Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:20]=[CH:19][S:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:31][CH2:32][CH2:33][S:34]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:20]=[CH:19][S:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)(=[O:36])=[O:35]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12

Procedure:
3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide was prepared according to the procedure for intermediate 11. 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.09 mmol) was reacted with triethyl amine (0.025 mL, 0.18 mmol) and 2-chloroethylsulfonyl chloride (0.012 mL, 1.08 mmol) to give 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cc(Cl)n3nccc3n2)c1

Procedure:
A mixture of 1.75 g. of 7-hydroxy-5-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine and 15 ml. of phosphorus oxychloride is refluxed for 2 hours. After evaporation at reduced pressure, ice is added to the residue and the desired compound is extracted with methylene chloride. After washing the organic layer with a saturated saline solution and drying with solid anhydrous sodium sulfate, evaporation gives the desired compound, m.p. 137°-139° C.
Reaction SMILES: CON=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[N:18][C:17]=34)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.Cl.[O:29]1CCOCC1>C(OCC)(=O)C>[N:25]1[CH:26]=[CH:27][C:22]([C:14]2[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[C:4](=[O:29])[CH2:5][CH2:6]4)=[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)=[CH:23][CH:24]=1
Reactant: C1COCCO1
Reactant: CON=C1CCc2cc(-c3c(-c4ccncc4)nn4cccnc34)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(-c3c(-c4ccncc4)nn4cccnc34)ccc21
Temperature: 100 °C

Procedure:
To 5-(2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidin-3-yl)-2,3-dihydroinden-1-one O-methyl oxime (0.090 g; Example 7, Step 5) in 1.3 mL dioxane was added 1.3 mL 4M hydrochloric acid and the mixture was heated to 100° C. for 5 hours. The cooled reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to yield 75 mg product as a yellow-brown-solid. This material was carried on without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[O:8]1[CH:10]([CH2:11][CH3:12])[CH2:9]1>C[Si](C)(C)N[Si](C)(C)C.Cl.[I-].[Zn+2].[I-]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][CH:10]([OH:8])[CH2:11][CH3:12])(=[O:7])[OH:6]
Reactant: CCC1CO1
Reactant: NCCCP(O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [I-]
Product: CCC(O)CP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 40° and treated with 0.64 g of anhydrous zinc iodide and 25 ml of 1,2-epoxybutane. An exothermic reaction occurs and the epoxybutane refluxes. Reflux is continued for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at room temperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in some 2.0M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of the water at 40° in vacuo affords a brown solid which is purified by ion-exchange chromatography on DOWEX® 50 W×8 (14-40 mesh) to give 3-aminopropyl(-2-hydroxybutyl)phosphinic acid, m.p. 184°-185° as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][CH:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH2:4][CH2:3]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>CCOCC>[CH3:22][N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:6]([CH:5]2[CH2:23][CH2:24][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CN1CCC(C(=O)Nc2ccccc2N(C)c2ccccc2)CC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCC(C2=Nc3ccccc3N(C)c3ccccc32)CC1
Temperature: 0 °C

