Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N>O1CCCC1>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#Cc1ccccc1O
Reactant: CCCCCCI
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: CCCCCCC#Cc1ccccc1O
Yield: 80 %

Procedure:
To a grey suspension of lithium amide [lithium shot, (0.59 g, 0.085M) in liquid ammonia (250 ml)] at -30° C. was added 2-hydroxyphenyl acetylene (50 g, 0.042M, prepared by the method of G. A. Russell et al, J. Org. Chem. 31, 248 (1966)) in dry tetrahydrofuran (50 ml). The solution was stirred at reflux for 1 h, then iodohexane (8.91 g, 0.042M), in dry tetrahydrofuran (50 ml) was added dropwise. The reaction was refluxed for 6 h, then the ammonia allowed to evaporate overnight. The resultant pale brown solution was refluxed for 18 h, then cooled and poured into water. Acidified with dilute sulphuric acid and extracted into diethyl ether (twice). The combined organic phases were washed with water (twice), saturated brine and dried (MgSO4). Evaporation in vacuo yielded a red oil which was purified by distillation to give 6.80 g (80%) of the product as a colourless oil. νmax (film) 1463, 1485, 1575, 1608 (weak), 2225 (weak), 3500 cm-1, δ(CDCl3) 0.89 (3H, distorted t, terminal CH3) 1.40 (8 H, m, alkylene chain), 2.43 (2H, t, J 7 Hz, acetylenic CH2), 5.80 (1H, s, OH), 6.87 (2H, m, aromatics) 7.22 (2H, m, aromatics).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=[C:2]1[N:14]([CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:8]
Reactant: CCn1c(Br)nc2ccccc21
Reactant: CNc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCn1c(N(C)c2ccccn2)nc2ccccc21

Procedure:
To a flask were added 1.0 g of 2-bromo-1-ethyl-1H-benzimidazole, 0.48 2-(methylamino)pyridine, 0.64 g of sodium tert-butoxide, and 25 ml toluene. The mixture was purged thoroughly with nitrogen and 250 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene and 64 mg of palladium acetate were added. The reaction mixture was heated to 90 C for 16 hours, and then cooled to 22 C. After quenching with 50 ml water, the product was extracted with 20 ml ethyl acetate. The product was extracted with 30 ml of 1M hydrochloric acid, and then basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using a gradient from 40% ethyl acetate in hexane to 70% ethyl acetate in hexane, resulting in 0.6 g of a yellow oil which crystallized on standing. The product was recrystallized from a mixture of 5 ml hexane with 1.5 ml 2-propanol. After filtration and drying of the product, a 0.44 g of a yellow solid was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17](=O)[C:18]([CH3:24])([CH3:23])[C:19](OC)=[O:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[C:18]([CH3:24])([CH3:23])[C:19](=[O:20])[NH:27][N:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2(C)C)cc1OCc1ccccc1

Procedure:
Prepared analogously as described for example C1 using methyl 3-[3-(benzyloxy)-4-methoxyphenyl]-2,2-dimethyl-3-oxopropanoate (compound D4) and hydrazine hydrate as starting compounds.
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[C:11]([CH3:19])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]([CH3:19])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Reaction time: 2 h

Procedure:
To a mixed solvent of ethanol (40 ml) and water (40 ml) were added ethyl 1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate (8.5 g) and sodium hydroxide (1.66 g), and the mixture was stirred at a refluxing temperature for 2 h. After the reaction, ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound, melting point: 194–195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6](Cl)[C:7]=1[F:8].[F-:14].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:14])[C:7]=1[F:8]
Reactant: [F-]
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [K+]
Product: Fc1cc(C(F)(F)F)cc(Cl)c1F

Procedure:
reacting the 3,5-dichloro-4-fluorobenzotrifluoride product of step (B) with potassium fluoride in the liquid phase at a temperature of about 170° to about 270° Celsius to form 3-chloro-4,5-difluorobenzotrifluoride.
Reaction SMILES: [C:1](#[N:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:7]([OH:9])[CH3:8]>>[C:1](=[NH:6])([O:9][CH2:7][CH3:8])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C#N
Reactant: CCO
Product: CCOC(=N)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
Pivalonitrile (13 g, 157 mmol) was dissolved in absolute ethanol (50 mL) and cooled in a salt-ice bath. HCl gas was bubbled through this solution for 1 h to saturate the solution. The reaction was warmed to RT. After 3 hr, the solvent was removed in vacuo to afford ethyl pivalimidate (16 g, 62%) as white solid. The crude ethyl pivalimidate (16 g, 97 mmol) was taken up in absolute ethanol (20 mL) and absolute ethanol saturated with ammonia (30 mL) was added. The reaction mixture was stirred at RT for 3 hr, whereupon ammonium chloride was filtered off and the salt washed with ethanol. The filtrate was concentrated in vacuo and the solid obtained was dried under vacuum to afford compound O.1, pivalimidamide (10 g, 76%). 1H NMR (DMSO-d6, 200 MHz): δ 8.6 (br s, 1H), 1.2 (s, 9H); LCMS m/z 101 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].I[CH3:19].[H-].[Na+].O>C1COCC1>[CH3:19][N:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
To ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (3 g, 13 mmol) in THF (50 ml) was added iodomethane (4 ml, 65 mmol) and sodium hydride (630 mg, 60% in mineral oil, 15.6 mmol) at 0° C. After warming the reaction mixture to room temperature, it was stirred for 1 day. Water (20 ml) was added and extracted organic layer with diethyl ether. With normal-phase preparative LC, purification preceded to gave title compound (3 g, 94%) as yellow solid.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CC2CCC3(CC2)OCCO3)cc1
Yield: 99.1 %

