Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME, (100 mL) under a nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium(0) (70 mg, 5 mol %). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give 2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR (CDCl3; 300 MHz) δ 1.38 (s, 9H), 1.59–1.93 (m, 1OH), 6.18 (m, 1H), 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](O)=[C:5]([CH2:7][OH:8])[CH:6]=1.C1([OH:16])C=CC=CC=1>>[OH:16][C:2]1[CH:3]=[CH:4][C:5]([CH2:7][OH:8])=[CH:6][CH:1]=1
Reactant: OCc1ccccc1O
Reactant: Oc1ccccc1
Product: OCc1ccc(O)cc1

Procedure:
The saligenol yield is 90.6% in relation to the phenol consumed.
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=CC=1C(O)=O.N1CCCC1>>[CH:32]1([CH2:31][NH:30][S:2]([C:5]2[CH:6]=[CH:7][C:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Solvent: C1CCNC1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1N1CCCC1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(cyclopropylmethyl-sulfamoyl)-benzoic acid and pyrrolidine and obtained in 38% yield. MS (m/e): 323.2 (MH−, 100%).
Reaction SMILES: [Na].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][C:7]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:6]=2[CH:5]=1.O>C(O)C>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:6]2[CH2:5]1
Reactant: C[n+]1ccc2c(c1)-c1ccccc1Cc1ccccc1-2
Agent: [I-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CN1CCC2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g Sodium is added with stirring and under a nitrogen atomsphere to a suspension of 0.5 g 2-methyl-9H-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyridinium iodide (formula IV, melting point > 300° C.) in 50 ml ethanol, after which the mixture is refluxed for 1 hour. The reaction mixture is then poured out into H2O and extracted with methylene chloride. The organic phase is washed with H2O, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:17]([C:14]2[C:13](=[O:20])[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:11]([CH3:10])[C:15]=2[CH3:16])=[O:18])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (2.54 g, 20 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (4.74 g, 20.4 mmol) in DCM (60 mL) were added EDCI (4.6 g, 24 mmol) and HOAT (0.54 g, 4 mmol). The reaction was stirred at 45° C. for 12 hours, then cool to rt, quenched with H2O (10 mL), and stirred for another 4 hours. The solid was obtained by filtration and washed with DCM (20 mL×3), then dried at 60° C. in vacuo for 12 hours to give the title compound as a pale yellow solid (6.37 g, 93.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][C:4]=2[N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:8]1[CH2:7][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccc2c(n1)CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(n1)CC(c1ccccc1)CC2=NNC(=N)N
Yield: 81.5 %

Procedure:
A mixture of 2-methyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.3 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.063 ml), water (0.063 ml) and ethanol (30 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 5-guanidinoimino-2-methyl-7-phenyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 82) (0.34 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1O>>[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:11][CH:10]1[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]2[O:13][C:2]([CH3:1])=[CH:3][C:4]1=2
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Oc1ccc2ccccc2c1Br
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc2ccccc2c1Br

Procedure:
The same method as in Example 38 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 1-bromo-2-naphthol instead of 8-hydroxyquinoline to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc[nH]c1C(=O)O
Temperature: 60 °C
Yield: 79.6 %

Procedure:
Methyl 3-methyl-1H-pyrrole-2-carboxylate (10 g, 0.07 mol, purchased at Aurora Building Blocks, reference number A00.567.027) was dissolved in 200 mL methanol and a solution of sodium hydroxide (2N, 108 mL, 0.22 mol) was added. The mixture was heated at 60° C. overnight. The solvent was evaporated and the residue was acidified to pH 2-3 with 2N hydrochloric acid. A white precipitate was formed and filtered and washed with cool water. The solid was dried in a vacuum oven to give 6.97 g (77% yield) of the desired compound. Purity 100%.
Reaction SMILES: C([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C:10]([NH:21][CH2:22][C:23](=[O:45])[NH:24][CH:25]2[CH2:28][N:27]([CH:29]3[CH2:34][CH2:33][C:32]([C:36]4[CH:37]=[N:38][C:39]([O:42][CH2:43][CH3:44])=[CH:40][CH:41]=4)([OH:35])[CH2:31][CH2:30]3)[CH2:26]2)=[N:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:43]([O:42][C:39]1[N:38]=[CH:37][C:36]([C:32]2([OH:35])[CH2:33][CH2:34][CH:29]([N:27]3[CH2:28][CH:25]([NH:24][C:23]([CH2:22][NH:21][C:10]4[C:11]5[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=5)[N:8]([C:6]([NH2:5])=[O:7])[N:9]=4)=[O:45])[CH2:26]3)[CH2:30][CH2:31]2)=[CH:41][CH:40]=1)[CH3:44]
Reactant: CCOc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C(=O)NC(C)(C)C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C(N)=O)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from de-protection of 3-[({1-[4-(6-ethoxy-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butylamide (as prepared in Example 82) with TFA using the procedure described in Example 81.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[CH:14](=O)[CH2:15][CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)[CH2:15][CH3:16]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
2,3,4,9-Tetrahydro-1H-beta-carbolin (2.5 g, 14.5 mmol) and propionaldehyde (1.06 ml, 14.5 mmol) were dissolved in THF (100 ml). Acetic acid (1.25 ml, 21.8 mmol) and sodium trisacetoxyborohydride (4.615 g, 21.8 mmol) were sequentially added to the reaction mixture and stirred for 1 h at room temperature. The reaction mixture was concentrated and the residue was dissolved in H2O (10 ml) and ethyl acetate (50 ml). The pH was adjusted to 9 by adding NaOH (2M). The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield the title product (2.84 g, 91%).
Reaction SMILES: [Na].[CH3:2][N:3]([CH2:5][CH2:6][OH:7])[CH3:4].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CN(C)CCO
Reactant: CCCCBr
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCOCCN(C)C

