Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[N:4][C:3]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[N:20]([CH3:22])[CH3:21]>C(O)(=O)C>[CH3:21][N:20]([CH3:22])[C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[C:10]1[N:1]=[C:2]2[C:3](=[N:4][CH:5]=[N:6][C:7]2=[O:8])[N:9]=1
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C(=O)Nc1nc[nH]c(=O)c1N
Solvent: CC(=O)O
Product: CN(C)c1cc([N+](=O)[O-])ccc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
One gram of 5-amino-4-(2-dimethylamino-4-nitro-benzoylamino)pyrimidin-6-one is refluxed for two hours in 50 ml of glacial acetic acid. The mixture is evaporated to dryness, and the residue is stirred out with ethanol in the warm.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:16])=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[C:18]([CH:21]1[CH2:26][CH2:25][O:24][C:22]1=[O:23])(=O)[CH3:19]>C(O)C>[C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:16])=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH:12][C:18](=[C:21]1[CH2:26][CH2:25][O:24][C:22]1=[O:23])[CH3:19]
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1cc(C)c(-c2cccc(N)c2C)c(C)c1
Solvent: CCO
Product: CC(Nc1cccc(-c2c(C)cc(C)cc2C)c1C)=C1CCOC1=O
Yield: 95.9 %

Procedure:
A solution of 3-mesityl-2-methylaniline (5.0 g, 22 mmol) and α-acetyl-γ-butyrolactone (14.2 g, 0.11 mol) in ethanol (100 mL) was heated at reflux for three days. The mixture was evaporated, and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (7.08 g) as white crystals.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:12]2[CH:18]([CH2:19][NH:20][C:21](=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([O:31]C)=O)[O:17][CH2:16][CH2:15][N:14]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].[Cl-].[NH4+]>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH:12]2[CH:18]([CH2:19][N:20]3[C:29](=[O:31])[C:24]4[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:22][C:21]3=[O:33])[O:17][CH2:16][CH2:15][N:14]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: COC(=O)c1ccccc1NC(=O)NCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(Cn2c(=O)[nH]c3ccccc3c2=O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A 28% solution (0.2 ml) of sodium methoxide in methanol was added dropwise to a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-[({[2-(methoxycarbonyl)phenyl]carbamoyl}amino)methyl]-1,4-oxazepane-4-carboxylate (190 mg) in methanol (5 mL), and the mixture was stirred at 80° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (135 mg).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.[C:16](Cl)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)C>N1C=CC=CC=1.CCCCCC>[Cl:13][C:12]([Cl:15])([Cl:14])[CH2:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1O
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)c1ccccc1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
--To a solution of 2,2,2-trichloroethyl salicylate (104 g) in dry pyridine (500 ml) at 0°-5° C. and under nitrogen was added (z,z,z)octadeca-6,9,12-trienoyl chloride (137.5 g) dropwise over a period of one hour. The reaction mixture was allowed to stir for twenty hours at room temperature and then the pyridine was removed in vacuo (25° C./0.5 mmHg). The residue was dissolved in diethyl ether (2000 ml) and water (1000 ml) and the resulting two phase system was shaken and acidified slowly to pH1 by addition of 2M hydrochloric acid. The diethyl ether layer was separated and washed with water (4×1000 ml), adding sodium chloride to break any emulsion that formed. After drying the organic layer (Na2SO4), the solvent was removed in vacuo to give an orange/brown oil. This was subjected to MPLC (Column size: 15 cm dia.×40 cm, Column packing: Matrex silica, pore size 60A, particle size 35-70 μm, Solvent: initially hexane, then 15% diethyl ether in hexane, Fraction size: 1000 ml). The requisite fractions were evaporated in vacuo to give 2,2,2-trichloroethyl-2-[(z,z,z) octadeca-6,9,12-trienoyl]benzoate. (189 g, 93% yield) as a pale yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2)#[N:13]>ClCCl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([C:12]#[N:13])[CH:15]=2)[NH:19][CH:18]=1)=[O:10]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1
Temperature: 27.5 °C
Yield: 74.9 %

Procedure:
Aluminium chloride (82.44 g) was added to dichloromethane (350 ml) under stirring at 25-30° C. The resulting mass was cooled to 0-5° C., followed by drop-wise addition of 4-chlorobutyryl chloride (87.5 g) for 30-45 minutes at 0° C. and then stirring for 5 minutes at the same temperature. A solution of 5-cyanoindole (50 g) in dichloromethane (350 ml) was added drop-wise to the resulting mass at 0-5° C. within 1-2 hours, followed by stirring for 30 minutes at the same temperature. The temperature of the reaction mass was gradually increased to 25-30° C., followed by stirring for 12-16 hours at the same temperature. The reaction mass was slowly poured into crushed ice (420 g) with slow stirring, the resulting mixture was cooled to 0-5° C. and then stirred for 1 hour at the same temperature. The separated solid was filtered, washed the material subsequently with dichloromethane (2×85 ml) and water (2×85 ml) and then dried at 25-30° C. to produce a solid material (Dry weight: 93 g). The resulting solid was dissolved in ethyl acetate (4000 ml) at 50-55° C., followed by the addition of activated carbon (5 g) and then stirring the mixture for 5 minutes at the same temperature. The resulting mass was filtered through celite bed and washed the bed with hot ethyl acetate (100 ml). The resulting filtrate was initially cooled to 25-30° C. and further cooled to 0-5° C., followed by stirring the mass for 1 hour at the same temperature. The separated solid was filtered, washed with chilled ethyl acetate (100 ml) and then dried the material at 50-55° C. until constant weight to produce 65 g of 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (Purity by HPLC: 99.2%; Yield: 74.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccs1
Reaction time: 8 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.349 g, 2.03 mmol) was diluted with THF (12 mL), treated with thiophene-2-carbonyl chloride (0.240 mL, 2.23 mmol) and stirred overnight. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.5 g, 88%).