Procedure:
A mixture of 9 g of crude 1-methyl-2'-(N-methylanilino)isonipecotanilide base, 10 g of phosphorus pentoxide and 30 ml of phosphorus oxychloride is heated under reflux for 4 hours, and the reaction mixture is diluted with ether and slowly added to an ice-cold solution of ammonium hydroxide. The mixture is filtered, and the ether layer is separated, dried over anhydrous potassium carbonate and evaporated to yellow solid residue (8.0 g). This crude cyclized base is dissolved in 100 ml of dilute acetic acid, the solution is clarified with activated charcoal and the filtrate is made basic with ammonium hydroxide. The precipitated base is collected, dissolved in 30 ml of ether, and the ether layer is dried over anhydrous potassium carbonate. This solution is filtered into 100 ml of petroleum ether. The product crystallizes as a yellow solid and is collected and dried in vacuo; 5-methyl-11-(1-methyl-4-piperidyl)-5H-dibenzo[b,e][1,4]-diazepine, m.p. 119°-121° C., is thereby obtained; IR (KBr) 6.15μ (anil C=N).
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]([Si:11]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:12][CH2:13][CH2:14][C:15]#[N:16])([CH3:10])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:7]([Si:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:12][CH2:13][CH2:14][C:15]([NH2:1])=[NH:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of NH4Cl (5.35 g, 0.1 mmol) in 60 mL of dry benzend at 0 C was slowly added 50 mL of 2 M solution of trimethylaluminum in toluene. After the addition was complete, the reaction was warmed to RT and was stirred for 2 h until gas evolution had ceased. A solution of 3-(tert-butyl-diphenyl-silanyloxy)-propionitrile (9.27 g, 0.03 mol) in 20 mL of dry benzene was added to the aluminum amide reagent and the resulting was heated up to 80° C. for 20 h. The reaction was slowly cooled to RT and then carefully poured into a slurry of 300 mL of Ch2Cl2 and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/CH2Cl2 (1:2). After concentration, flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2 M NH3 in MeOH=100:30) gave the desired compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH2:25][CH:26]([N:35](C)[C:36](OCC[Si](C)(C)C)=O)[CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[N+](CC)(CC)(CC)CC.[F-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH2:25][CH:26]([NH:35][CH3:36])[CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1)[C@@H]1CCCN(C(=O)NCC(CC2(O)CCCCC2)N(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(CNC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(F)c2)C1)CC1(O)CCCCC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)piperidine-1-carboxamide (9.7 mg, 0.015 mmol) in anhydrous THF (1 mL) was added Et4NF (3 mg). The solution was stirred at 45° C. for 2 h and evaporated under reduced pressure. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(3-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-2-(methylamino)propyl)piperidine-1-carboxamide (4.5 mg, 50%) as its TFA salt. 1H NMR (400 MHz, CD3OD): 7.32 (t, 1H), 7.16 (d, 1H), 7.14 (d, 1H), 6.94 (td, 1H), 4.36 (t, 1H), 3.88 (t, 1H), 3.53 (m, 1H), 3.40 (m, 1H), 3.26 (s, 3H), 2.61 (s, 3H), 2.48 (m, 1H), 2.47 (m, 1H), 1.94 (t, 2H), 1.90 (td, 1H), 1.76 (tt, 1H), 1.69-1.22 (m, 18H), 0.99 (m, 1H); MS m/z 524 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][SH:8].C[O-].[Na+].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:42][C@@:40]3([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]3[OH:43])[C@H:35]3[C@H:26]2[C:27]2[CH:28]=[CH:29][C:30]([OH:44])=[CH:31][C:32]=2[CH2:33][CH2:34]3)=[CH:21][CH:20]=1>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]2[CH2:42][C@@:40]3([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]3[OH:43])[C@H:35]3[C@H:26]2[C:27]2[CH:28]=[CH:29][C:30]([OH:44])=[CH:31][C:32]=2[CH2:33][CH2:34]3)=[CH:23][CH:24]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCl)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: SCc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(OCCCCCSCc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
A solution containing 0.17 cm3 of 2-pyridine methanethiol, 81 mg of sodium methylate, 234 mg of the product obtained in Stage D of Example 3 and 4 cm3 of methanol is heated for 3 hours under reflux. The methanol is distilled off, the residue is taken up with ethyl acetate, washed with water, dried and brought to dryness under reduced pressure. 360 mg of residue is collected which is chromatographed on silica (eluant ethyl acetate-essence G 8/2) and in this way 280 mg of expected product is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])[N:21]=[N:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[CH:13][C:12]=2[CH3:35])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[N:20]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)=[C:12]([CH3:35])[CH:13]=2)=[C:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[N:21]1
Reactant: COC(=O)c1ccc(-c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of 4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic acid methyl ester (4.55 g, 1 equiv) and 1N NaOH (44.6 mL, 5 equiv) in MeOH (200 mL) is heated to 75° C. for 1 h. The reaction mixture is cooled to room temperature and is concentrated under reduced pressure. The residue is dissolved in water (200 mL) and the solution is acidified with 5N HCl. The resulting precipitate is filtered and dried under reduced pressure to give the title compound (4.21 g, 95%). ES/MS m/e (35Cl/37Cl) 496.3/498 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:31]=1[CH3:32])[CH2:7][O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[CH3:2].[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:31]=1[CH3:32])[CH2:7][O:8][C:9]1[C:13](/[CH:14]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1)[CH3:2]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(OCC)OCC)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
To a mixture of 3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.44 g), tetraethyl methylenediphosphonate (0.31 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.34 g, yield 55%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: C1C[N:4]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1CCN2C(=NCCC2)CC1.[S:45]([C:49]1[CH:50]=[C:51]([O:63][CH2:64][C:65]([OH:67])=O)[C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([S:59]([OH:62])(=[O:61])=[O:60])=[CH:54][CH:53]=2)([OH:48])(=[O:47])=[O:46]>CN(C=O)C>[S:45]([C:49]1[CH:50]=[C:51]([O:63][CH2:64][C:65]([NH2:4])=[O:67])[C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([S:59]([OH:62])(=[O:61])=[O:60])=[CH:54][CH:53]=2)([OH:48])(=[O:47])=[O:46]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)COc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: NC(=O)COc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Reaction time: 8 h
Yield: 33 %

