Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:25])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:3]=[O:4].C(Br)(C)C.[Mg].[C:31]([O:34][C:35](C)(C)[CH3:36])(=[O:33])[CH3:32].[Cl-].[NH4+]>CCOCC>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:25])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:3]([OH:4])[CH2:32][C:31]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CC(C)Br
Solvent: CCOCC
Product: CCOC(=O)CC(O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 66 %

Procedure:
To a mixture of ether (344 ml) and 2,6,10,14,18-pentamethyl-5,9,13,17-nonadecatetraenal (34.4 g), Grignard reagent (prepared by adding portionwise isopropyl bromide (18.5 g) to a mixture of ether (100 ml) and metallic magnesium (3.7 g), adding further t-butyl acetate (17.4 g) thereto while cooling with ice and then stirring the resultant mixture for 1 hour) is dropwise added while cooling with ice. The resultant mixture is stirred at room temperature for 3 hours, and the reaction mixture is poured into an aqueous saturated solution of ammonium chloride. The ether layer is separated, washed with water, dried and evaporated. The residual material is chromatographed on silica gel (500 g) using a mixture of benzene and ethyl acetate (9.5:0.5 by weight) to give ethyl 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-2-ol-1-carboxylate (28.5 g) as a pale yellow oil. IR: 3480, 1030 cm-1 (OH); 1720, 1180 cm-1 (COO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)C(=O)O)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H](O)C(=O)O)cc1Cl
Temperature: -35 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere a mixture of 2.6 g (12.23 mmol) 3-(3-chloro-4-methyl-phenyl)-2-oxo-propionic acid and 2.1 mL (15.1 mmol) triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.87 g (18.30 mmol) (1R)-B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C. The cooling bath was removed and the reaction mixture was stirred overnight at RT. While cooling with ice 30 mL 1 M NaOH and 60 mL diethyl ether were added dropwise and the mixture was stirred for 15 min. The aqueous phase was separated off, the organic phase was extracted twice with 20 mL 1 M NaOH and once with 20 mL water. The combined aqueous phases were acidified with semiconc. HCl while cooling with ice, extracted twice with 60 mL EtOAc and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)#[CH:25]>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:24]#[C:25][C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)nc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C#Cc2ccc(C(F)(F)F)cc2)nc1
Yield: 28 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 28% yield, starting from 2-(2-(6-bromopyridin-3-yl)ethylsulfonamido)benzenesulfonamide and 4-ethynyl-alpha,alpha,alpha-trifluorotoluene. Purification by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[F:11].ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Product: Nc1cccc(Br)c1F