Procedure:
A solution of 28 g of 8-benzylidene-1,4-dioxa-spiro[4.5]decane and 1 g of 5% palladium on carbon in 250 mL of ethanol was allowed to stir overnight under 1 atm of hydrogen. The catalyst was filtered off and the solution concentrated to give 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[C:3]=12.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(C)c3)c2c1N
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(C)c3)c2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridine-5-carboxylate (Description 57) (880 mg, 2.70 mmol) in DCM (10 mL) at RT was added dropwise N-bromosuccinimide (528 mg, 2.97 mmol) pre-dissolved in DCM (15 mL). The reaction mixture stirred at RT under nitrogen atmosphere for ca. 1 h. The reaction mixture was then quenched with saturated NaHCO3 aqueous solution and the aqueous layer separated and re-extracted with DCM (ca. 30 mL). The combined organic layer was then passed through a phase separator and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-40% ethyl acetate in cyclohexane afforded the title compound (900 mg). LCMS (A) m/z: 405/407 [M+1]+, Rt 1.55 min (acidic).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([CH3:22])[CH2:18][C:19]([OH:21])=[O:20])=[CH:9]1>CO>[CH3:2][O:20][C:19](=[O:21])[CH2:18][C@H:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1)[CH3:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(CC(=O)O)c1c[nH]c2ccccc12
Solvent: CO
Product: COC(=O)C[C@@H](C)c1c[nH]c2ccccc12

Procedure:
3-(1H-Indol-3-yl)-butanal (130 mg, 0.690 mmol) was dissolved in tert-butyl alcohol (27 mL) and 2-methyl-2-butene (4.7 mL) and subsequently was stirred for 10 min. To this solution was added an aqueous solution (4.7 mL) of NaClO2 (75 mg, 0.83 mmol) and NaH2PO4 (115 mg, 0.830 mmol) in one portion. The reaction mixture was stirred at room temperature for 12 h. The organics were removed by concentrating in vacuo. The residue was diluted with 10 mL of H2O, and adjusted to a neutral pH with 1M HCl. Extraction with EtOAc (3×10 mL), drying over Na2SO4, and concentration in vacuo provided 3-(1H-indol-3-yl)-butanoic acid. TMS-diazomethane was added dropwise to a solution of the crude 3-(1H-indol-3-yl)-butanoic acid in methanol (7 mL) until a yellow color persisted. The residual TMS-diazomethane was quenched by the dropwise addition of acetic acid until the yellow color disappeared. The reaction was then treated with an excess of saturated aqueous sodium bicarbonate, extracted with Et2O (3×20 ml), dried over Na2SO4 and purified by silica gel chromatography (20:80 EtOAc/hexanes to provide (R)-3-(1H-indol-3-yl)-butyric acid methyl ester. [α]D=−7.6 (c=1.0 benzene); reported rotation for (S)-3-(1H-indol-3-yl)-butyric acid methyl ester [α]D=+10.9 (c=2.12, benzene).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C>[Br:24][C:14]1[S:13][C:12]([C:10]2[S:11][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCc1ccc(-c2cccs2)s1
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2ccc(Br)s2)s1

Procedure:
Under a light shielded condition, a 5-hexyl-2,2′-bithiophene (0.66 g, 2.63 mmol)/DMF (10 mL) solution was added to NBS (0.56 g, 3.16 mmol) and reacted for one hour. The reaction mixture was then washed with water and was extracted with diethyl ether. The organic layer was dried with MgSO4, and then the solvent was removed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([CH3:35])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11](=[O:30])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([CH3:35])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:28]3[CH:27]=[CH:26][CH:25]=[CH:22][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)=[O:30])[C:7]([N:45]1[CH2:44][CH2:43][N:42]([CH:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH2:47][CH2:46]1)=[O:9]
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1O

Procedure:
Prepared analogously to Example 7i from 100 mg (0.20 mmol) (S)-2-(3-chloro-4-hydroxy-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 37.5 mg (0.22 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>CC(O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([S:34](=[O:36])(=[O:35])[NH2:37])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: NS(N)(=O)=O
Solvent: CC(C)O
Product: NS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Yield: 51.2 %

