(C)[C:19](C)=CC=C[CH:23]=1>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>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:19][CH:18]=[CH2:23])[C:10](=[O:13])[CH:9]=[CH:8]2)[CH3:2]
Reactant: Cc1ccccc1C
Reactant: C=CCOc1ccc2ncc(F)c(CC)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCn1c(=O)ccc2ncc(F)c(CC)c21
Temperature: 150 °C
Yield: 27 %

Procedure:
8-Ethyl-7-fluoro-2-(2-propen-1-yloxy)-1,5-naphthyridine (0.660 g, 2.84 mmol) was dissolved in xylene (14 ml) at rt under argon, whereupon tetrakis(triphenylphosphine)palladium (0.329 g, 0.284 mmol) was added. The reaction was then heated to 150° C. for 30 mins. Reaction was then cooled, a solid then precipitated out which was filtered. The filtrate was then purified by column chromatography on silica gel eluting with 0-100% EtOAc in hexane then 0-20% MeOH in EtOAc gradient to give title compound as a white solid (0.181 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Br:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:39]([C:38]1[CH:42]=[CH:43][C:35]([Br:34])=[CH:36][CH:37]=1)=[O:40])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Br)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-bromobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-bromophenyl 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 664/666 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (d, J=4.2 Hz, 2H), 4.30 (ddd, J=10.0, 4.3 and 4.2 Hz, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.58 (t, J=9.6 Hz, 1H), 5.93 (t, J=9.4 Hz, 1H), 6.33 (d, J=9.0 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.73-7.77 (m, 4H), 7.80 (d, J=8.2 Hz, 1H), 8.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](O)=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]([N:25]([O:26][CH3:27])[CH3:24])=[O:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)O)c(-c2cccc(F)c2)c2ncccc12
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a mixture of 8-(3-fluorophenyl)-5-vinylquinoline-7-carboxylic acid (66 mg, 0.22 mmol), N,O-dimethylhydroxylamine hydrochloride (32.9 mg, 0.338 mmol) in N,N-dimethylformamide (0.4 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.149 g, 0.338 mmol). After stirring at room temperature for 30 minutes, N,N-diisopropylethylamine (0.118 mL, 0.675 mmol) was added to the resulting mixture. The reaction was stirred at room temperature overnight, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The resdiue was purified on silica gel, eluting 0 to 50% ethyl acetate in hexane, to give the desired product (32 mg, 42%). LCMS calculated for C20H18FN2O2 (M+H)+: m/z=337.1; Found: 337.1.
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:20](O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH3:20][C@@H:6]1[CH:7]=[C:8]2[C@@H:18]([CH2:17][C@H:16]3[C:19]4[C:13](=[CH:12][CH:11]=[CH:10][C:9]2=4)[NH:14][CH2:15]3)[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCN1CCC[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: CC[SiH](CC)CC
Product: CCCN1C[C@H](C)C=C2c3cccc4c3[C@@H](CN4)C[C@H]21
Yield: 7 %

