Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCl.C[O:4][C:5](=[O:17])[C:6]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH2:7][OH:8].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.Cl>C(OCC)(=O)C.C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH2:7][O:8][CH2:27][O:28][CH3:29])[C:5]([OH:4])=[O:17])=[CH:11][CH:12]=1
Reactant: COC(=O)C(C)(CO)c1ccc(F)cc1
Reactant: COCCl
Agent: CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC(C)(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a methyl chloride (10 mL)-and-THF (5 mL) solution of 2-(4-fluorophenyl)-3-hydroxy-2-methylpropionic acid methyl ester (825 mg) synthesized according to the method described in Tetrahedron Letters, 1999, vol. 40, p. 5467, IPEA (2 mL) and chloromethyl methyl ether (0.74 mL) were added at 0° C. The reaction solution was agitated at 0° C. for 1 hour, and then at room temperature for 10 hours. 1N hydrochloric acid and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. To a methanol (5 mL) solution of the obtained residue, 5N sodium hydroxide aqueous solution (4 mL) was added, and the reaction solution was agitated at room temperature for 10 hours. 5N hydrochloric acid (4 mL) and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure to obtain 850 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Br[C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15].O>C1(C)C=CC=CC=1.C(O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=2[NH2:15])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(F)cc1Br
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(F)cc1-c1ccc(Cl)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
Under protective gas atmosphere, a mixture consisting of 30.0 g (0.17 mol) of 4-chloro-3-fluorophenylboronic acid and 29.7 g (0.16 mol) of 2-bromo-4-fluoroaniline in 170 ml of toluene and 17 ml of ethanol is treated with 3.6 g (0.003 mol) of tetrakis(triphenylphosphine)palladium(0) and stirred for 16 h at 80° C. After addition of 200 ml of toluene and 200 ml of water, the organic phase is separated off, dried over magnesium sulphate and concentrated in vacuum. Column chromatography (petroleum ether/acetone 4:1) yields 26.1 g (70% of theory) of 4′-chloro-5,3′-difluorobiphenyl-2-yl-amine with a logP (pH 2.3) of 3.18.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34](OS(C)(=O)=O)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:81][C:82]1[CH:87]=[CH:86][N:85]=[CH:84][CH:83]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:43])=[C:34]([S:81][C:82]4[CH:87]=[CH:86][N:85]=[CH:84][CH:83]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: Sc1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccncc2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 5 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a solution of diphenylmethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylate (10.01 g, 8.98 m mol) in DMF (200 ml) was added 4-mercaptopyridine (2.00 g, 18.0 m mol) at −15° C., followed by dropwise addition of N,N-diisopropylethylamine (1.16 g, 8.98 m mol). The mixture was stirred at −15° C. for 4.5 hours and at 5° C. for 1 hour. The mixture was poured into a mixture of ice water (1.2 l) and 6N HCl (3 ml) and the precipitates were collected by filtration and washed with water. The powder was dissolved in THF, and ethyl acetate and water were added. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give diphenylmethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-(4-pyridylthio)-3-cephem-4-carboxylate (1.37 g).