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1>C(OCC)C>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#CBr
Solvent: CCOCC
Product: N#CNc1ccc(Br)cc1
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of cyanogen bromide (5.0 g, 47 mmol), and 4-bromoaniline (17.8 g, 103.4 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen atmosphere. The reaction was filtered, and the filtrate was concentrated in vacuo at room temperature to give 4-bromophenylcyanamide (8.5 g, 92%) as an off white solid.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[NH2:50][CH:51]([CH2:62][CH3:63])[C@@H:52]([C:54]1[O:55][C:56]([CH:59]2[CH2:61][CH2:60]2)=[N:57][N:58]=1)[OH:53].[F:64][C:65]([F:83])([CH2:80][CH2:81][CH3:82])[CH2:66][C@H:67]([NH:71][C:72]([N:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1)=[O:73])[C:68](O)=[O:69]>C(Cl)Cl>[CH:59]1([C:56]2[O:55][C:54]([CH:52]([OH:53])[C@@H:51]([NH:50][C:68]([C@@H:67]([NH:71][C:72]([N:74]3[CH2:79][CH2:78][O:77][CH2:76][CH2:75]3)=[O:73])[CH2:66][C:65]([F:83])([F:64])[CH2:80][CH2:81][CH3:82])=[O:69])[CH2:62][CH3:63])=[N:58][N:57]=2)[CH2:61][CH2:60]1
Reactant: CCC(N)[C@H](O)c1nnc(C2CC2)o1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(O)c1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
PyBOP (171.73 mg, 0.33 mmol), diisopropylethylamine (0.0575 mL, 0.33 mmol) and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-butan-1-ol; compound with trifluoro-acetic acid (0.30 mmol) are added to a solution of (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (88.29 mg, 0.30 mmol) in dry methylene chloride (4 mL) and the reaction mixture is stirred overnight at room temperature. The reaction is quenched with aqueous sodium bicarbonate, extracted twice with methylene chloride, the organic extracts are dried over sodium sulfate and evaporated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives morpholine-4-carboxylic acid ((S)-1-{(S)-1-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-hydroxy-methyl]-propylcarbamoyl-}3,3-difluoro-hexyl)-amide as a solid (87 mg). LC/MS 97%, 474 (M+1).
Reaction SMILES: [CH3:1][C@@:2]1([OH:19])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[C:16](F)[C:14]([NH2:15])=[N:13][C:11]1=[O:12].C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=C(F)C(=O)NC1=O>>[CH3:1][C@@:2]1([OH:19])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(F)c(N)nc1=O
Agent: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Walton et al. described the synthesis of 2′-C-methyladenosine from 2-C-methyl-D-ribono-lactone (Walton et al., J. Am. Chem. Soc., 88(19):4524-5 (1966)). In this case, the lactone was converted into its 2,3,5-tri-O-benzoyl derivative, and then reduced with bis(3-methyl-2-butyl)borane to provide an anomeric mixture of 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose (Id.). Attempts at separating the anomeric mixture both on acid-washed alumina and on silica gel resulted in rearrangement to 1,3,5-tetra-O-benzoyl-2-C-methyl-α-D-ribofuranose (Id.). In order to avoid rearrangement, the additional steps of treating the mixed anomers with benzoyl chloride in pyridine to obtain 1,2,3,5-tetra-O-benzoyl-2-C-methyl-(α)/(β)-D-ribofuranose, and of isolating the final product by chromatography were needed (Id.). Later Walton et al. described the synthesis of 2′-C-methyl-5-fluorocytidine, 2′-C-methyl-5-fluorouridine, and 2′- and 3′-C-methylcytidine via the Hilbert-Johnson reaction (Walton et al., Antiviral Nucleosides 12:306-309 (1969)). However, unexpectedly large amounts of O-glycoside formed when 2′-C-methylcytidine was synthesized from N-acetylcytosine-mercury, and mercury itself is a toxic reagent whose avoidance is desirable (Id.). In both synthetic procedures described by Walton et al., the final product yield was only about 11%.
