Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:59]([C:63]1[CH:71]=[CH:70][C:66]([C:67](O)=[O:68])=[CH:65][CH:64]=1)([CH3:62])([CH3:61])[CH3:60]>CCOC(C)=O.C1COCC1>[C:59]([C:63]1[CH:64]=[CH:65][C:66]([C:67]([N:14]2[CH2:15][CH2:16][C:10]3([O:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11]3)[CH2:12][CH2:13]2)=[O:68])=[CH:70][CH:71]=1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: c1ccc(C2=NOC3(CCNCC3)C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)N2CCC3(CC2)CC(c2ccccc2)=NO3)cc1
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene (E) was slowly added as a hydrochloride salt (250 mg) to a solution of N-ethyldiisopropylamine (560 μl, 3 mmol), 1-hydroxybenzotriazole hydrate (133 mg, 1 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (318 mg, 1 mmol) and 4-tert-butylbenzoic acid (176 mg, μmol) in abs. THF (8 ml). The reaction mixture was stirred overnight and diluted with EtOAc. The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. NaCl solution and sat. aq. NH4Cl solution and the solvent removed under vacuum. The desired product (4-tert-butylphenyl)-(3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)methanone was obtained in a yield of 0.42 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25]O)[S:23][CH:24]=1)=[CH:16][CH:15]=3.C(N(S(F)(F)[F:38])CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][F:38])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CF)n4)ccc3n(C)c21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
150 mg (0.319 mmol) of compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 3 ml of CH2Cl2. 51 μl of (diethylamino)sulphur trifluoride (DAST) are added at 0° C. The mixture is stirred at 0° C. for 2 hours. A further 100 μl of DAST are added (presence of starting product) and the mixture is left to stir at ambient temperature for a further 16 hours. H2O is added, the mixture is extracted with CH2Cl2, and the organic phase is dried over MgSO4, filtered and concentrated to dryness, adsorbing onto silica. Purification is carried out on a silica column, elution being carried out with EtOAc/40% cyclohexane and then with EtOAc/30% cyclohexane. The residue is taken up in MeOH and the precipitate is filtered off, and washed with MeOH and then with a minimum amount of Et2O.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.Cl.[C:26]([O-])(O)=[O:27].[Na+]>C1COCC1.C(O)C.CN(C=O)C>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[C:21]([CH:26]=[O:27])[CH:22]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(Cl)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1nnc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium is added dropwise at −75° C. to a solution of 2,2,6,6-tetramethyl-piperidine in THF. The solution is stirred at 0° C. for 30 minutes. After cooling to −75° C., a solution, precooled to −75° C., of 3-chloro-6-methoxypyridazine in THF is added dropwise. The reaction is stirred at −75° C. for 30 minutes. Subsequently, DMF precooled to −75° C. is added dropwise, and the mixture is stirred at −75° C. for a further 90 minutes. A mixture of conc. aqueous HCl (5 ml), ethanol (20 ml) and THF (25 ml), is added to the reaction mixture, which is warmed to room temperature, and saturated aqueous NaHCO3 solution is slowly added. THF is removed in a rotary evaporator, and the aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried with MgSO4 and filtered, and the solvent is removed in a rotary evaporator. The residue is purified on silica gel (eluent ethyl acetate in heptane). MS (Cl+) m/z 172 (M+).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.N>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Solvent: O
Product: Nc1cccc2c1C(=O)c1cc([N+](=O)[O-])ccc1C2=O
Yield: 90 %

Procedure:
A suspension of 317 g of 1,7-dinitroanthraquinone (94%) in 2 liters of water was stirred with 340 g of ammonia (molar ratio 20 : 1; pressure 40 atms) in an autoclave for a period of 2 hours at a temperature of 180° C. After venting, the reaction mixture was filtered under suction at room temperature. The mother liquor was recycled, whilst the residue was dried. Yield: 274 g of a 90% 1-amino-7-nitroanthraquinone (92% of the theoretical yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[C:18]([O:23][CH3:24])(=[O:22])[CH:19]1[O:21][CH2:20]1>CN(C=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:20][CH:19]([OH:21])[C:18]([O:23][CH3:24])=[O:22])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: COC(=O)C1CO1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
3,6-Dibromocarbazole (0.300 g, 0.923 mmol) was dissolved in DMF (1.2 mL) and cooled to 0° C. NaH (60% dispersion in mineral oil, 0.074 g, 1.846 mmol) was added and the reaction stirred for 1 h at 0° C. Methyl glycidate (0.471 g, 4.615 mmol) was added and the reaction was stirred and warmed to ambient temperature over 3.5 h. Upon completion by TLC the reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography (SiO2, 0-30% EtOAc/Hexane) to afford the desired product (125 mg, 32%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Br:61][CH2:62][C:63](=[O:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66].[OH-].[Na+]>>[Br:61][CH2:62][C@@H:63]([OH:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66]
Reactant: CCOC(=O)CC(=O)CBr
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CBr
Temperature: 30 °C
Reaction time: 13 h
Yield: 89.1 %