Procedure:
The dendrimer (DAB-Am-32; 185 mg; Mw: 3,514) dissolved in DMF (10 mL) then added PyBop (1.84 g; 2.1 eq; Mw: 520.4), followed by a solution of DBU (1 mL) and 3,6-disulfo-1-naphthoxyacetic acid (1.22 g; 2 eq; Mw: 362.3) in DMF (10 mL). The reaction mixture was left to stir overnight at R.T under N2. The solvent was removed under reduced pressure. Then purified through a sephadex (LH20) column followed by an Ion-exchange (IR120; Na+) and freeze-dried to yield SPL7320 as a white powder (402 mg, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(O)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(O)cc2C1=O
Yield: 28 %

Procedure:
A solution of 16 g of 6-hydroxy-1-indanone, 22.3 ml of 3-buten-2-ol and 160 mg of p-toluenesulfonic acid in 170 ml of 2,2-dimethoxy-propane was boiled under reflux for 38 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). In addition to 7.5 g of educt, there were obtained 6.21 g (28%) of (RS)-2-(2-buten-1-yl)-6-hydroxy-1-indanone as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16]3(O[C@H](C4C=CC=CC=4)[C@@H](C4C=CC=CC=4)[O:17]3)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:35]2[NH:39][C:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[CH:37][CH:36]=2)[CH2:13][C@H:14]2[CH2:34][CH2:33][C:16](=[O:17])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(=O)C2)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 55 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
To a solution of 2-(5-{1-[3-chloro-4-(methylsulfonyl)phenyl]-2-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]ethyl}-1H-pyrrol-2-yl)pyridine (580 mg) in tetrahydrofuran (4.5 mL) was added 1M hydrochloric acid (4.5 mL), and the mixture was stirred at 55° C. for 5 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (360 mg, yield 90%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 443 (MH+).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][CH3:16])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1cnn(C(C)(C)C)c(=O)c1C
Temperature: 25 °C

Procedure:
The crude product 2.0 g (0.01 mol) of 2-tert.-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone as synthesized in the above and 1.4 g (0.01 mol) of methyl iodide were dissolved in 20 ml of dimethylformamide and then added with 2.0 g of sodium carbonate with stirring at room temperature. The reaction liquid was stirred for 3 hours at 70° C. After allowing to cool the reaction liquid was poured into 200 ml of water and extracted with 50 ml of benzene. The benzene layer was washed successively with 50 ml of 10% sodium hydroxide, 50 ml of 1N hydrochloric acid and 100 ml of water, dried over anhydrous sodium sulfate and freed of solvent by distillation to give 2.0 g of a crude product. The crude product was recrystallized from 20 ml of isopropyl ether to give 1.4 g of 2-tert.-butyl-4-methyl-5-methylthio-3(2H)-pyridazinone.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]([C:12]1([N:24]([CH:26]=[O:27])[CH3:25])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:11]>C(Cl)Cl>[ClH:1].[CH3:8][O:9][C:10]([C:12]1([N:24]([CH:26]=[O:27])[CH3:25])[CH2:16][CH2:15][NH:14][CH2:13]1)=[O:11]
Reactant: COC(=O)C1(N(C)C=O)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1(N(C)C=O)CCNC1
Reaction time: 1 h
Yield: 100 %

