Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[O:3][C:4]1C=CC(N2C=NC(C3C=CC(C(CC)CC(N=[N+]=[N-])=O)=CC=3)=N2)=C[CH:5]=1.[N:32]([CH2:35][CH:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57]([F:60])([F:59])[F:58])=[CH:52][CH:51]=3)[N:46]=2)=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[C:33]=[O:34].[CH:61]([C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][C:65]=1[NH:71][C:72]([NH2:74])=[S:73])([CH3:63])[CH3:62]>>[CH:61]([C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][C:65]=1[N:71]1[C:4](=[O:3])[CH2:5][S:73]/[C:72]/1=[N:74]\[C:33]([NH:32][CH2:35][CH:36]([C:39]1[CH:40]=[CH:41][C:42]([C:45]2[N:49]=[CH:48][N:47]([C:50]3[CH:51]=[CH:52][C:53]([O:56][C:57]([F:59])([F:58])[F:60])=[CH:54][CH:55]=3)[N:46]=2)=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])([CH3:63])[CH3:62]
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: CCC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CCC(CN=C=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCC(CNC(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1 H-1,2,4-triazol-3-yl)phenyl)pentanoyl azide/3-(4-(1-isocyanatobutan-2-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C42a) and 1-(2-isopropyl-5-methylphenyl)thiourea and isolated as a pink solid (0.110 g, 43%).
Reaction SMILES: C([O-])([O-])=O.[Ca+2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH2:15])[C:9]=2[O:8][CH2:7]1.[I:16](Cl)(=O)=O.I(Cl)(=O)=O.C[N+](C)(C)CC1C=CC=CC=1>C(Cl)Cl.CO.O>[I:16][C:11]1[C:10]2[O:6][CH2:7][O:8][C:9]=2[C:14]([NH2:15])=[CH:13][CH:12]=1
Reactant: Nc1cccc2c1OCO2
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1ccc(I)c2c1OCO2
Temperature: 25 °C
Yield: 62.4 %

Procedure:
CaCO3 (3.9 g) was added to a mixture of 1,3-benzodioxol-4-amine (4.11 g) in DCM (40 ml) and CH3OH (20 ml). This mixture was stirred at room temperature. N,N,N-trimethyl benzenemethanaminium dichloroiodate (11.5 g) was added portionwise at room temperature. The resulting reaction mixture was stirred for 15 minutes at room temperature. The mixture was diluted with water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 80/20). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 3.5 g (46.9%) of 7-iodo-1,3-benzodioxol-4-amine (intermediate 2-a).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=1.I[CH3:21]>C1COCC1>[CH3:21][N:12]([CH2:11][C:10]#[C:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC#Cc1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 30 mg, 0.95 mmol) in anhydrous THF (3 mL) at 0° C. was added a solution of 47 (109 mg, 0.47 mmol) in anhydrous THF (2 mL) dropwise over 15 min. To the resultant solution was added a solution of iodomethane (150 μL, 2.42 mmol) in THF (5 mL) over 10 min, the ice bath was removed and the solution was stirred at ambient temperature for 16 h. The reaction was stopped by the addition of water (5 mL) and the aqueous fraction was extracted with EtOAc (3×20 mL), washed with water, dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 25/75, Rf=0.18) to afford the title compound 49 (69 mg, 60% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.65 (s, 1H), 8.52 (m, 1H), 7.69 (m, 1H), 7.24 (m, 1H), 4.29 (s, 2H), 2.97 (s, 3H), 2.97 (s, 9H); LRMS (ESI) m/z calcd for C14H19N2O2 [M H]+ 247. found 247.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17](F)=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].C([O:34]C(C1C2NC3C=CC(N)=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C.[H+].[B-](F)(F)(F)F.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:34])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(N)cc21
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
For the preparation of 9-fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester, to a stirred solution of 9-amino-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 41C) (0.024 g, 0.055 mmol) in 1.0 mL of MeCN was added 11 μL of 48% HBF4 water solution at −10° C. under N2 for 10 minutes. 9 μL of tBuONO (90%, 0.066 mmol) was added to the reaction mixture and stirred at −10° C. for 20 minutes. The reaction mixture was warmed to room temperature for 1 hour and monitored by LC-MS. The solvents were removed in vacuo, and the residue was washed with Et2O/hexane (1:1) once and benzene twice. After having dried in high vacuo for several hours, a brown solid was obtained. The solid in 1.5 mL of xylenes was heated at 145° C. reflux under N2 for 1 hour and then concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (0.012 g) as a light yellow solid. 1H-NMR (CDCl3): δ 10.68 (1H, s), 7.83 (1H, s), 7.62 (2H, m), 7.44 (1H, dd), 7.29 (1H, m), 7.13 (2H, m), 6.93 (1H, m), 4.23 (2H, q), 1.56 (6H, s), 1.22 (3H, t). MS (ESI): 425 (MH+).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:30])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH:4]1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])(CC)C.[CH2:36]([O:43][C:44]([C:46]([NH2:59])([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH:47]=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>O1CCCC1.C1CCCCC1>[C:49]([C:46]([NH2:59])([CH:47]=[CH:10][CH:4]1[C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:3]1([CH3:2])[CH3:30])[C:44]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:45])([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]
Reactant: CC1(C)CCC(C)(C)C1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(C=O)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C1C=CC(N)(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The 2,2,5,5-tetramethyl cyclopentylmethyl triphenylphosphonium bromide is suspended in tetrahydrofuran at 0° C. under argon. Sec-Butyllithium in cyclohexane is added followed by a solution of 2-benzyloxycarbonyl-2-CBZ-aminoacetaldehyde in tetrahydrofuran. After one hour, water is added to the reaction mixture. The organic layer is separated, washed with water and dried over MgSO4 and evaporated to yield the alkene, benzyl 2-CBZ-amino-4-(2,2,5,5-tetramethylcyclopentyl)-3-butenoate.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH2:45][CH3:46])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.NC(N)=S>>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH2:45][CH3:46])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: NC(N)=S
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC)CS[C@H]12)c1csc(N)n1
Yield: 69 %