Procedure:
A mixture of 1.5 g (6.7 mmol) of 6-desmethyllysergine (prepared by the N-demethylation of lysergine by cyanogen bromide), 1.8 g (13 mmol) of anhydrous potassium carbonate, 2.2 g (13 mmol) of 1-iodopropane and 50 ml of dry dimethylformamide was stirred for 42 hours. The solvent was evaporated in vacuo and the residue was digested with two 75 ml portions of ether and then filtered. The ether extracts were evaporated and the resulting solid residue was suspended in cold ether and collected by filtration to give 0.72 g (40%) of single spot material by thin layer chromatography (methanol:chloroform, 1:9). The NMR of the material was consistent with that expected for 6-propylergoline. Reduction was accomplished as described previously by stirring a mixture of 5 ml TFA, 1.3 g (11.1 mmol) of triethylsilane and 0.72 g (2.7 mmol) of 6-propyllysergine for 6 hours. The resultant was worked up as described above and gave 0.05 g of the title compound (7%) following HPLC and recrystallization from methanol/petane, mp. 135°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CC(O)=O.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1Cl
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
4-Amino-2-(2-chloro-phenylamino)-3-fluoro-5-nitro-benzoic acid methyl ester 5b (0.30 g, 0.88 mmol) is suspended in AcOH (5 mL) and zinc dust (0.29 g, 4.42 mmol) is added. After 15 minutes, the reaction is complete. The reaction mixture is diluted with ethyl acetate and filtered through Celite. The filtrate is washed with water, saturated NaHCO3, 10% K2CO3 and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 0.13 g (48%) pure desired product as a whitish brown foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:31])([F:30])[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:17]([F:31])([F:30])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1ccc(OCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
To a solution of 4-benzyloxyphenol (5 g) and 2,2,2-trifluoroethyl-p-toluenesulphonate (5 g) in dimethylformamide (50 ml) was added sodium hydride (60% dispersion in oil, 2.3 g) and the solution heated to 110° C. for 16 h. The mixture was cooled, diluted with water and the product extracted into ethyl acetate. The organic phase was washed with water, brine and dried (MgSO4). The solvent was remove in vacuo and the residue chromatographed on silica gel (eluting with 10% diethyl ether/hexane) to give the the title compound as a solid, m.p. 72-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([O-:16])(=[O:15])[CH3:14].[NH4+:17].C(O)(=O)CC(O)=O>C(O)C>[NH2:17][CH:6]([C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:14][C:13]([OH:16])=[O:15]
Reactant: [NH4+]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Solvent: CCO
Product: COc1ccc(C(N)CC(=O)O)cc1OC
Temperature: 25 °C
Yield: 56 %

Procedure:
A stirred suspension of 3,4-dimethoxybenzaldehyde (131 grams, 788 mmol) and ammonium acetate (121.5 grams, 1576 mmol) in ethanol (95%, 400 mL) was heated to 45°-50° C. resulting in an orange solution. To this solution was added malonic acid (82.0 grams, 788 mmol) and the solution was refluxed overnight. A white solid precipitated on heating, the slurry was allowed to cool to room temperature and was filtered. The solid was washed with ethanol, air dried, and dried in vacuo (60° C.,<1 mm) to afford 3-amino-3-(3',4'-dimethoxyphenyl)propionic acid as a white solid, (100.14 grams, 56% yield), no further purification was carded out: mp 208.0°-210.0° C.; 1H NMR (D2 O/NaOD/TSP)δ7.08-6.91 (m, 3H), 4.22 (t, J=7 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.55 (dd, J=2, 7Hz, 2H); 13C NMR(D2 O/NaOD/TSP)δ182.9, 150.8, 149.8, 140.7, 121.6, 114.6, 112.8, 58.6, 55.4, 49.8.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][C:13]=1[C:31]([F:34])([F:33])[F:32].[NH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C(Cl)Cl>CO.C(O)(=O)C>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([CH2:27][NH:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][C:13]=1[C:31]([F:34])([F:33])[F:32]
Reactant: NCCCC(=O)O
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CNCCCC(=O)O)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (18 mg, 0.28 mmol) was added to a solution of 4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.25 mmol) and 4-aminobutanoic acid (0.25 mmol) in a mixture of methanol (3 mL), DCM (3 mL) and acetic acid (38 μl). The mixture was stirred at room temperature overnight and was filtered through a frit under positive pressure. The solvent was removed in vacuo and the residue purified by reverse phase HPLC to give the title compound as a off-white solid. LC/MS (Method A): 494 (M−H)−, 496 (M+H)+. HPLC (Method K) Rt=17.93 min (Purity: 93.64%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:25][C:26]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:27]=1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[Cl:40])=[O:29]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:35]([C:34]3[CH:38]=[CH:39][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:26]=4[CH3:25])=[C:32]([Cl:40])[CH:33]=3)=[O:36])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)Cl)cc1Cl
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A mixture of 1.0 g of 6,11-dihydro-5H-dibenz[b,e]azepine, 0.80 g of N,N-diisopropylethylamine and 2.01 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-3-chlorobenzoyl chloride in 100 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 1.79 g of the desired product as a crystalline solid, m.p. 254°-256° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH2:9](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>O.C(O)(=O)C>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][C:7]2[C:6]3[CH:5]=[CH:4][O:3][C:2]=3[N:1]=[CH:9][N:8]=2)=[CH:35][CH:34]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(CCN)cc1
Reactant: N#Cc1ccoc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CCNc2ncnc3occc23)cc1
Temperature: 130 °C