Procedure:
The recombinant E. coli HB101(pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 1.3 g, 3.2 mg of NADP, and then 1 g of ethyl 4-bromoacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 18 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel chromatography, to obtain 900 mg of ethyl (S)-4-bromo-3-hydroxybutyrate. The optical purity of the ethyl (S)-4-bromo-3-hydroxybutyrate was analyzed as follows and found to be 100% e.e. That is, the sample was converted to a carbamate using phenyl isocyanate under the presence of pyridine and the optical purity of the carbamate was measured by an HPLC method. 1H-NMR(CDC13)δ(ppm): 1.38(3H,t), 2.75(2H,m), 3.28(1H,br), 3.51(2H,m), 4.18(3H,q), 4.25(1H,m); Column: Chiralcel OJ (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/2-propanol of 9/1: Flow rate: 0.8 ml/min.; Detection: 254 nm; Elution time: 24.2 minutes for (S), 27.8 minutes for (R).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:6]=2.[CH2:32]([O:39][C:40]1C=CC2C3N(CC(N(C(C)C)C(N)=O)(C)C)C(COCC)=NC=3C=NC=2[CH:49]=1)[C:33]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])([CH3:16])[CH3:15])[C:33]([CH2:32][O:39][CH2:40][CH3:49])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N(C(N)=O)C(C)C
Reactant: CC(C)NC(=O)NC(C)(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C

Procedure:
The material from Part B was combined with N-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea from another experiment, suspended in toluene, and concentrated under reduced pressure. The N-(2-{[3-amino-7-(benzyloxy)quinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea (4.57 g, 10.8 mmol) was converted into N-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N-isopropylurea using the method described in Part D of Example 45. The crude product was purified using flash chromatography (silica gel, elution with 6% methanol in dichloromethane) to afford 3.81 g of N-{2-[7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea as an off white solid.
Reaction SMILES: [OH-].[K+].C([O:6][C@H:7]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])(=O)C.O.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:6][C@H:7]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17]
Reactant: CC(=O)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1N[C@H](c2ccccc2)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a mixture of 200 mL of THF and 280 mL of 1 M aqueous potassium hydroxide solution at 0° C. was added a solution of 4.59 g (22.4 mmol) of cis-3-acetoxy-4-phenylazetidin-2-one in 265 ml of THF via a dropping funnel over a 40 min period. The solution was stirred at 0° C. for 1 h and 100 mL of water and 100 mL of saturated sodium bicarbonate were added. The mixture was extracted with four 200 mL portions of ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to give 3.54 g (97%) of racemic cis-3-hydroxy-4-phenylazetidin-2-one as white crystals, m.p. 147°-149° C. This material was resolved into its enantiomers by recrystallization of its 2-methoxy-2-(trifluoromethyl)phenylacetic ester from hexane/acetone followed by hydrolysis [α]25Hg 177° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[S:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=S)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reaction time: 1 h

Procedure:
To a suspension of 35 in toluene is added Lawesson's Reagent. The suspension is heated at reflux while stirring for 1 h. The reaction mixture is cooled over ice to precipitate the product. The product is then filtered, washed with hexane, and dried to give 156.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:22](Br)[CH3:23])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]21[O:21][CH2:20][CH2:19][O:18]2>O.CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:22]([CH3:23])[C:1]#[N:2])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]21[O:21][CH2:20][CH2:19][O:18]2
Reactant: [C-]#N
Reactant: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C#N)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
7.35 g of sodium cyanide were dissolved in 10 ml of water under heat, incorporated with 60 ml of dimethylsulfoxide, cooled to room temperature and then incorporated with a solution of 51 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethyl bromide in 90 ml of dimethylsulfoxide. The reaction mixture obtained was agitated at 70° C. for one hour, thereafter incorporated with water and extracted with ethyl acetate. The extract was washed with water, dried and then freed of the solvent at a reduced pressure to obtain a residue. The thus obtained residue was adhered to a silica gel-packed column and then eluted with isopropyl ether hexane (2/1). The eluate obtained was freed of the solvent thereby to obtain 32.7 g of 2-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]propionitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13]CC)=O)=[C:9]([NH2:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31](Cl)[C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:11](=[O:13])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][CH:28]=3)[C:31]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[N:16][C:9]=2[N:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(N)c1C(=O)OCC
Product: CCOC(=O)c1nn(-c2ccccc2)c2nc(-c3ccc(-c4ccccc4)cc3)n(-c3ccc(Cl)cc3)c(=O)c12

