Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][OH:18].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:17][OH:18])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Product: COc1c(Cl)nc(Cl)nc1N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1.2 g, 5.62 mmol), (S)-1-pyrrolidin-2-yl-methanol (1.1 mL, 11.3 mmol) and triethylamine (1.08 mL, 7.75 mmol) in IMS (36 mL) was stirred at RT for 20 mins, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [(S)-1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol (1.08 mg, 70%). LCMS (method A): RT=2.98 min, [M+H]+=278/280.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A suspension of glycine ethylester, monohydrochloride (13.96 g, 100 mmol) and benzophenone imine (18.1 g, 100 mmol) in distilled dichloromethane (600 mL) was stirred at room temperature (RT) for 24 hours (h.). The mixture was diluted with water (250 mL) and the dichloromethane extract was separated, dried (MgSO4), filtered and concentrated under reduced pressure and in vacuo to obtain ethyl-N-(diphenylmethylene)-glycinate as a white solid (25.3 g, 95%). Ref.: M. J. O'Donnell, R. L. Polt J. Org, Chem. 47, 2663, 1982.
Reaction SMILES: [OH-].[Na+].[SH2:3].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[I:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>O>[I:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:32])=[S:3]
Reactant: S
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(=S)c1ccccc1I
Reaction time: 4 h

Procedure:
A solution of sodium hydroxide (10.68 g) in water (14 ml) and alcohol (55 ml) was stirred and treated with hydrogen sulphide at 20° until the mixture did not give an immediate alkaline reaction with phenolphthalein. The solution was cooled to 10°-15° and treated slowly with o-iodobenzoyl chloride (33.66 g). The mixture was stirred for 11/4 hours. The precipitated sodium chloride was filtered off and washed with ethanol (25 ml.) The filtrate was concentrated slightly in vacuo and treated with cold water (80 ml). The solution was covered with ether (100 ml) and stirred while the pH was adjusted to 1.3 with 2N-hydrochloric acid. The ether layer was separated and the aqueous layer was further extracted with ether. The combined ether extracts were washed with water and dried. The ether solution was mixed with water and adjusted to pH 7 with dilute sodium hydroxide solution. The aqueous layer was separated, swirled briefly in vacuo and freeze dried. Trituration of the freeze dried product with ether gave the title compound (28.6 g) as a pale yellow solid. νmax. (Nujol) 15.32 cm-1 (COS-).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][CH:15]=[N:14][C:13]=2[CH3:17])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl.O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Cl:28][C:15]1[O:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:17])[N:14]=1
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)c(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
A solution of Example 1B (1.01 g, 4.12 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C., then lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 4.6 mL, 4.6 mmol) was added slowly. The reaction was allowed to stir at −78° C. for 20 minutes, and then hexachloroethane (1.95 g, 8.23 mmol) was added all at once. The reaction was allowed to warm to room temperature, and stir overnight. After this time, the reaction mixture was poured into water and extracted with ether. The extracts were dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (eluant of 100% hexane, then gradient to 15% ethyl acetate-hexane) to yield the title compound as a white solid (780 mg, 68% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.91 (m, 1H), 7.66 (m, 2H), 2.42 (s, 3H).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(NCC)C.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[S:25]([OH:28])(=[O:27])=[O:26]>>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([OH:17])(=[O:3])=[O:2].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[S:25]([OH:28])(=[O:26])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)c1cc(O)ccc1O
Solvent: CCNCC
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
A process according to claim 1 wherein stoichiometric molar quantities of tosyl chloride or p-toluene sulphonyl chloride and either the diethylamine salt or the ammonium salt of 2,5-dihydroxybenzene sulphonic acid is used to obtain the ammonium salt of 2,5-dihydroxybenzenesulphonic acid monotosylate.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A 1M solution of borane-tetrahydrofuran complex (30 ml) was added dropwise to a stirred solution of 2-phenoxybenzoic acid (5.35 g) in dry THF (50 ml), cooled to 0° C. (effervescence). Following the addition, the mixture was stirred at 0° C. for 15 minutes, then at room temperature for 1.5 hours. It was poured into water and extracted with ether. The extracts were washed successively with water, aqueous sodium bicarbonate, aqueous sodium carbonate, then dried and concentrated under reduced pressure to give 2-phenoxybenzyl alcohol (4.83 g, 97%) as a colourless oil.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[C:36]2=[O:51])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[C:36]2=[O:51])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Yield: 85 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)-imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 85% yield: mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J=11.4 Hz, 2H), 7.60 (d, J=11.4 Hz, 2H), 4.51 (s, 2H), 4.00 (t, J=8.1 Hz, 2H), 3.47 (t, J=8.1 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[NH:16][C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)[nH]c1C(=O)O
Temperature: 45 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
A suspension of ethyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methyl-1H-imidazole-5-carboxylate (0.10 g, 0.28 mmol) in 1 N aqueous sodium hydroxide (2 mL) was stirred at 45° C. for 16 h, and then at 65° C. for 5 h. The reaction mixture was cooled to 0° C. then acidified with 10% aqueous hydrochloric acid to pH ˜2. The precipitate was filtered, washed with water, and then with acetone into a separate flask. The acetone filtrate was concentrated in vacuo and co-concentrated with methanol to dryness (×2). The residue was combined with the solid to afford the title compound (0.060 g, 65%): MS (ES−) m/z 324.2 (M−1).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH3:18])[CH3:17])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@@H]12N(C3C=NC4C(=CC=CC=4)N=3)C[C@@H]1CCNC2.[N:37]1[N:38]([C:42]2[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=2[C:44](O)=[O:45])[N:39]=[CH:40][CH:41]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:18][N:16]([CH3:17])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:44]([C:43]4[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=4[N:38]4[N:39]=[CH:40][CH:41]=[N:37]4)=[O:45])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(N(C)C)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Agent: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-methyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate L) for (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H26N8O, 418.501; m/z found 419.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.13-7.73 (m, 2H), 7.65-7.28 (m, 2H), 7.24-6.88 (m, 1H), 5.51-5.10 (m, 1H), 4.66-2.65 (m, 14H), 2.32-1.85 (m, 5H).