Procedure:
A mixture of the compound obtained in Example 66 (391 mg, 0.80 mmol), sulfamide (1.54 g, 16.0 mmol), 2-propanol (20 mL) and distilled water (10 mL) was stirred under reflux for 4 days. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with, dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate were added diethyl ether and ethyl acetate, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (230 mg, 0.41 mmol, Yield 51%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[CH:32][CH:31]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
4-Nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 87%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[CH3:28][C:29]1[N:33]([CH2:34][C:35]([N:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][CH:45]=[C:46]([C:48](O)=[O:49])[N:47]=3)[CH2:39][CH2:38]2)=[O:36])[N:32]=[C:31]([C:51]([F:54])([F:53])[F:52])[CH:30]=1>ClCCl.O>[CH3:28][C:29]1[N:33]([CH2:34][C:35]([N:37]2[CH2:38][CH2:39][N:40]([C:43]3[S:44][CH:45]=[C:46]([C:48]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:49])[N:47]=3)[CH2:41][CH2:42]2)=[O:36])[N:32]=[C:31]([C:51]([F:54])([F:52])[F:53])[CH:30]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)O)cs2)CC1
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (82 mg), dimethylaminopyridine (10 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (150 mg) are added to a solution of 2-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)-1,3-thiazole-4-carboxylic acid (XXXIV-1, 300 mg) in dichloromethane (5 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried with sodium sulphate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)-1,3-thiazole-4-carboxylate (45 mg, 12%).
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>O>[C:19]1([C:2]2([O:1][C:25](=[O:28])[CH2:26][CH3:27])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(=O)OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 4 g. (0.0125 mole) of 3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole, 1.19 g. (0.0125 mole) of propionyl chloride and 7 g. of potassium carbonate in 50 ml. of chloroform was allowed to stir for 2 hours. Then 0.4 g. of additional propionyl chloride was added and allowed to stir another 30 minutes. The mixture was treated with 50 ml. of water and allowed to stir 30 minutes. The chloroform layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil was crystallized from benzene-isooctane and yielded 3.0 g. (64%) of product which melted at 140°-142° C. After an additional recrystallization the analytical sample melted at 142°-144° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:46]=[CH:45][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[C:24]2=O)=[CH:20][CH:19]=1.[OH-].[Na+]>C1(C)C=CC(C)=CC=1.O>[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[C:24]2=[S:2])=[CH:45][CH:46]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CS(=O)(=O)Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CS(=O)(=O)Nc1ccc(Cn2c(=S)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Phosphorus pentasulfide (444 mg, 1.0 mmol) was added to a suspension of N-{4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (7) (300 mg, 0.61 mmol) in para-xylene (20 mL) under a blanket of argon. The reaction mixture was heated to the boil over a period of 10 h. Following cooling, there was added to the reaction mixture water (1 mL) followed by 2N NaOH solution in water (10 mL), and the mixture was stirred at RT for 30 min. The reaction mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. After purifying the residue by means of column chromatography (SiO2; cyclohexane/EtOAc 2:1), the desired product N-{4-[3-(4-trifluoromethoxybenzyl)-2-thioxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (8) (162 mg, 52% of theory, mp: 167-170° C.) was obtained. After recrystallizing from methanol, there were obtained crystals having a melting point of 175-179° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21]>C(O)(=O)C.C(O)C>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21].[C:9]1([C:5]2[N:4]3[CH2:3][CH2:2][NH:1][CH2:17][C:8]3=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCn1cccc1-c1ccccc1
Agent: C=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2ccc3n2CCNC3)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 40 %

Procedure:
Crude 1-(2-aminoethyl)-2-phenylpyrrole (0.3 g) was dissolved in 5 ml of acetic acid under argon and treated with 0.1 ml of a 36.5% aqueous formaldehyde solution. The reaction mixture was stirred at room temperature for 64 hours and subsequently concentrated in a vacuum. The residue was stirred briefly with 50 ml of methylene chloride and 20 ml of 10% ammonia solution. The phases were separated, the organic phase was dried with MgSO4 and freed from solvent. The residue, 0.4 g of yellow oil, was chromatographed on 70 g of silica gel with methylene chloride/methanol (49:1) as the eluent. The product, 0.3 g of yellow oil, was taken up in a 20-fold amount of ethanol and treated with 2 equivalents of a saturated solution of fumaric acid in ethanol. The separated crystals were recrystallized from ethanol. There was obtained 0.2 g (40%) of 1,2,3,4-tetrahydro-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 182°- 184° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1.O>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:10][C:9]2[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]3[S:12][C:2]([CH3:1])=[C:3]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:4]=23)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4ccc(Br)cc4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
To a solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 4) (100 mg, 0.352 mmol) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The resulting reaction mixture was stirred for 45 min before addition of 4-bromobenzenesulfonyl chloride (225 mg, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was diluted with water (15 mL) and the aqueous layer re-extracted with DCM (30 mL×3). The organics were combined, dried over a phase separating column and concentrated. To the residue was added MeOH (ca. 0.5 mL) and a solid crashed-out which was collected by filtration and rinsed with MeOH (ca. 2 mL). The solid was then dried, to afford the title compound (104 mg). LCMS (A) m/z: 503/505 [M+1]+, Rt 1.11 min (basic).