Procedure:
5.8 g (0.25 mol) sodium was added to a solution of 22 g (0.25 mol) N,N-dimethylaminoethanol in 350 ml dry toluene. After all the sodium had reacted, 35 g (0.25 mol) butyl bromide was added and the reaction mixture was subsequently refluxed for 2 hours. The reaction mixture was then cooled and washed with water. The toluene layer was extracted with dilute hydrochloric acid. The aqueous layer was subsequently rendered basic with respect to phenolphthalein and extracted with ether. The ether layer was dried and ether evaporated off. The residue was distilled. The dimethyl(2-butoxyethyl)amine obtained had a boiling point of 163°-164° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1.[C:55](O)(=[O:58])[CH2:56][OH:57].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][N:46]([C:56](=[O:57])[CH2:55][OH:58])[CH2:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1
Reactant: O=C(O)CO
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CO)CC1

Procedure:
HATU (28.9 g) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3% MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum: (DMSO d6) 1.65–1.81 (m, 2H), 1.99–2.10 (m, 2H), 3.26–3.34 (m, 1H), 3.37–3.47 (m, 1H), 3.60–3.68 (m, 1H), 3.81–3.89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46–7.55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)+ 460.94.
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.Br[CH2:15]C(=O)CC.C(O)C>[Pt](=O)=O.CO>[CH2:2]([C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1)[CH3:15]
Reactant: CCC(=O)CBr
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: CCc1cn2c(n1)CNCC2

Procedure:
2-Ethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15][OH:16]>>[C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]=[C:15]=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: NC1CCCCC1c1ccccc1
Agent: Cl
Product: O=C=N[C@@H]1CCCC[C@H]1c1ccccc1
Temperature: 110 °C

Procedure:
To a solution of 2-phenylcyclohexylamine (2.28 mmol) in methanol was added HCl (4.0 M in dioxane, 0.57 mL). The solution was concentrated and treated with phosgene solution (20% in toluene, 16.0 mL). The reaction was heated at 110° C. overnight and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([OH:37])=[C:31]([CH2:38][CH3:39])[CH:30]=3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([OH:37])=[C:31]([CH2:38][CH3:39])[CH:30]=3)[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 6H), 1.30–1.80 (brm, 8H), 2.00–2.20 (brm, 5H), 2.43 (q, J=19.06 Hz 4H), 2.60 (s, 3H), 2.80 (brm, 7H), 3.34 (m, 3H), 6.70 (s, 2H), 6.99 (s, 1H). Anal. Calcd. For C30H38O4N4, C, 69.47; H, 7.38; N, 10.80. Found: C, 69.45; H, 7.35; N, 10.75.
Reaction SMILES: Cl.Cl.CN(C)[C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.C(O)(=O)/C=C/C(O)=[O:36].CN(C)C(=O)COCCN1CCN(C(C2C=CC=CC=2)C2C=CC([Cl:60])=CC=2)CC1>>[ClH:23].[ClH:60].[C:24]1([CH:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:7][CH2:6][C:5]([OH:30])=[O:36])[CH2:11][CH2:12]2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cl
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 77.8 %