Procedure:
The 2-amino-3-cyanofuran produced in the preceding step was combined with 4.2 mL of triethylorthoformate, and 0.5 mL of acetic anhydride, and the mixture was heated to 130° C. for two hours. Then was added 1.8 g of sodium acetate and 3 g of 2-(4-methoxyphenyl)ethylamine, followed by 3 mL of acetic acid. The resulting mixture was heated for two hours at 130°-138° C., then cooled and diluted with water. The product was extracted with large volumes of ether. The ether extracts were combined, washed with water, dried over magnesium sulfate, and concentrated. The residue was recrystallized from ether and petroleum ether. Yield 0.65 g. M.P. 135°-136° C.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:32])=[O:14])[CH:10]=[CH:11][CH:12]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>CN(C=O)C>[CH2:33]([NH:35][C:36](=[O:37])[N:25]([C@H:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([C:13](=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=2)[C@@H:16]([CH3:32])[CH2:17]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:34]
Reactant: COc1cccc(C(=O)N2c3ccccc3[C@H](Nc3ccccc3)C[C@@H]2C)c1
Reactant: CCN=C=O
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCNC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccc(OC)c2)c2ccccc21
Temperature: 90 °C

Procedure:
(±)-Cis-3-ethyl-1-[1-(3-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-1-phenyl-urea was synthesized using general procedure A, substituting ethyl isocyanate for acetyl chloride using the following procedure. To a solution of (±)-cis-(3-methoxy-phenyl)-(2-methyl-4-anilino-3,4-dihydro-2H-quinolin-1-yl)-methanone in DMF was added ethyl isocyanate and reaction mixture was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated. Crude mixture was purified by flash chromatography on silica gel using gradient elution hexane-ethyl acetate (5-20%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]1.Cl.[NH2:16][CH:17]([CH2:23][SH:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH:8]1([C:12]([NH:16][CH:17]([CH2:23][SH:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(N)CS
Reactant: O=C(O)C1CCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (15 mL) was added to a suspension of cyclobutanecarboxylic acid (2.57 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DMF (40 mL). The resulting mixture was cooled in an ice bath and a solution of T3P (1.57M in THF, 20.6 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.20 g.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6]/[CH:7]=[C:8](\[CH3:15])/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[O:4].[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(OCC)C>[Cl-:1].[CH3:15]/[C:8](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:7]\[CH2:6][O:5][C:3](=[O:4])[CH2:2][N:19]1[CH:20]=[CH:21][N+:17]([CH3:16])=[CH:18]1
Reactant: Cn1ccnc1
Reactant: CC(C)=CCC/C(C)=C/COC(=O)CCl
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/COC(=O)Cn1cc[n+](C)c1
Product: [Cl-]
Temperature: 40 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Geraniol ester [2] (2.307 g, 10 mmol) and N-methylimidazole (0.821 g, 10 mmol) were mixed in and stirred in a sealed vessel at 40° C. for 24 hrs. A light-brown solid was formed and suspended in anhydrous diethylether. The solid precipitate was filtered, washed with diethylether and dried under reduced pressure (0.01 mbar) to give imidazolium chloride [3] in 67% yield as light-yellow hygroscopic solid. The product was pure according to 1H NMR and directly subjected to the next step without further purification. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=9.36 (s, 1H), 7.82 (s, 2H), 5.37 (s, 2H), 5.33 (t, J=7.0 Hz, 1H), 5.07 (s, 1H), 4.68 (d, J=7.1 Hz, 2H), 3.93 (s, 3H), 2.03 (m, 4H), 1.66 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=166.9, 142.6, 137.8, 131.1, 123.7, 123.6, 123.3, 117.8, 62.4, 49.4, 35.9, 25.8, 25.5, 17.6, 16.1. mp 160° C. (dec), T5%onset 125° C.