Procedure:
191 mg of this benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-ethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate were then treated with 40 mg of thiourea, as described in Preparation 4, to give 117 mg of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, in the form of a pale pink powder, which was then treated with 1.5 ml of trifluoroacetic acid in a mixture of anisole and methylene chloride. When diisopropyl ether was added to the mixture, a precipitate was obtained and this was collected by filtration, to give 90 mg of 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C@H:12]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:14][C:15](O)=[O:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:46][C:47]([CH3:59])([CH3:58])[CH2:48][CH2:49][NH:50][CH2:51][C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1>ClCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([C@H:12]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:13][CH2:14][C:15]([N:50]([CH2:49][CH2:48][C:47]([CH3:59])([CH3:58])[CH3:46])[CH2:51][C:52]2[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=2)=[O:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCC(=O)O)C1CCCCC1
Reactant: Cn1ccnc1CNCCC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cn1ccnc1CN(CCC(C)(C)C)C(=O)CC[C@H](c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butyric acid (0.085 mg, 0.19 mmol) in dichloromethane (2.0 mL) was added isobutyl chloroformate (0.025 mL, 0.19 mmol) and N-methylmorpholine (0.021 mL, 0.019 mmol). The reaction mixture was stirred at this temperature for 0.5 h. The reaction mixture was then reacted with a solution of (3,3-dimethyl-butyl)-(1-methyl-1H-imidazole-2-ylmethyl)-amine (0.037 mg, 0.19 mmol) in dichloromethane (0.5 mL) and stirred at 0° C. for 0.5 h. To this reaction mixture was added CHCl3, and the resulting mixture was washed with H2O and saturated aqueous NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated in vacuo to yield crude material. The crude material was purified by silica gel column chromatography using 4% MeOH in CHCl3 to yield 4-(2-amino-6-phenoxy-quinolin-3-yl)-4-(S)-cyclohexyl-N-(3,3-dimethyl-butyl)-N-(1-methyl-1H-imidazol-2-ylmethyl)-butyramide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[CH:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(C(c2ccccc2)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1

Procedure:
A solution of 4-(4-chlorobenzhydryl)piperazine 1 (2 mmols) and chloro-(4-chlorophenyl)phenylmethane 21 (Aldrich, 2 mmols) in methylene chloride (10 mL) and Et3N (0.3 mL) is stirred under an inert atmosphere. The solution is warmed and the course of the reaction is followed by TLC. When the reaction is complete, dil. aq. Na2CO3 is added to the solution, shaken, and the layers are separated. The aqueous layer is extracted with additional CH2Cl2, the combined organic extracts are washed with half-saturated brine, dried (Na2SO4), filtered and concentrated under reduced pressure giving the crude product. The desired compound 1,4-bis-(4-chlorobenzhydryl)piperazine 22 is obtained by purification of the crude product with the use of HPLC.
Reaction SMILES: [OH-:1].[Na+].S(=O)(=O)(O)O.[C:8]([OH:11])(=O)[CH3:9]>>[OH:1][CH2:9][C:9]([C@@H:8]([C@H:8]([C@H:9]([CH2:8][OH:11])[OH:1])[OH:11])[OH:11])=[O:1]
Reactant: CC(=O)O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Yield: 85 %

