Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:14]2[C:15]3[C:20](=[CH:19][C:18]([C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[O:23])=[CH:17][CH:16]=3)[CH:21]=[C:13]2[C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[O:12])[CH:37]=[CH:36][N:35]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2ccnc(Cl)c2)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (42%).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].N1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:29])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1.[CH3:20][O:19][CH:3]1[CH:2]([O:1][C:28]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:29])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reactant: C1COCCN1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Product: COC1C(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Reaction time: 3 h
Yield: 203.3 %

Procedure:
To a mixture of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (9.2 g) and pyridine (10.3 g) in dichloromethane (92 ml) was added portionwise 4-nitrophenyl chloroformate (13.1 g) at ambient temperature. After stirring for 3 hours, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(4-nitrophenoxycarbonyloxy)-1-oxaspiro[2,5]octane was prepared in the reaction mixture. To the mixture morpholine (28.4 g) was added in one portion. The solution was stirred for 8 hours at ambient temperature and then diluted with diethyl ether (300 ml). The solution was washed with brine, 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide and brine successively. The solvent was dried and evaporated in vacuo to give 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-morpholinocarbonyloxy-1-oxaspiro[2,5]octane (13.1 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.0500 g, 0.129 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0198 g, 0.136 mmol) and piperidine (0.0877 g, 0.103 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperazine-1-carboxylate (0.0625 g, 94%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:15]3[C:23]4[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:11][CH2:12][C:13]#[N:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1.CO>C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:15]3[C:23]4[C:18](=[C:19]([CH2:24][S:25]([CH3:26])=[O:38])[CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:11][CH2:12][C:13]#[N:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
157 mg (0.42 mmol) of the compound from Example 52 were introduced into 28 ml of dichloromethane at 0° C., 102 mg (0.42 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol and a little ethyl acetate were added, and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated, and the solvents were removed from the organic phase in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) and afforded 141 mg (86% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]=1[CH3:22])=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[CH2:22][Br:23])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1CBr
Yield: 59.7 %

Procedure:
A mixture of 5-bromo-1-(4-methoxy-benzyl)-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (3.5 g, 9.6 mmol), N-bromosuccinimide (1.87 g, 10.5 mmol), and benzoyl peroxide (231 mg, 0.96 mmol) in CCl4 (90 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-25% EtOAc/hexanes) to give 2.55 g of the title compound. MS: (+) m/z 468.00 (M+Na).
Reaction SMILES: ClC1C(F)=C(C=CC=1)CNC([C@@H]1C[C@]2(CO)[C@@H](C2)N1C(=O)CN1C2=NC=CC=C2C(C(=O)C)=C1)=O.C(O[C:41]([N:43]1[CH2:48][C@H:47]2[C@H:45]([CH2:46]2)[C@H:44]1[C:49](=[O:62])[NH:50][C@@H:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=1[F:61])[CH2:52][OH:53])=[O:42])(C)(C)C.[C:63]([C:66]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[N:68]([CH2:75]C(O)=O)[CH:67]=1)(=[O:65])[CH3:64]>CCOC(C)=O>[Cl:60][C:56]1[C:55]([F:61])=[C:54]([C@H:51]([NH:50][C:49]([C@H:44]2[N:43]([C:41](=[O:42])[CH2:75][N:68]3[C:69]4[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=4)[C:66]([C:63](=[O:65])[CH3:64])=[CH:67]3)[CH2:48][C@H:47]3[C@@H:45]2[CH2:46]3)=[O:62])[CH2:52][OH:53])[CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Agent: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@@H]3C[C@@H]3[C@H]2C(=O)N[C@H](CO)c2cccc(Cl)c2F)c2ccccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide from (1S,2S,5R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (prepared using similar protocols as described in Scheme B9) and (3-acetyl-indol-1-yl)-acetic acid. White powder. TLC, Rf (EtOAc)=0.10; MS (UPLC/MS): 498.3/500.4 [M+H]+, 542.4/544.3 [M+HCOO]−; tR (HPLC conditions a): 3.10 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([CH3:7])[CH3:6].[C-]#[N:14].[Na+]>CS(C)=O.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][C:2]#[N:14]
Reactant: [C-]#N
Reactant: CC(C)(CCCCl)C1OCCO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CCC#N)C1OCCO1
Temperature: 25 °C
Yield: 107.3 %

Procedure:
0.74 g (3.8 mmol) of 2-(4-chloro-1,1-dimethylbutyl)-1,3-dioxolane) and 0.50 g (7.7 mmol) of sodium cyanide in 5 mL of DMSO was heated to 100° C. with stirring. After 18 hours the solution was cooled to RT, diluted with water, and the mixture extracted with ether (3×). The combined ether extracts were washed with water (3×), dried over MgSO4, and concentrated in vacuo to afford 0.69 g (90%) of the desired compound as a light yellow liquid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[CH2:5]1.[CH2:11]=O.[P:13]([OH:16])([OH:15])[OH:14].O>C(O)C>[CH3:2][N:3]([CH2:11][P:13]([OH:16])([OH:15])=[O:14])[CH:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[CH2:5]1
Reactant: C=O
Reactant: CNC1CCS(=O)(=O)C1
Reactant: OP(O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(CP(=O)(O)O)C1CCS(=O)(=O)C1
Yield: 86.3 %