Reaction SMILES: Cl.[CH3:2][S:3]([CH2:6][C:7]([OH:9])=O)(=[O:5])=[O:4].[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:7](=[O:9])[CH2:6][S:3]([CH3:2])(=[O:5])=[O:4])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CS(=O)(=O)CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 24.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(methylsulfonyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 87, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(methylsulfonyl)acetyl)pyrrolidine-2-carboxamide (7.6 mg, 24.8%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.55 (m, 2H), 7.27 (m, 2H), 7.23-7.16 (m, 7H), 6.94 (m, 2H), 4.50 (m, 1H), 4.38 (d, 2H), 3.82 (m, 1H), 3.35 (m, 1H), 3.08 (s, 3H), 2.63 (m, 3H), 1.92 (m, 2H). MS (EI) for C27H27FN2O5S. found 511.6 (MH+).
Reaction SMILES: C(O)C.Cl.[CH:5]1([C:8]2[CH:9]=[C:10]([C:50]([O:52]CC)=[O:51])[C:11](=[O:49])[N:12]3[C:17]=2[C:16]([O:18][CH3:19])=[C:15]([C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[CH:25]([CH3:29])[N:24](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([C:50]([OH:52])=[O:51])[C:11](=[O:49])[N:12]3[C:17]=2[C:16]([O:18][CH3:19])=[C:15]([C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[CH:25]([CH3:29])[NH:24][CH2:23]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(OC)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C4C)ccn2c1=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(-c2ccc3c(c2)CNC3C)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
6.0 ml ethanol, 2.0 ml of THF and 1.0 ml of 1N hydrochloric acid were added to 248.0 mg of ethyl 1-cyclopropyl-9-methoxy-8-(1-methyl-2-tritylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylate (XIV) and the resulting mixture was stirred at a room temperature for 30 minutes. The solvent was distilled off under reduced pressure and water was added to the resulting residue, which was washed with ethyl acetate, and thereafter, the resulting water layer was concentrated under reduced pressure. 10 ml of water, 5 ml of ethanol and 3 ml of 1N sodium hydroxide were added to the residue and the resulting mixture was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and thereafter, dissolved in 4 ml of water and neutralized with 1N hydrochloric acid. The precipitated crystal was separated by filtering to obtain 99.1 mg of 1-cyclopropyl-9-methoxy-8-(1-methylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[CH:18]([C:20]1[S:24][C:23]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:21]=1)=O.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:18][C:20]2[S:24][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:21]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc(-c3cccs3)s2)c1C(=O)OCC

Procedure:
2,5-Diamino-thiophene-3,4-dicarboxylic acid diethyl ester (30 mg, 0.25 mmol) was mixed with 5-formyl-2,2′bithiophene (40 mg, 0.25 mmol) in isopropanol and refluxed for five hours following the catalytic addition of TFA. The solvent was removed and the product isolated as a yellow solid after purification by flash chromatography (42 mg, 64%). 1H-NMR (300 MHz, [D] DMSO): δ=8.19 (s, 1H), 7.89 (s, 2H), 7.58 (d, 1H, 3J=5.2 Hz), 7.50 (d, 1H, 3J=3.9 Hz) 7.41 (d, 1H, 3J=3.6 Hz), 7.34 (d, 1H, 3J=3.9 Hz), 7.11 (t, 1H, 3J=3.6 Hz), 4.25 (q, 2H, 3J=7.1 Hz), 4.12 (q, 2H, 3J=7.2 Hz), 1.31 (t, 3H, 3J=7.2 Hz), 1.19 (t, 3H, 3J=7.0 Hz). 13C-NMR (300 MHz, [D] acetone): δ=165.5, 164.8, 161.7, 146.1, 142.3, 141.9, 137.7, 137.6, 133.5, 133.4, 131.1, 129.2, 126.9, 125.8, 125.3, 61.5, 60.5, 14.8, 14.6. EI-MS: m/z 434.9 ([M]+, 96%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][C:8]=2[N+:19]([O-])=O)[CH2:3][CH2:2]1>CCOC(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:9][C:8]=2[NH2:19])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCOCC1
Solvent: CCOC(C)=O