Procedure:
This material was prepared from 1-bromo-2-fluoro-3-nitrobenzene, following the procedure used for SM-9, step 2 (94%): LCMS(m/z) 189.9, tR=0.74 minute; 1H NMR (300 MHz, CDCl3) δ 3.81 (br s, 2H) 6.64-6.75 (m, 1H) 6.80 (t, J=8.2 Hz, 1H) 6.84-6.95 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1.[CH3:35][NH:36][C:37]([C:39]1[CH:49]=[CH:48][C:42]([CH:43]=[CH:44][C:45](O)=[O:46])=[CH:41][CH:40]=1)=[O:38].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Si:17]([O:16][CH2:15][C:10]1[C:9]([Cl:34])=[C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH2:2][NH:1][C:45](=[O:46])[CH:44]=[CH:43][C:42]2[CH:48]=[CH:49][C:39]([C:37](=[O:38])[NH:36][CH3:35])=[CH:40][CH:41]=2)[CH:13]=[CH:12][C:11]=1[Cl:14])([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)O)cc1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of 2-aminomethyl-1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (465 mg) in anhydrous dimethylformamide (7 ml) were added 4-(methylcarbamoyl)cinnamic acid (206 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (219 mg) and 1-hydroxybenzotriazole (185 mg). The mixture was stirred at ambient temperature for 3 hours and partitioned between ethyl acetate and water. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (622 mg) as a brownish powder.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>CN(C)C=O.O>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([C:32]([F:31])([F:41])[F:42])[CH:34]=3)=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4cccc(C(F)(F)F)c4)cc3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 53 mg (0.17 mmol) of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 3 mL of dimethylformamide (DMF) was added 72 mg (0.22 mmol) of cesium carbonate (Cs2CO3), followed by 0.034 mL (0.22 mmol) of 3-(trifluoromethyl)-benzyl bromide, and the resulting heterogeneous mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate, and the combined organic extracts were concentrated to give a residue which was chromatographed on silica gel (Biotage; DCM) to afford 65 mg (80% yield) of desired 7-cyclohexyl-6-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H NMR; LC-MS—calcd for C27H23F3N4O [M++H]+: 477.18, found: 477.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][OH:24])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (5)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151.) as brown solid (38%). MS 512 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.[NH2:11][CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][CH:12]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC(N)Cc1ccccc1
Reactant: Cn1cc(Br)cc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)cc1C(=O)NC(CNC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a 50 mL round-bottomed flask was added 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid (610 mg, 3.0 mmol), 1,1-dimethylethyl (2-amino-3-phenylpropyl)carbamate (748 mg, 2.99 mmol) [prepared according to the procedure of Preparation 2] and PyBrop (1.71 g, 3.67 mmol) in Chloroform (15 mL). DIEA (1.8 mL, 10.3 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (Hex/EtOAc) affording the title compound (335 mg, 26%): LC-MS (ES) m/z=438 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:7]([O:27][C:21]1[CH:20]=[CH:19][C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine (0.034 mL) and acetic anhydride (0.034 mL) were sequentially added to a methylene chloride (0.54 mL) solution of 5-tert-butylsalicylic acid (0.054 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and 1 mol/L hydrochloric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.049 g of 2-acetoxy-5-tert-butylbenzoic acid as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:19][C@H:18]2[NH:20][CH2:21][C@@H:13]1[CH2:14][CH:15]=[CH:16][CH2:17]2.C(OCC)(=O)C.[O:28]1[CH2:30][CH:29]1[CH2:31][O:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[CH:36][NH:37]2>C(O)C>[NH:37]1[C:38]2[C:34](=[C:33]([O:32][CH2:31][CH:29]([OH:28])[CH2:30][N:20]3[CH2:21][CH:13]4[N:12]([CH2:11][C:2]5[CH:3]=[CH:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=5)[CH2:19][CH:18]3[CH2:17][CH:16]=[CH:15][CH2:14]4)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2Cc1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2Cc1ccc2ccccc2c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC(COc1cccc2[nH]ccc12)CN1CC2CC=CCC1CN2Cc1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
Z-(1S,6S)-7-naphthalen-2-ylmethyl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (30 mg, 0.064 mmol), ethyl acetate (0.5 mL) and 4-oxiranylmethoxy-1H-indole (50 mg, 0.26 mmol) were placed in a μW tube with ethanol (3 ml) and heated to 95° C. for 900 sec. The solvent was evaporated to yield a crude oil, which was purified via flash chromatography (15% Ethyl acetate/heptane to 100% Ethyl acetate) to yield the title compound as a residue.
Reaction SMILES: B1C2CCCC1CCC2.[CH3:10][O:11][C:12](=[O:26])[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([F:22])[C:14]=1[CH2:23][CH:24]=[CH2:25].[OH-:27].[Na+].OO>C1COCC1>[CH3:10][O:11][C:12](=[O:26])[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([F:22])[C:14]=1[CH2:23][CH2:24][CH2:25][OH:27]
Reactant: [OH-]
Reactant: C=CCc1c(F)ccc([N+](=O)[O-])c1C(=O)OC
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])ccc(F)c1CCCO
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a 2 L, three necked, round-bottomed flask were charged 892 mL (0.45 mol) of 9-BBN (0.5M) and 100 mL of THF. After cooling to 0° C., 71 g (0.3 mol) of 2-allyl-3-fluoro-6-nitrobenzoic acid methyl ester in 150 mL of THF was added over 30 minutes and the mixture was stirred at room temperature for 5 hours. After cooling to 0° C., 700 mL of 1M NaOH aq was added into the reaction mixture, which was stirred for 30 minutes. To the mixture, 200 mL of hydrogen peroxide (35%) was added over 30 minutes then stirred at room temperature for 1 hours. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, a solution of sodium thiosulfate and brine, and was dried over sodium sulfate. The solvent was removed under reduced pressure to give 104 g of 3-fluoro-2-(3-hydroxy-propyl)-6-nitro-benzoic acid methyl ester as orange oil. The crude product was used for the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(#N)C>[C:19]([O:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5])(=[O:21])[CH3:20]
Reactant: N#CC(CO)c1cccc(Oc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)OCC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 86 %