Reaction SMILES: [Mg].[CH2:2](I)[CH3:3].C([Mg]I)C.[CH:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[C:10]1=[O:19])[CH2:16]2.C12CC3CC(CC(C3)C1O)C2>CCOCC.O1CCCC1>[CH2:11]([C:10]1([OH:19])[CH:9]2[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:2][CH:3]1[CH2:17]3)[CH2:18]2)[CH3:12]
Reactant: CCI
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC[Mg]I
Agent: OC1C2CC3CC(C2)CC1C3
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1(O)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 mL of ether was added 3.7 g (0.15 gram atom) of magnesium. To the mixture was added dropwise a solution of ethyl iodide (30 g, 0.19 mol) in ether (30 mL). The solution of ethylmagnesium iodide thus prepared was added dropwise to a solution of 2-adamantanone (20 g, 0.13 mol) in tetrahydrofuran (100 ml), and the mixture was stirred at room temperature overnight. GC analysis indicated that reduction products, i.e., 2-adamantanol and 2-ethyl-2-adamantanol were formed in 75% and 25%, respectively.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10](=[O:26])[N:11]([C:22]([CH3:25])([CH3:24])C)[S:12](=[O:21])(=[O:20])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:28]1CCC[CH2:29]1>>[CH2:1]([NH:8][C:9]1[C:10](=[O:26])[N:11]([CH:22]2[CH2:24][CH2:29][CH2:28][CH2:25]2)[S:12](=[O:20])(=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N1C(=O)C(NCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Reactant: BrC1CCCC1
Product: O=C1C(NCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1C1CCCC1

Procedure:
The title compound was prepared from 4-(benzylamino)-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (Example 23) and bromocyclopentane in a similar way as described for Example 2 and 3. 1H NMR (500 MHz, CDCl3): δ 7.48-7.36 (m, 5H), 7.31-7.26 (m, 3H), 7.04-6.99 (m, 2H), 5.61-5.53 (m, 1H), 4.39 (p, 1H), 4.05 (d, 2H), 2.27-2.10 (m, 4H), 1.97-1.87 (m, 2H), 1.7-1.6 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 158.8, 136.5, 135.2, 131.7, 129.8, 128.9, 128.7, 128.1, 127.4, 124.9, 107.9, 55.2, 48.3, 29.4, 24.1; Mass Spectrum: M−H+ 383.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][N:14](C=O)[CH3:15]>>[CH3:13][N:14]([CH3:15])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol), in DMF (2 mL) was added dropwise to a suspension of NaH (151 mg, 6.31 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for one hour then heated to 55° C. overnight. The reaction mixture was then poured into ice water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated to give dimethyl-(5-nitro-pyridin-2-yl)-amine as a yellow solid. LCMS calcd for C7H11N3 (m/e) 137, obsd 138 (M+H).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(C#N)cc3)CCC2)cc1
Yield: 86.7 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 500 mg (1.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 540 mg (3.7 mmol) of 4-cyanophenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (19:1) gave 480 mg (89%) of 1-[2-(4-cyanophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as an oil: NMR (CDCl3) d 2.07 (m, J=7 Hz, 2H) , 2.42 (s, 3H) , 2.89 (t, J=7 Hz, 4H) , 7.05 (d, J=8 Hz, 2H) , 7.11 (d, J=8 Hz, 2H) , 7 . 26 (d, J=8 Hz, 2H) , 7.48 (d, J=8 Hz, 2H ) .