Procedure:
The procedure described in Example 13 is followed with the difference that, instead of the (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide dihydrochloride, 106.4 g (0.2 moles) of (RS)-N,N-dimethyl-{2-[4-(α-phenyl-p-chloro-benzyl)piperazin-1-yl]ethoxy}-acetamide fumarate is used, and, after adjusting the pH of the reaction mixture to 3.8, the precipitated fumaric acid is filtered to facilitate the extraction with dichloromethane. Thus, 71.8 g (77.8%) of the title compound are obtained, m.p.: 225-228° C. The purity of the product corresponds to the quality requirements given in Eur. Pharm., 3, 1997, 1084.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24](=[O:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]1[CH:24]([OH:26])[CH3:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.50 g of 1-benzyloxycarbonyl-2-acetyl-4-tert-butyloxycarbonyl-piperazine in 150 mL of 1:1 THF-EtOH was added 1.35 g of sodium borohydride, in several portions. The mixture was stirred at room temperature for 30 min, then quenched by slow addition of 100 mL of saturated NaHCO3. The mixture was diluted with 150 mL of water and the phases were separated. The aqueous phase was extracted with 2×100 mL of EtOAc. The combined organics were washed with 100 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 2:1 hexanes-EtOAc, to yield 3.05 g of diastereomer 1 and 272 g of diastereomer 2. Data for diastereomer 1. Rf 0.63 (1:1 hexanes-EtOAc). 1H NMR (500 MHz, DMSO-d6, 75° C.): δ7.24-7.40 (m, 5H), 5.10 (s, 2H), 4.52 (d, J=5.0 Hz, 1H), 4.20 (d, J=13.1 Hz, 1H), 3.71-3.92 (m, 4H), 2.76-2.96 (m, 3H),1.40 (s, 9H), 1.00 (d, J=5.5 Hz, 3H). Mass spectrum (ESI) 309.1 (M-BOC). Data for diastereomer 2. Rf 0.53 (1:1 hexanes-EtOAc). 1H NMR (500 MHz, DMSO-d6, 75° C.): δ7.23-7.40 (m, 5H), 5.08 (s, 2H), 4.41 (br s, 1H), 3.74-3.92 (m, 5H), 3.02-3.11 (m, 1H),2.98 (dd, J=3.4, 13.5 Hz, 1H), 2.28 (br t, J=11.7 Hz, 1H), 1.40 (s, 9H), 1.16 (d, J=6.0 Hz, 3H).
Reaction SMILES: Cl.CS([S:7][CH2:8][CH2:9][NH2:10])=C(O)O.[C:11]([NH:14][CH2:15][CH2:16][SH:17])(=[O:13])[CH3:12].C(N(CC)CC)C>CO>[NH2:10][CH2:9][CH2:8][S:7][S:17][CH2:16][CH2:15][NH:14][C:11](=[O:13])[CH3:12]
Reactant: CS(SCCN)=C(O)O
Reactant: CC(=O)NCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCSSCCN

Procedure:
The method of S. J. Brois et al. (loc. cit.) was employed. Methyl-2-aminoethylsulfenylthiocarbonate hydrochloride in methanol solution was treated with acetylcysteamine at 0° C. The reaction, without triethylamine accelerator, was practically instantaneous.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a 100 mL volume three-necked flask with Dean-Stark, 9.38 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 32 ml of toluene and 4.51 g of benzaldehyde were added under a nitrogen atmosphere, and the mixture was subjected to azeotropic dehydration under 100 mmHg at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 12.51 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH2:22])=[N:19][CH:20]=1>>[O:9]=[S:7]1(=[O:10])[CH2:8][C:4]2[CH:3]=[C:2]([NH:1][CH2:22][CH2:21][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:23])=[CH:20][N:19]=3)[CH:12]=[CH:11][C:5]=2[CH2:6]1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)C2
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Product: O=S1(=O)Cc2ccc(NCCc3ccc(C(F)(F)F)cn3)cc2C1

Procedure:
In analogy to the procedure described for the synthesis example 25 (step 1), the title compound (2,2-dioxo-2,3-dihydro-1H-2lambda(6)-benzo[c]thiophen-5-yl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 357.1 [M+H]+) was prepared from 5-amino-2,3-dihydro-1H-2lambda(6)-benzo[c]thiophene-2,2-dione instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:13]=[C:12]([Cl:22])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.[CH2:23]([NH:26][CH2:27][C:28]#[CH:29])[C:24]#[CH:25].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:22][C:12]1[CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])[CH:15]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:11])[N:26]([CH2:27][C:28]#[CH:29])[CH2:23][C:24]#[CH:25]
Reactant: C#CCNCC#C
Reactant: O=C(O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C#CCN(CC#C)C(=O)CCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 0.20 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)valeric acid and 0.05 g of dipropargylamine dissolved in 10 ml of chloroform was added 0.11 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(N,N-dipropargylcarbamoyl)butyl-oxy)benzene (92% yield), nD25.0 1.5481.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][CH2:11]N.N.[OH-].[Na+]>>[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][NH:6][C:4](=[O:5])[CH:3]=[CH2:2]
Reactant: CN(C)CCCN
Reactant: NC(=O)CCO
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: C=CC(=O)NCCCN(C)C

Procedure:
59.3 g of β-hydroxypropionic acid amide and 68 g of 3-dimethylaminopropylamine were heated for 5 hours in a temperature range of 125°-168° C. until the evolution of ammonia was complete. After adding 1 g of pulverised sodium hydroxide the reaction mixture was distilled.