Product: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-(4-morpholino-3-nitrophenyl)morpholine (5600 mg, 19 mmol) in EtOAc was added stannous chloride, dihydrate (18 g, 95 mmol). The reaction was stirred at rt for 10 min and at reflux for 90 min. After this time LC/MS shows desired product. The reaction was cooled to rt and the precipitate was collected and washed with aq. 1N sodium hydroxide solution, water and brine and dried under vacuum overnight. After this time the solid was dissolved in EtOAc and washed with aq. 1N sodium hydroxide solution and brine, dried, filtered and evaporated in vacuo to give desired product. The filtrate was diluted with EtOAc (300 mL) and washed with aq. sodium hydroxide and brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give additional desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C1(=O)[NH:17]C(=O)C2=CC=CC=C12.[K].C1OCCOCCOCCOCCOCCOC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(OCC)(=O)C>[C:7]1([S:4]([CH2:3][CH2:2][NH2:17])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=S(=O)(CCCl)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ((2-chloroethyl)sulfonyl)benzene (1.02 g, 5.0 mmol), potassium phthalimide (1.02 g, 5.5 mmol), 18-crown-6 (50 mg), and tetrabutylammonium iodide (50 mg) in dioxane was heated to reflux, stirred for 24 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in ethanol (10 mL), treated with hydrazine hydrate (1 mL), heated to reflux, stirred for 2 hours, cooled to room temperature, filtered through diatomaceous earth (Celite®), and rinsed with ethyl acetate. The filtrate was treated with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in diethyl ether (5 mL), treated with 1M HCl in diethyl ether (10 mL), and filtered. The solid was washed with diethyl ether, suspended in ethyl acetate (80 mL), washed with 2M Na2CO3 and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:14][C:15]2[CH:19]=[C:18]([N:20]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[N:22]=[CH:21]3)[S:17][C:16]=2[C:29]([O:31][CH3:32])=[O:30])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example B14, 110.5 mg of 4-fluoro-2-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](C)=O)=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC#N>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[CH:6][C:7]=1[SH:8]
Reactant: COc1cc(C)cc(S(C)=O)c1F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1cc(C)cc(S)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a mixture of 2-fluoro-1-methoxy-5-methyl-3-(methylsulfinyl)benzene (486 mg) and CH3CN (20 mL) was added TFAA (1.02 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, and concentrated in vacuo. The residue was dissolved in a mixture of MeOH (3.5 mL) and TEA (3.5 mL) at 0° C. The solution was stirred at room temperature for 1 h, and concentrated in vacuo. The residue was diluted with saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The organic layer was extracted with 1N NaOH. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (214 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10]N(C)C)=[CH:2]1.[C-:14]#[N:15].[Na+]>CS(C)=O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:14]#[N:15])=[CH:2]1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2ccccc12
Temperature: 80 °C
Yield: 153.7 %

Procedure:
Dissolve a mixture of the (1H-Indol-3-ylmethyl)-dimethylamine (3.54 mmol), sodium cyanide (0.500 g, 10.62 mmol), and ethyl acetate (1.7 mL, 17.7 mmol) in dry dimethyl sulfoxide (12 mL) and heat to 80° C. under nitrogen for 3 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate (150 mL), and wash with water (50 mL), Dry the organic layer over anhydrous magnesium sulfate, and remove the solvent in vacuo to yield (1H-indol-3-yl)-acetonitrile 0.850 g (96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OCC)=O)[CH:15]([CH3:24])[CH2:14]2)=[CH:4][CH:3]=1.[OH-].[K+]>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:24])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1CN(CCCCC(c2ccc(F)cc2)c2cccnc2)CCN1
Reaction time: 96 h
Yield: 67.6 %

Procedure:
A mixture of 12 parts of ethyl 4-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-2-methyl-1-piperazinecarboxylate, 16 parts of potassium hydroxide and 128 parts of 2-propanol was stirred for 4 days at reflux temperature. After cooling, the reaction mixture was evaporated. Water was added to the residue and the mixture was evaporated till all traces of 2-propanol were removed (this was repeated twice). The residue was taken up in water and the product was extracted with dichlormethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichlormethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6.7 parts (67.6%) of 1-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-3-methylpiperazine as a residue (int. 39).