Procedure:
6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid ethyl ester is prepared from 5-amino-1-phenyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester and N-(4-chloro-phenyl)-biphenyl-4-carboximidoyl chloride by following a similar procedure as described in example 2 and purified by preparative LC/MS. 1H NMR (CDCfe) δ(ppm) 8.14(d, 2H), 7.36˜7.57(m, 12H), 7.33(d, 2H), 7.14(d, 2H), 4.53(q, 2H), 1.46(t, 3H); HPLC-MS calculated for C32H23ClN4O3 (M+H+): 547.2. Found: 547.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH2:23]([N:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[CH:31]=[N:30][C:29]=2[C:28]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:27]1)[CH:24]=[CH2:25]>C1COCC1>[CH2:23]([N:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[CH:31]=[N:30][C:29]=2[C:28]([C:37]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:42])[C:38]([F:41])([F:39])[F:40])=[CH:27]1)[CH:24]=[CH2:25]
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: C=CCn1cc(C(=O)C(F)(F)F)c2ncn(C)c(=O)c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (94 mg, 0.32 mmol, 1.1 equiv.) in 1.5 mL of THF was added n-BuLi (2.5 M in hexanes, 0.13 ml, 0.32 mmol, 1.1 equiv.) followed by a chilled (−78° C.) solution of 5-allyl-3-methyl-7-(2,2,2-trifluoro-acetyl)-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (83 mg, 0.29 mmol, 1 equiv.) in 1 mL of THF. After 15 minutes, the mixture was quenched with water, warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hex (0-60% gradient) to provide 44 mg (30%) of the title compound as a yellow foam. MS m/z 498.31 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(C2CC(=NNC(=N)N)c3c(C)coc3C2)cc1
Yield: 72.2 %

Procedure:
A mixture of 3-methyl-6-(4-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml) and ethanol (30 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(4-methylphenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 33) (0.30 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[NH:5][C:6]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[NH:5][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(-c2ccccc2[N+](=O)[O-])[nH]c1-c1cccnc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2N)[nH]c1-c1cccnc1
Yield: 94.7 %

Procedure:
A mixture of 4-methyl-2-(2-nitrophenyl)-5-(3-pyridyl)imidazole (4.99 g) and 10% palladium on carbon (1.0 g) in a mixture of tetrahydrofuran (150 ml) and methanol (150 ml) was hydrogenated at ambient temperature under atmospheric pressure of hydrogen gas. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 2-(2-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (4.22 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32]C)=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC(c4ccccn4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC(c4ccccn4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[4-(pyridin-2-yl)piperidin-1-yl]quinoxaline-6-carboxylate (84 mg, 0.19 mmol) in methanol (30 ml) and water (1.0 ml) was added sodium hydroxide (30 mg, 0.75 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 ml), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-3-[4-(pyridin-2-yl)piperidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (61.1 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>CCCCCC>[CH2:1]([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([Cl:18])=[O:15])[CH3:12])[CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Product: CCC[C@H](N[C@@H](C)C(=O)Cl)C(=O)OCC
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
To a slurry of N-[1-(S)-ethoxycarbonyl-1-butyl]-(S)-alanine (III, 1.5 g, 0.0069 moles) in n-hexane (10 ml) was purged dry hydrogen chloride gas at 25-30° C. under agitation. To this was added finely grounf phosphorous pentachloride (1.8 g, 0.0086 moles) in four lots, each after an interval of 10 mns. After the complete addition the reaction mixture was agitated for 1.5 hrs. The solid precipitated was filtered, washed with hexane to give 1.88 g of the title compound (I).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[F:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[F:18])[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: OCCc1ccc(O)cc1
Product: OCCc1ccc(Oc2ccc(F)c(Cl)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D120 starting from 4-(2-hydroxyethyl)phenol and (3-chloro-4-fluorophenyl)boronic acid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:10]([NH2:11])=[C:9]([I:17])[CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:10]([NH:11][CH3:19])=[C:9]([I:17])[CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(I)c(N)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNc1c(I)cc(-c2c(C)noc2C)cc1[N+](=O)[O-]
Yield: 59.3 %

Procedure:
To a flask containing 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline (1000 mg, 2.78 mmol, 1 equiv) was added DMF (15 mL, 0.2 M), cesium carbonate (1.4 gm, 4.17 mmol, 1.5 equiv.) and idomethane (260 μL, 4.17 mmol, 1.5 equiv). After an hour, the reaction was quenched with water and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Purification was carried out by flash column chromatography to furnish 4-(3,5-dimethylisoxazol-4-yl)-2-iodo-N-methyl-6-nitroaniline (615 mg, 60%). 1H NMR (400 MHz, cdcl3) δ 7.81 (t, J=3.0 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 2.97 (s, 3H), 2.40 (d, J=16.8 Hz, 3H), 2.26 (d, J=14.2 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:17][C:18](=O)[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>CCOCC>[CH2:7]([NH:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCNC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCNCC

Procedure:
15.4 g of lithium aluminium hydride were suspended in 300 ml of abs. ether under reflux. 61 g of N-decylacetamide (product of a) were dissolved in 300 ml of ether and the solution was added dropwise in the course of 2 hours to the solution heated to reflux. The heterogeneous mixture was stirred under reflux for 15 hours. Then 32 ml of water were added dropwise at room temperature in the course of 1 hour. After stirring for 30 minutes, the solid was collected by suction filtration and washed repeatedly with ether. The filtrate was evaporated and the residue distilled in a high vacuum. Yield: 35 g of a fraction with a boiling point of 62°-64° C. (0.2 torr).