Procedure:
Methanesulfonyl chloride (1.5 g) was added to a solution of 9 (1.2 g) in pyridine (2 ml). After being kept at room temperature for 2 days, ice was added and the mixture was extracted with chloroform. The organic layer was washed with water and evaporated to give methyl 4,6-O-isopropylidene-1,3-di-O-methanesulfonyl-α-L-sorbofuranoside as a syrup. The syrup was stirred in 60% acetic acid at 55° C. for 2.5 hours. The solution was brought up to pH about 10 with 10N sodium hydroxide and heated at 40° C. for 3 hours. The reaction mixture was neutralized with 10N sulfuric acid and concentrated. The residue was triturated with ethanol. After the salt was filtered off, the ethanol solution was concentrated and the residue was dissolved in a mixture of ethanol and 10N sulfuric acid (1:4). The solution was heated to 80° C. for 30 min. Ethanol was evaporated off and the mixture was heated for 5 minutes. The reaction mixture was neutralized with 10N sodium hydroxide and the salt was removed by repeated precipitation with ethanol. After filtration, the filtrate was concentrated to give L-fructose in more than 85% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:42](=O)[CH2:43][CH3:44].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:42][CH2:43][CH3:44])[CH2:26][CH2:27]2)=[CH:20][CH:21]=1
Reactant: CCC=O
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CCCN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.7 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), propionaldehyde (0.186 mL, 2.6 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 36 mg (70%) of the title compound as a yellow solid. MS (ESI) m/z 517 (M+H)+1.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:15]([N:12]1[CH:13]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]=[CH:11]1)[CH2:16][CH2:17][CH3:18]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cnc(-c2ccccc2)c1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
To the suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in 30 ml of anhydrous DMF is added a solution of 4-phenylimidazole (7.21 g, 50 mmol) in 30 ml of DMF at room temperature, the resulting mixture is stirred at 70° C. 1 h, and then cooled to room temperature followed by the dropwise addition of iodobutane (9.66 g, 52.5 mmol, 1.05 eq.). The mixture is stirred at room temperature for 1 h, heated to 70° C. and stirred for an additional 8 h. The reaction mixture is cooled to room temperature, poured into 200 ml of ice-water, extracted with ethyl acetate (100 ml×3). The combined organics are washed with water, brine, dried over anhydrous sodium sulfate, filtered, evaporated at reduced pressure and purified by flash chromatography on silica gel to obtain 9.08 g of 1-butyl-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.77 (2H, d, J=7.6 Hz), 7.49 (1H, s), 7.36 (2H, t, J=7.6 Hz), 7.23(1H, m), 7.20 (1H, s), 3.95 (2H, t, J=7.2 Hz), 1.80 (2H, m), 1.36 (2H, m), 0.96 (3H, t, J=7.2 Hz); MS (+VE) m/z 201 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]([C:12]1[CH:13]=[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:15]([O:24]COCCOC)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:11])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:24])=[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
At ambient temperature, to a stirred solution of (2-n-butyl-benzofuran-3-yl)-(2'-[(2-methoxyethoxy)methoxy]-[1,1';3',1"]terphenyl-5'-yl)-methanone (0.371 g, 0.695 mmol) in CH2Cl2 (3.71 mL) was added trifluoroacetic acid (3.71 mL). After 0.5 h, the reaction was diluted with ether (50 mL), washed with H2O (3×), dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 10% acetone/hexane to give 0.281 g (90%) of the title compound. 1H NMR (DMSO-d6) δ 0.77 (t, 3 H), 1.22 (sextet, 2 H), 1.64 (quintet, 2 H), 2.87 (t, 2 H), 7.29-7.65 (m, 14 H), 7.66 (s, 2 H), 9.39 (s, 1 H).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]#[N:14])=O.[CH2:15]([SH:18])[CH2:16][SH:17].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[S:17]1[CH2:16][CH2:15][S:18][CH:1]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:11](=[O:12])[CH2:10][CH2:9][CH:8]1[C:13]#[N:14]
Reactant: SCCS
Reactant: N#CC1CCC(=O)C1CCCCC=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#CC1CCC(=O)C1CCCCC1SCCS1