Procedure:
A mixture of N-methyltetrahydro-3-thiophenamine 1,1-dioxide hydrochloride (37.2 parts, 0.20 mole); 90 percent paraformaldehyde (6.8 parts, 0.22 mole); orthophosphorous acid (18.0 parts, 0.22 mole); and water (30 parts) was heated at its reflux temperature for 3 hours. After cooling, the solution was stirred into ethanol (150 ml.) and the sticky, white precipitate was triturated under more ethanol. After being dried in vacuo over P2O5 the product weighed 42.0 g. (86.3 percent yield). m.p. 222°-225° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=[C:15]([NH2:38])[CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].CN(C)[C:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][C:61]=2N(C)C)C=CC=1.[I-].[Na+]>CN(C=O)C>[C:45]1([CH2:44][O:43][C:41](=[O:42])[CH2:40][N:38]([C:15]2[CH:16]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])[CH:14]=2)[CH2:40][C:41](=[O:42])[O:43][CH2:53][C:62]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCP(=O)(OCC)OCC)c1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(CBr)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCP(=O)(OCC)OCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 86 %

Procedure:
A mixture of 1.82 g (3.27 mmol) of [3-[3-amino-5-(octadecyloxy)phenoxy]propyl]phosphonic acid diethyl ester, 1.6 ml (9.82 mmol) of benzyl bromoacetate, 1.8 g (8.19 mmol) of 1,8-bis-(dimethylamino)naphthalene and 0.14 g (0.92 mmol) of sodium iodide in 40 ml of acetronitrile and 15 ml of DMF was stirred at reflux under argon for 48 hours. The reaction mixture was concentrated at reduced pressure and the residue was dissolved in ethyl acetate. The extract was washed with 0.05N HCl, dried and concentrated a reduced pressure to an oil which was purified by HPLC using 55% ethyl acetate-hexane. This gave 2.41 g (86% yield) of N-[3-[3-(diethoxyphosphinyl)propoxy-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[C:32]([O:37][CH3:38])[CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c(Br)c3-c3ccccc3)CC2)ccc1Br

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1.5) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.78-7.84 (d, 2H), 7.32-7.42 (m, 3H), 7.18-7.22 (d, 1H), 6.44-6.52 (d, 1H), 6.36-6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.84 (s, 3H), 3.76-3.82 (m, 4H), 3.12-3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.6, 154.8, 150.2, 144.6, 130, 128.8, 128.6, 126.4, 109.2, 102, 56, 51, 50, 49.6, 45.6, 42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]1[NH2:44]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:44][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:42][CH2:43][CH:34]1[CH3:33])=[O:31]
Reactant: CC1CCc2ccccc2C1N
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2c3ccccc3CCC2C)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methyl-1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([O:14][C:23](=[O:25])[CH3:24])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Reactant: CC(=O)OC(C)=O
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(OC(C)=O)cc21

Procedure:
A solution of 10 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester in 100 ml of acetic anhydride is heated to the reflux temperature for 4 hours under anhydrous conditions. It is then evaporated to dryness in vacuo. The evaporation residue is mixed with 200 ml of toluene and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum gives, in the fraction boiling at 195°-200° C/0.06 /mm Hg, 5-benzoyl-6-acetoxy-indane-1-carboxylic acid methyl ester in the form of a colourless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[C:23](O)=[O:24])[CH3:12].Cl.[NH2:27][CH:28]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[O:30]=[C:29]1[CH:28]([N:27]2[C:23](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][C:14]=3[O:13][CH:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH3:12])[C:17]2=[O:18])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(Oc1cccc(C(=O)O)c1C(=O)O)c1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)c1ccc2ccccc2c1
Yield: 64 %

Procedure:
A mixture of 3-(1-naphthalen-2-yl-ethoxy)-phthalic acid (0.36 g, 1.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.16 g, 1.0 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (100 mL), and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the product at 95:5 CH2Cl2-methanol, 0.27 g, in 64% yield; mp 174-176° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.69 (99.65%); 1H NMR (DMSO-d6) δ 1.71 (d, J=6.0 Hz, 3H), 1.99-2.09 (m, 1H), 2.51-2.65 (m, 2H), 2.84-2.97 (m, 1H), 5.13 (dd, J=12.5 Hz, J=5.3 Hz, 1H), 6.00 (q, J=6.0 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.44-7.53 (m, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.9 Hz, H), 7.87-7.96 (m, 3H), 8.00 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 23.7, 31.0, 48.8, 76.5, 115.5, 117.2, 121.5, 123.6, 124.5, 126.2, 126.4, 127.6, 127.8, 128.5, 132.5, 132.7, 133.4, 136.7, 139.4, 154.8, 165.3, 166.7, 170.0, 172.8; Anal. Calcd for C5H20N2O5: C, 70.08; H, 4.71; N, 6.54. Found: C, 69.71; H, 4.51; N, 6.28.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1.N([O-])=O.[Na+].[ClH:20]>>[Cl:20][C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1
Reactant: Cl
Reactant: Nc1nc2nc(C(F)(F)F)nc(O)c2s1
Agent: O=N[O-]
Agent: [Na+]
Product: Oc1nc(C(F)(F)F)nc2nc(Cl)sc12
Temperature: 25 °C