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][NH:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:32])=[O:3])=[CH:10][CH:11]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2ccc(NCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(NCCCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 e], {6-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynylamino]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as green solid.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:16]4=[C:17]5[CH:23]=[CH:22][NH:21][C:18]5=[N:19][CH:20]=[C:15]4[NH:14][C:13]3=[O:24])[CH2:3]1)[CH2:9]2.C(S(F)(F)([F:31])(CC)N)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl>[F:31][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:16]4=[C:17]5[CH:23]=[CH:22][NH:21][C:18]5=[N:19][CH:20]=[C:15]4[NH:14][C:13]3=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CC3CC1CC(O)(C3)C2
Reactant: CCS(N)(F)(F)(F)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5-Hydroxyadamantan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (92 mg) was suspended in dichloromethane, and diethyl aminosulfur trifluoride (DAST) was added. The mixture was stirred at ambient temperature for 1 hour. The saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The obtained solid was collected by filtration and washed with diisopropyl ethylether to obtain (5-fluoroadamantan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (34 mg).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:6]2[N:5]=1)=O.COCC(O)C.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[CH:40]=2)[CH2:34][CH2:33]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>>[CH3:18][N:16]1[CH:17]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([N:32]4[CH2:33][CH2:34][CH:35]([O:38][C:39]5[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=5)[CH2:36][CH2:37]4)=[N:5]3)=[CH:10][CH:11]=2)[CH:14]=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3cnc(N4CCC(Oc5cccc(N)c5)CC4)nn23)cn1
Yield: 2.7 %

Procedure:
2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine (100.0 mg, 0.3827 mmol) was dissolved in 1-Methoxy-2-propanol (374.1 uL, 3.827 mmol) and added to 4-(3-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (223.8 mg, 0.7654 mmol) and N,N-Diisopropylethylamine (200.0 uL, 1.148 mmol). The substance was microwaved at 200 C for 15 min. The reaction was concentrated, dissolved in 1 mL of DMSO and placed onto the Gilson. Lyophilized overnight to give 3-{1-[7-(1-Methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-piperidin-4-yloxy}-phenylamine as a yellow solid (4 mg, 3%). LCMS (E/I+) 417 (M+H). NMR 1H (DMSO-d6)-8.82 (s, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 7.24 (t, 1H, J=8.05 Hz), 7.05 (d, 1H, J=4.71 Hz), 6.87 (d, 1H, J=4.76 Hz), 6.77 (d, 1H, J=8.04 Hz), 6.69 (s, 1H), 6.65 (d, 1H, J=8.04 Hz), 4.62-4.68 (m, 1H), 4.08-4.16 (m, 2H), 3.93 (s, 3H), 3.50-3.6 (m, 2H), 2.04-2.12 (m, 2H), 1.66-1.76 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])=[C:4]([CH3:22])[CH:3]=1.[NH2:23][C:24]([NH2:26])=[O:25].Cl.O1CCOCC1>CCO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:26][C:24](=[O:25])[N:23]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[C:14]4[CH3:20])[CH:9]=2)=[C:4]([CH3:22])[CH:3]=1
Reactant: NC(N)=O
Reactant: Cc1cc(N)ccc1C(=O)/C=C/c1ccc2[nH]nc(C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(N)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 110 °C

Procedure:
To a solution of (E)-1-(4-amino-2-methylphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (0.480 g, 1.64 mmol) in EtOH (5 mL) were added urea (0.900 g, 15 mmol) and 4N HCl/dioxane (5 mL, 20 mmol). The reaction mixture was heated to 110° C. for 17 hours, cooled down and concentrated in vacuo. The product was purified by SiO2 flash chromatography (ethyl acetate to 60:40 ethyl acetate/methanol) and preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate), followed by concentration in vacuo and lyophilization to afford the title compound as an acetate salt (58 mg, 11%). 1H NMR (400 MHz, d6-DMSO): δ 8.6 (s, 1H), 8.15 (d, 1H), 7.54 (d, 1H), 7.20 (d, 1H), 7.01 (s, 1H), 6.49 (m, 2H), 5.56 (s, 2H), 2.54 (s, 3H), 2.3 (s, 3H), 1.89 (s, 1H); MS (EI) for C19H17N5O: 332.3 (MH±).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C@@H:20]3[C:32]4[NH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH2:23][CH2:22][NH:21]3)=[CH:19][C:14]=2[O:13][CH2:12]1.[K+].[Br-]>>[CH2:1]([NH:8][C:9]([N:21]1[CH2:22][CH2:23][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:31][C:32]=2[C@H:20]1[C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][O:13][C:14]=2[CH:19]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c3c([nH]c2c1)[C@@H](c1ccc2c(c1)OCO2)NCC3
Reactant: S=C=NCc1ccccc1
Agent: [Br-]
Agent: [K+]
Product: S=C(NCc1ccccc1)N1CCc2c([nH]c3ccccc23)[C@H]1c1ccc2c(c1)OCO2
Yield: 80 %

Procedure:
Addition of benzyl isothiocyanate to (1R)-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-β-carboline (1R isomer of compound (III)) provided Example 2b in 80% yield: mp 205–207° C. H1 NMR (DMSO-d6) δ: 11.0 (s, 1H), 8.5 (t, J=5 Hz, 1H), 7.8 (s, 1H), 7.6 (s, 1H), 7.43 (d, J=7 Hz, 1H), 7.4–7.28 (m, 8H), 6.85 (dd, J=1.4, 8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 5.88 (s, 2H), 4.88 (overlapping dd, J=4.7, 14 Hz, 2H), 4.11 (dd, J=4.4, 14 Hz, 1H), 3.51–3.44 (m, 1H), 2.94–2.84 (m, 1H), 2.78 (dd, J=4, 15 Hz, 1H); MS ES+m/e 442 (p+1), ES−m/e 440 (p−1); IR (KBr, cm−1): 1518, 1503, 1487; Elemental analysis: Anal. Calcd for C26H23N3O2S: C, 70.72; H, 5.25; N, 9.51. Found: C, 70.30; H, 5.27; N, 9.42; 74% ee.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:23]([O:22][C:20]([N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[C:3]1[C:2]([NH:1][C:33]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][N:27]=2)=[O:34])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1cnccn1
Reactant: COC(=O)c1cccc(N)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cnccn2)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 58.4 %

Procedure:
A solution of methyl 3-amino-2-(bis(tert-butoxycarbonyl)amino)benzoate 13 (3.8 g, 10.4 mmol), pyrazine-2-carboxylic acid 10 (1.54 g, 12.5 mmol), HATU (7.9 g, 20.8 mmol) and DIPEA (2.68 g, 20.8 mmol) in DMF was heated at 50° C. for 12 h. The reaction mixture was poured into H2O and the resulting precipitate was collected by filtration and dried under vacuum. The crude residue was purified by flash chromatography to give 14 (2.87 g, 58% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 92.2 %

Procedure:
1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (975.0 mg) as a pale brown oil (92.2%).
Reaction SMILES: [CH:1]1([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C@:18]2([CH3:24])[CH2:22][O:21]C(=O)[NH:19]2)[CH:12]=[CH:11]3)[CH2:3][CH2:2]1.C(O)C.O.[OH-].[Li+].O>>[NH2:19][C@@:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][CH:1]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:2][CH2:3]3)[CH:9]=2)[CH:14]=1)([CH3:24])[CH2:22][OH:21]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC(C5CCCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC(C4CCCCC4)CC3)ccc2c1
Yield: 24.1 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(Bicyclohexyl-4-yloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), and 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 46 mg of the desired product as a white solid (46%). ESI-MS: 365 (M-16)+. 1H NMR (400 MHz, CDCl3) δ=7.99-7.55 (m, 3 H), 7.29-7.12 (m, 1 H), 7.08 (s, 2 H), 4.70 (s, 1 H), 4.32-4.17 (m, 1 H), 3.27-2.99 (m, 2 H), 2.32-0.81 (m, 25 H).