Procedure:
17 g [0.063 mol] of 2-(4-formylbutyl)-3-oxo-cyclopentane-carbonitrile were dissolved in 200 ml of toluene and stirred for 30 minutes at room temperature with [0.08 mol]=6.7 ml of 1,2-ethanedithiol and 2 ml of boron trifluoride etherate, washed with water and sodium bicarbonate solution, dried over sodium sulfate and concentrated. 15.6 g of a light color oil were obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15]([C:18]2[CH:19]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[S:21][CH:22]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:20]1[S:21][CH:22]=[C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Product: Cc1noc(NS(=O)(=O)c2cc(S(=O)(=O)c3ccccc3)cs2)c1Br
Yield: 26 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzenesulfonyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-benzenesulfonylthiophene-2-sulphonyl chloride in 26% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 181°-184° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:15])=[C:7]([N+:12]([O-:14])=O)[CH:8]=2)[CH2:3]1.[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]3[N+:12]([O-:14])=[N:16][C:17]([NH2:18])=[N:15][C:6]3=[CH:5][C:4]=2[CH2:3]1
Reactant: N#CN
Reactant: CN1CCc2cc([N+](=O)[O-])c(N)cc2C1
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2cc3c(cc2C1)nc(N)n[n+]3[O-]
Temperature: 60 °C
Yield: 68.7 %

Procedure:
A mixture of 6-nitroaniline 255 (2.3 g, 10.7 mmol) and cyanamide (2.0 g, 46.6 mmol) was melted at 100° C. The mixture was cooled to 60° C. and cHCl (5 mL) was slowly added. The solution was heated at 100° C. for 90 min, then a further three aliquots of cyanamide (2.1 g) and cHCl (5 mL) were added over 3 h. The solution was cooled to 50° C. and made basic with NaOH solution (7.5 M, 20 mL). The solution was heated at 100° C. for another 90 min, cooled and diluted with water (50 mL). The solid was filtered and washed with water to give 1-oxide 256 (1.70 g, 66%) as a brown solid: mp 170-175° C.; 1H NMR [(CD3)2SO] δ 7.90 (s, 1H, H-10), 7.25 (s, 1H, H-5), 7.15 (br s, 2H, NH2), 3.62 (s, 2H, H-6), 2.96 (t, J=5.9 Hz, 2H, H-8), 2.62 (t, J=5.9 Hz, 2H, H-9), 2.35 (s, 3H, NCH3); 13C NMR δ 159.8, 146.8, 144.3, 132.0, 128.4, 121.9, 118.3, 57.3, 51.9, 45.4, 28.3; MS (APCI) m/z 232 (MH+, 100%). Anal. calcd for C11H13N5O.½H2O: C, 55.0; H, 5.9; N, 29.1. Found: C, 55.6; H, 5.5; N, 28.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10]1(O)(C)[CH:15]=[CH:14][C:13](C)=[CH:12][CH2:11]1.[OH-].[Na+].C(Br)CCCCC>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:14][CH2:15][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CC1=CCC(C)(O)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCCCBr
Product: CCCCCCOc1cc(C)ccc1C
Temperature: 80 °C

Procedure:
In 250 g of ethanol were dissolved 250 g (2.05 mol) of 2,5-dimethylphenol (or p-xylenol), 90 g (2.25 mol) of sodium hydroxide and 371 g (2.25 mol) of n-hexyl bromide. The solution was heated for 2 hours in an oil bath at 80° C. Water, 500 g, was added to the reaction mixture, from which an oily matter was separated. Vacuum distillation of the oily matter yielded 384 g of 2,5-dimethyl-1-n-hexyloxy-benzene. Next, 129 g (0.625 mol) of 2,5-dimethyl-1-n-hexyloxybenzene was dissolved in 625 g of 1,2-dichloroethane. To the solution kept in an ice bath, 100 g (0.625 mol) of bromine was added dropwise at a temperature below 5C. At the end of dropwise addition, 500 g of water was added. The organic layer was separated therefrom and washed with 300 g of an aqueous solution of 5 wt % sodium hydrogen carbonate. The organic layer was concentrated to remove the solvent, leaving an oily matter. Vacuum distillation (boiling point 114-124° C./0.5 Torr) of the oily matter yielded 174 g of 4-bromo-2,5-dimethyl-n-hexyloxybenzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:15]2[CH2:16][CH2:17][C:12]([F:11])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: FC1(c2ccccc2)CCNCC1
Reactant: Clc1nccc(I)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC1(c2ccccc2)CCN(c2ccnc(Cl)c2Cl)CC1
Temperature: 110 °C

Procedure:
A mixture of D10 (2 g, 7.302 mmol), 4-fluoro-4-phenylpiperidine hydrochloride (2.048 g, 9.493 mmol) [C.A.S. 1056382-25-2] and DIPEA (5.055 ml, 29.209 mmol) in CH3CN (10 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM from 4:1 up to 1:4 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D18 (0.88 g, 37%) as a white solid.