Procedure:
To a solution of the compound (3.00 g) obtained in Step 6 in 6N hydrochloric acid (45 ml) was added sodium nitrite (8.76 g) in several portions with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (1.46 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=O)C.O.[NH2:16][NH2:17]>C(O)C>[NH:11]([C:8]1[S:9][CH:10]=[C:6]([C:4]([NH:16][NH2:17])=[O:3])[N:7]=1)[C:12]([NH2:14])=[NH:13]
Reactant: CCOC(=O)c1csc(NC(=N)N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)NN)cs1
Yield: 82.1 %

Procedure:
16.7 g (0.0779 mol) of 2-guanidino-4-thiazole carboxylic acid ethyl ester was combined with 25 ml (0.514 mol) of hydrazine hydrate in 200 ml absolute ethanol. The slurry was heated to reflux. After 1.5 hour reflux a solid began to form from the clear solution. After 2 hours reflux the reaction slurry was cooled and the resulting solid was collected by filtration and was washed with isopropyl alcohol and ether to give 12.8 g (82%) 2-guanidino-4-thiazole carboxylic acid hydrazide, mp 247° (dec.).
Reaction SMILES: [H-].[Li+].[OH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CN(C)C=O>[CH2:33]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C@@H:13]([C:18]([O:31][CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([O:16][CH3:17])=[O:15])[N:6]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(CO)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Oc1nc(C)cc(COCc2ccccc2)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a 0° C. mixture of lithium hydride (0.235 g, 29.4 mmol) in tetrahydrofuran and dimethylformamide (30 mL: 10 mL) is added the compound of Example 11 (3.0 g, 7.3 mmol) and the mixture stirred for 0.5 hr. Benzyl bromide (1.257 g, 7.3 mmol) is then added and the reaction stirred 12 hr at room temperature. The reaction is poured into ice-water (100 mL) and the quenched mixture extracted with ethyl acetate (2×100 mL). Concentration gives crude product that is purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:9) to yield the title compound (2.5 g, 69%). MS m/z 499.0 (M+.1).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:19]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCC1(C(=O)OCC)CCNCC1
Yield: 113.2 %

Procedure:
A mixture of ethyl isonipecotate (31.8 mmol; 5.0 g), anhydrous potassium carbonate (63.6 mmol; 8.8 g) and 1-bromobutane (31.8 mmol; 4.36 g) in absolute ethanol (63 ml) was stirred at reflux for 3 hours. After cooling, the carbonate was removed by filtration and the filtrate evaporated under reduced pressure. 7.68 g of ethyl 4-butylisonipecotate were obtained in the form of an oil, which was used for the following reaction without further purification. This product was dissolved in anhydrous ethyl ether (32 ml) and added dropwise to a suspension of lithium aluminium hydride (41.3 mmol; 1.57 g) in the same solvent (20 ml) cooled to 0° C. The reaction mixture was stirred at room temperature for 15 hours. After cooling to 0° C., ice was added cautiously and the hydroxides thus formed were removed by filtration. After separating the two phases, the ether phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 5.1 g (94%) of final compound as a clear oil.
Reaction SMILES: [NH2:1][C@:2]1([CH2:24][OH:25])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[CH2:3]1.[OH-].[K+].[C:28](Cl)(Cl)=[O:29].CCOC(C)=O>C1(C)C=CC=CC=1.O>[CH2:17]([O:16][CH2:15][C:14]#[C:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:28](=[O:29])[O:25][CH2:24]3)[CH2:3]2)=[CH:8][CH:9]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@]1(CO)CC[C@@H](c2ccc(C#CCOCc3ccccc3)cc2)C1
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1N[C@@]2(CC[C@@H](c3ccc(C#CCOCc4ccccc4)cc3)C2)CO1
Yield: 79 %

Procedure:
To a solution of ((1R,3R)-1-amino-3-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)cyclopentyl)methanol (25 g, 55.9 mmol) in toluene (200 mL) was added a solution of potassium hydroxide (12.54 g, 224 mmol) in water (40 mL) followed by a solution of 20% phosgene in toluene (41.5 g, 84 mmol). After about 4 hours EtOAc was added and the organic layer was separated and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/DCM) to provide (5R,7R)-7-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (20 g, 44.3 mmol, 79% yield) as a brown oil.
Reaction SMILES: [I-:1].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CC(C)=O>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][I:1])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCI
Temperature: 25 °C

Procedure:
A solution of sodium iodide (13.5 g, 90 mmol) and 1-(tert-butyldimethylsilyloxy)-6-chloro-hexane (Preparation 20) (8.35 g, 22 mmol) in acetone (70 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was worked-up (hexane) to give the desired compound as yellow oil.