Reaction SMILES: [Br-].C([N+]1N=C([C@@H](OC)C)N([NH:18][CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]([O:23][CH3:24])[O:21][CH3:22])C=1[C@@H](OC)C)C1C=CC=CC=1.[BH4-].[Li+].[OH-].[Na+]>O1CCCC1>[C:25]1([CH:19]([NH2:18])[CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(OC)C(Nn1c([C@H](C)OC)n[n+](Cc2ccccc2)c1[C@H](C)OC)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
6 ml of tetrahydrofuran (THF) and 3.5 mmol of 1-benzyl-4-(1-phenyl-2,2-dimethoxyethylamino)-(S,S)-3,5-bis(1-methoxyethyl)-1,2,4-triazolium bromide are introduced into a 100 ml round-bottomed flask equipped with a reflux condenser and a magnetic stirrer and then 1.75 ml of a 2 mol/l solution of lithium borohydride in THF are added at ambient temperature over a period of 1 to 2 h approximately. The reaction medium is subsequently left stirring at ambient temperature for 3 h and then brought to reflux for 3 h. After returning to ambient temperature, 20 ml of a 20% aqueous sodium hydroxide solution are added and then the aqueous phase is extracted with dichloromethane. The resulting organic phase is dried over anhydrous magnesium sulphate and then concentrated. The amine is purified by distillation. 0.19 g of the expected compound is obtained.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=Nc3ccccc3OC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(C2COc3ccccc3N2)cc1
Temperature: 90 °C
Yield: 93 %

Procedure:
To a slurry of 3-phenyl-2H-1,4-benzoxazine (17 g, 81.2 mmol) in 100 mL absolute ethanol is added sodium borohydride (6.07 g, 162.4 mmol) and water (25 mL). The mixture is heated at 90° C. for 2 h. The mixture is cooled and concentrated, then partitioned between CH2Cl2 and water. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. The resulting oil is dried under high vacuum to give 15.95 g (93%) of 3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][S:5](=[O:14])(=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.[CH3:22][NH2:23]>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[S:5](=[O:14])(=[O:13])[NH:6][C:7]3([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:3]=2[CH2:2][NH:23][CH3:22])=[CH:16][CH:17]=1
Reactant: CN
Reactant: O=S1(=O)NC2(CCCCC2)C(CBr)=C1c1ccc(Cl)cc1
Solvent: CCO
Product: CNCC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC12CCCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
4-Bromomethyl-3-(4-chlorophenyl)-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide, made as described in Example 2, (270 mg, 0.69 mmol) was dissolved in ethanol (30 mL). Methylamine (70% solution in water, 8 mL) was added and the mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated to yield 80 mg (34%) of 3-(4-Chlorophenyl)-4-methylaminomethyl-2-thia-1-azaspiro[4.5]dec-3-ene 2,2-dioxide as a solid. MS (IS): 341 [MH]+
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C(Cl)CCl.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (353 mg, 1.0 mmol), Hunig's base (0.35 ml, 2.0 mmol), EDC (231 mg, 1.2 mmol) and aza-HOBt (136 mg, 1.0 mmol) in dichloromethane (DCM) (10 ml) was added morpholine (0.131 ml, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. After this time, the mixture was washed with water (5 mL) and NaHCO3 solution (5 mL×3), and concentrated to provide the crude product which was purified by Combiflash automated silica gel chromatography (0-100% EtOAc in hex) to afford 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoate (244 mg, 0.58 mmol, 58% yield) as a white solid. MS: 422 ([M+H]+).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Br.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][CH:23]=[C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.[C:45]1([CH2:51][O:52][C:53]([C:55]2([NH2:61])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)=[O:54])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:45]1([CH2:51][O:52][C:53]([C:55]2([NH:61][C:30]([C:29]3[CH:33]=[CH:34][C:26]([C:24]4[N:25]=[C:21]([N:18]5[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]5)[S:22][CH:23]=4)=[CH:27][CH:28]=3)=[O:31])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]2)=[O:54])[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(-c3ccc(C(=O)NC4(C(=O)OCc5ccccc5)CCCCC4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, 5.29 g (374 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 8.84 g (23.0 mmol) of 4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide, 4.19 g (27.6 mmol) of 1-hydroxybenzotriazole, 6.44 g (27.6 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 11.9 g (92 mmol) of N,N-diisopropylethylamine in 120 ml of dimethylformamide. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, ether was added to the residue to wash the crystal to obtain 11.8 g (quantitative) of the title compound.