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][C:22]=1[CH:23]=O>>[Cl:20][C:21]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][C:22]=1[CH2:23][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: O=Cc1cc(-c2ccccn2)ccc1Cl
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccn2)ccc1Cl

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-chloro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 437.10 g/mol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:24])[CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:24])[CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(O)CCCN
Reaction time: 3 h

Procedure:
TFA (2 mL) was added to a solution of 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester in methylene chloride (10 mL) and the mixture was stirred for 3 h and then concentrated under reduced pressure to give crude 5-amino-2-hydroxy-pentanoic acid methyl ester (1 g).
Reaction SMILES: Cl.[CH2:2]([CH:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7]1)[CH2:3][CH2:4][CH3:5].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.O.ClCCl>C1(C)C=CC=CC=1>[CH2:2]([C:6]1[N:10]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1NC(=O)C2(CCCC2)N1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
A preferred embodiment of the process comprises reacting a 2-butyl-1,3-diazaspiro[4.4]nonan-4-one hydrochloride and 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile in a water-immiscible organic solvent such as dichloromethane or toluene, in the presence of methyl-tributylammonium chloride and aqueous sodium or potassium hydroxide, separating the organic phase of dichloromethane or toluene, washing the separated organic phase with water, optionally drying the organic phase over a desiccant, filtering the organic phase, evaporating the organic phase to an oily residue and finally crystallizing the oily residue from an organic solvent, such as methyl tert butyl ether to give 4'-[[2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3yl]methyl][1,1'-biphenyl]-2-carbonitrile. This compound is an intermediate in the synthesis of the compound 2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one known by the trademark (Irbesartan) and can be easily converted to Irbesartan and its salts according to the process described in U.S. Pat. No. 5,270,317. The compound Irbesartan antagonizes the action of angiotensin II.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[O:16]1[C:20]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[CH:19][N:18]=[CH:17]1>O1CCOCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]4[O:16][CH:17]=[N:18][CH:19]=4)[CH:22]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Nc1cccc(-c2cnco2)c1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3cnco3)c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution containing 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (20 mg, 0.071 mmol) and 3-(1,3-oxazol-5-yl)-aniline (17 mg, 0.11 mmol) in aqueous dioxane (1 mL, 95:5 dioxane/water) was stirred at room temperature for 4 weeks. The reaction mixture was diluted with MeOH/water and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 63% yield (18 mg). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H) 7.09-7.16 (m, 1 H) 7.35 (t, J=7.93 Hz, 1 H) 7.45 (d, J=8.06 Hz, 1 H) 7.52 (t, J=1.83 Hz, 1 H) 7.56 (dd, J=8.79, 2.20 Hz, 1 H) 7.61 (s, 1 H) 8.00 (d, J=1.71 Hz, 1 H) 8.06 (d, J=8.30 Hz, 1 H) 8.43 (s, 1 H) 10.96 (s, 1 H). MS (ESI+) m/z 405 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[S:32][C:33]([CH3:36])=[N:34][N:35]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[S:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: Cc1nnc(-c2cccc(I)c2)s1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)s4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.10 g, 0.32 mmol) and 1-iodo-3-(5-methyl-[1,3,4]thiadiazol-2-yl)benzene (0.10 g, 0.32 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palldium(0), copper(I) iodide and triphenylphosphine. The mixture was refluxed for 0.20 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate provided the title compound as a white solid (0.135 g, 87%), m.p. 97-99° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:14])[CH2:5]P(=O)(OCC)OCC.[CH:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1)=O.[Cl-].[NH4+]>O1CCCC1>[O:3]=[C:4]([CH3:14])/[CH:5]=[CH:15]/[C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)/C=C/[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of sodium hydride (793 mg) and anhydrous tetrahydrofuran (80 ml) under ice-cooling was added diethyl 2-oxopropylphosphonate (3.85 g). The mixture was stirred for 15 minutes and then a solution of t-butyl trans-4-formylcyclohexylcarbamate (3.00 g) in anhydrous tetrahydrofuran (30 ml) was added thereto. The mixture was warmed to 25° C. and stirred for 3 hours. To the reaction mixture was added saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 3.46 g of t-butyl trans-4-[(E)-3-oxo-1-butenyl]cyclohexylcarbamate.
Reaction SMILES: [N+]([C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-])=O.[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:4]1[S:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: Oc1cccc(Br)c1
Reactant: N#Cc1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cccc(Br)c2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a solution of 5-nitrothiophene-2-carbonitrile (1.79 g, 11.6 mmol) and 3-bromophenol (2.00 g, 11.6 mmol) in dimethylsulfoxide (22 mL) was added potassium carbonate (1.76 g, 12.8 mmol), and the solution was stirred at 70° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 5-(3-bromophenoxy)-thiophene-2-carbonitrile (2.00 g, 62%) was obtained as a yellow oil.