Procedure:
Added 4M HCl/dioxane (2 ml) to a solution of 3-(Formyl-methyl-amino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3T) (50 mg, 0.175 mmol) in MeCl2 (2 ml) at room temperature then stirred for 1 hour. The solvent was evaporated yielding 4T as a white solid (45 mg, 100%) ESMS (MH 187).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:30][C:18]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=[C:12]2[C:17]=1[CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2ccc(NC(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
A mixture of 179 (50 mg, 0.17 mmol), NBS (33 mg, 0.18 mmol) and K2CO3 (28 mg, 0.20 mmol) in MeCN (3 mL) was heated at 60° C. under N2 for 30 min. The solvent was removed under reduced pressure and the residue was purified by chromatography eluting with petroleum ether/EtOAc (9:1) followed by recrystallization (petroleum ether) to give methyl 8-bromo-7-[(tert-butoxycarbonyl)amino]-2-naphthoate (180) (57 mg, 90%) as colorless crystals: mp 137-140° C.; 1H NMR (CDCl3) δ 8.89 (d, J=1.2 Hz, 1H), 8.49 (d, J=9.1 Hz, 1H), 8.01 (dd, J=8.6, 1.7 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.35 (br s, 1H), 4.00 (s, 3H), 1.57 (s, 9H). Anal. (C17H18BrNO4) C, H, N, Br.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][Cl:20])[CH2:11][CH2:10]1)C)(C)(C)C.FC(F)(F)C([O-])=O.ClCCCC#C[C@H]1CC[C@H]([NH2+]C)CC1>>[Cl:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:7][CH3:6])[CH2:14][CH2:13]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCCCl)CC1
Agent: C[NH2+][C@H]1CC[C@H](C#CCCCCl)CC1
Agent: O=C([O-])C(F)(F)F
Product: CN[C@H]1CC[C@H](C#CCCCCl)CC1

Procedure:
In analogy to example 32.1, trans-[4-(5-Chloro-pent-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester was converted to trans-[4-(5-Chloro-pent-1-ynyl)-cyclohexyl]-methyl-ammonium trifluoroacetate. The compound was purified by dissolving the salt in water, washing it with Et2O (3×). The water phase was adjusted to pH 8 (with aqueous saturated NaHCO3) and extracted with EtOAc (3×) to give trans-[4-(5-Chloro-pent-1-ynyl)-cyclohexyl]-methyl-amine, MS: 314 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:25][NH:26][CH2:27][CH2:28][OH:29].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O.O1CCCC1.O.C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([N:26]([CH3:25])[CH2:27][CH2:28][OH:29])=[O:11])=[CH:13][CH:14]=1
Reactant: CNCCO
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCO)C(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A suspension of the bis(4-chlorophenyl)acetic acid (10.40 g, 36.99 mmol) in dichloromethane (100 ml) was treated with oxalyl chloride (6.2 ml, 71.07 mmol) and dimethylformamide (1 drop). The mixture was stirred at room temperature overnight and was then concentrated under vacuum and coevaporated with toluene. The residue was dissolved in tetrahydrofuran (50 ml) and this solution was added to a mixture of 2-(methylamino)ethanol (6.0 ml, 74.7 mmol) in tetrahydrofuran (100 ml), water (50 ml) and sodium bicarbonate (10 g). The reaction was stirred at room temperature for 1 hour, then diluted with ethyl acetate. This was washed with water, HCl 1N, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residual white solid was crystallized from ethyl acetate to give the title compound (10.81 g, 86%).