Procedure:
A 175 mg (0.738 mmol) sample of the above 3-hydroxy-2-(3-phenoxyphenyl)propanenitrile was acylated with acetic anhydride (74 μL) in acetonitrile (300 μL) using the procedure described in Example 5 to give 147 mg (86% yield) of 3-acetoxy-2-(3-phenoxyphenyl)propanenitrile as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.CCN(CC)CC>CN(C=O)C>[N+:11]([C:5]1[C:6]([S:8][C:9]#[N:10])=[N:7][C:2]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)=[N:3][CH:4]=1)([O-:13])=[O:12]
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CSc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A mixture of 2-chloro-5-nitro-4-thiocyanatopyrimidine (5.0 g, 23 mmol, WO 2003/032994) and benzimidazole (2.72 g, 23 mmol) in 200 mL of DMF was cooled to 0 C and Et3N (2.33 g, 23 mmol) was added. The ice-bath was removed and the contents were stirred for 3 h at RT. The reaction mixture was diluted with water and filtered. The solid was washed with water, followed by ice-cold methanol and dried in vacuo to provide 3.1 g of 1-(5-nitro-4-thiocyanatopyrimidin-2-yl)benzimidazole. 1H NMR (300 MHz, DMSO-d6) □□ 9.70 (s, 1H), 9.15 (s, 1H), 8.90-8.80 (m, 1H), 7.95-7.80 (m, 1H), 7.55-7.35 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1)=O)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:16])[CH3:15].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]
Reactant: CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCNCC1=O
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-ethyl-3-oxopiperazine (5.9 g) was dissolved in dichloromethane (100 ml), cooled in an ice-bath, and trifluoroacetic acid (145 ml) added. The mixture was stirred at the same temperature for 2 hours. Solvent was evaporated to yield 1-ethyl-2-oxopiperazine product as a salt with 3 moles of trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixture of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (Alfa, 5 g, 32.5 mmol) in concentrated sulfuric acid (50 mL) at −5° C. was added KNO3 (3.29 g, 32.6 mmol) and the reaction mixture was stirred for 3 h. The reaction mixture was poured into ice water (500 mL) carefully and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 2-10% EtOAc in petroleum ether) to give 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone as yellow solid (4.59 g, 71%). 1H NMR (CDCl3, 400 MHz): δ 10.95 (s, 1H), 8.79 (d, J=7.2 Hz, 1H), 6.92 (d, J=11.2 Hz, 1H), 2.63 (d, J=5.2 Hz, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[S:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([CH3:14])[N:13]=1.O>CN(C)C=O>[CH3:14][C:12]1[N:13]=[C:9]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:10][C:11]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1sc(Cl)nc1C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Sc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Thiophenol (1.90 ml) was dissolved in N,N-dimethylformamide (10 ml) Sodium hydride (60% oil suspension, 740 mg) was added by portions under ice-cooling, and the mixture was stirred at room temperature for 15 min. Thereafter, a solution of ethyl 2-chloro-4-methylthiazole-5-carboxylate (3.05 g) in N,N-dimethylformamide (10 ml) was added dropwise, and the mixture was stirred at the same temperature for 20 min. Water (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml). The ethyl acetate layer was washed twice with water (50 ml) and then with saturated brine (30 ml), and dried (Na2SO4). Ethyl acetate was evaporated under reduced pressure and the obtained residue was purified by column chromatography to give ethyl 4-methyl-2-phenylsulfanylthiazole-5-carboxylate (3.85 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:34])([F:33])[F:32])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:30](=[O:29])[C:31]([F:34])([F:33])[F:32]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cccc3n(CCCCCNC(=O)C(F)(F)F)c(=O)c1n23

Procedure:
To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentyl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring under ice-cooling, 1.43 ml (12.0 mmol) of trifluoroacetic acid ethyl ester. The mixture was stirred for one hour at the same temperature. The solvent was distilled off. To the residue was added ethyl acetate—tetrahydrofuran. The mixture was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate), which was recrystallized from ethyl acetate—n-hexane to afford 2.57 g (72.6%, a pale yellow crystals) of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[C:13]([O:26][CH3:27])[CH:14]=[C:15]([CH2:24][NH2:25])[C:16]=1[NH:17]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40]1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:29]([CH2:28][C:12]1[C:11]2[S:10][C:9]3[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:8]=3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:17]([C:39](=[O:46])[CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:16]=2[C:15]([CH2:24][NH2:25])=[CH:14][C:13]=1[O:26][CH3:27])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C(=O)CCCC(=O)O
Temperature: 0 °C
Yield: 71.1 %

Procedure:
A mixture of 360 mg (0.67 mmol) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-4-yl)-acetate, 91.7 mg (0.80 mmol) of glutaric anhydride and 63.7 mg (0.80 mmol) of pyridine in 5 ml of toluene was treated with 10 mg of N,N-dimethylaminopyridine. The mixture was heated to 110° under argon for 48 hours and then poured into ice-water, whereupon the mixture was acidified with 1N hydrochloric acid and exhaustively extracted with methylene chloride. The organic phase was dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with chloroform/methanol (9:1), whereupon 310 mg (71%) of 5-(4-benzyloxycarbonylmethyl-6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-10yl)-5-oxo-pentanoic acid were obtained as a white solid of m.p. 65°-68°.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).