Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][C:5]([C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([CH3:8])[O:4]1.[CH3:21][C@H:22]1[CH2:27][C@@H:26]([CH3:28])[CH2:25][NH:24][CH2:23]1>CCOCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([C:5]2([CH3:8])[O:4][CH:3]([CH2:2][N:24]3[CH2:25][C@H:26]([CH3:28])[CH2:27][C@H:22]([CH3:21])[CH2:23]3)[CH2:7][CH2:6]2)([CH3:20])[CH3:19])=[CH:13][CH:14]=1
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: CC(C)(COc1ccc(Cl)cc1)C1(C)CCC(CBr)O1
Solvent: CCOCC
Product: C[C@@H]1C[C@H](C)CN(CC2CCC(C)(C(C)(C)COc3ccc(Cl)cc3)O2)C1
Yield: 45 %

Procedure:
16 g (0.044 mole) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-5-methyl-tetrahydrofuran are stirred together with 11 g (0.097 mole) of cis-3,5-dimethylpiperidine at a bath temperature of 140° C. for about 14 hours. The resulting reaction mixture is taken up in ether and the mixture is washed several times with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60, ether-petroleum ether 1:1). 7.8 g (45% of theory) of 5-[1-(4-chlorophenoxy)-2-methylprop-2-yl]-2-(cis)-(3,5-dimethylpiperidin-1-ylmethyl)-5-methyl-tetrahydrofuran of refractive index nD20 1.5049 are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[C:17]([O:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC1(CO)COC(=O)N1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OCC1(C)COC(=O)N1
Yield: 69.1 %

Procedure:
A solution of 10.5 g of 2-amino-2-methyl-1,3-propanediol and 12.3 g of diethyl carbonate, 0.5 g of sodium ethoxide in 100 ml of toluene was refluxed for 20 hours, cooled and concentrated at reduced pressure to give 13.6 g of crude product. Recrystallization from ethanol gave 9.23 g (67%) of4-hydroxymethyl-4-methyloxazolidin-2-one, m.p. 115 C. To a solution of 2.62 g of 4-hydroxymethyl-4-methyloxazolidin-2-one and 5 ml of triethylamine in 100 ml of dichloromethane was added dropwise 4.6 g of dodecanoyl chloride in 10 ml of dichloromethane. After 3 hours at room temperature the reaction mixture was concentrated, the residue was taken up in ether and washed with aqueous sodium bicarbonate. The ether layer was dried and concentrated to give 4.33 g (69%) of a thick yellow oil. Recrystallization from dichloromethane/hexane (1:10) gave 2.73 g (45%) of white crystals, m.p. 53-55 C.
Reaction SMILES: [CH:1]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](#[N:21])[CH3:20]>>[CH:1]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]([OH:15])[CH2:20][C:19]#[N:21])[CH:16]=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=Cc1cccc(OCC2CCCCCCC2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCC2CCCCCCC2)c1

Procedure:
Addition of acetonitrile to 3-(cyclooctylmethoxy)benzaldehyde gave 3-(3-(cyclooctylmethoxy)phenyl)-3-hydroxypropanenitrile as a yellow oil. Yield (0.90 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.25-7.31 (m, 1H), 6.91-6.95 (m, 2H), 6.84-6.89 (m, 1H), 5.01 (t, J=6.2 Hz, 1H), 3.72 (d, J=6.8 Hz, 2H), 2.74 (d, J=2.0 Hz, 2H), 1.97-2.04 (m, 1H), 1.33-1.79 (m, 14H).
Reaction SMILES: [F:1][C:2]([F:34])([CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[F:34][C:2]([F:1])([CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:26]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@H](C)CC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 98.7 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-6-methyl-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (F) in acetonitrile (319 ml), diisopropyl ethylamine (68.9 ml, 368 mmol) and benzyl bromide (46.7 ml, 366 mmol) were added and the mixture was stirred for about 13.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (369 ml) and water (283 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (226 ml). The organic layers were combined and washed with 1M-hydrochloric acid (339 ml), saturated sodium bicarbonate water (339 ml) and saturated aqueous sodium chloride (339 ml). After drying with anhydrous magnesium sulfate (50 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane=1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-((6S)-4,4-difluoro-3-hydroxy-6-methyloctyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]heptanoate (3) (76.16 g; 130.7 mmol; yield: 98.7%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C@H:8]1[C@@H:11]([CH3:12])[NH:10][C:9]1=[O:13])=[O:6])[CH3:3].C([Li])CCC.[P:20](Cl)(=[O:25])([O:23][CH3:24])[O:21][CH3:22].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][C@H:11]1[N:10]([P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])[C:9](=[O:13])[C@H:8]1[NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:14])[CH3:3])=[O:6]
Reactant: C[C@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COP(=O)(Cl)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COP(=O)(OC)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1C
Temperature: 25 °C

Procedure:
(3S-cis)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-2-azetidinone (918 mg) dissolved in dry tetrahydrofuran (25 ml) was cooled to -78° C. under an inert atmosphere and 1.56 M n-butyl lithium (3 ml) was added while stirring. After thirty minutes dimethyl phosphorochloridate (3.0 ml) was added and the mixture was stirred at -78° C. for 2 hours. Saturated sodium chloride solution (20 ml) was added and the mixture allowed to warm to room temperature and extracted three times with 30 ml ethyl acetate portions. The combined extracts were dried (Na2SO4) and solvent was removed in vacuo yielding an oil. Chromatography of the oil dissolved in 4 ml of ethyl acetate on a 34 g silica gel column eluting with ethyl acetate yielded 875 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:22]([CH3:21])[O:23][CH3:24])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 8042.2 %

Procedure:
The title compound was synthesized from tert-butyloxycarbonyl-L-phenylalanine (2.65 g, 0.1 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.07 g, 11 mmol) according to the procedure given for 1. The synthesis yielded compound 5 as an oil (2.48 g, 81%): Rf 0.40 (ethyl acetate/hexane, 1:1), Rf 0.78 (chloroform/methanol/acetic acid, 85:10:5); 1H-NMR (CDCl3, 17° C.)δ 1.38 (9H, s, C(CH3)3, 3.05 (2H, m, CH2), 3.18 (3H, s, N--CH3),3.66 (3 H, s, O--CH3), 4.97 (1H, m, CH), 5.18 (1H, d (br.),NH), 7.17-7.28 (5H, m, C6H5).
Reaction SMILES: Br[CH2:2][CH:3]([CH3:7])[CH2:4][O:5][CH3:6].[Mg].[N:9]1[CH2:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]=12.[Cl-].[NH4+]>CCOCC.ClCCCl>[OH:22][C:15]1([CH2:2][CH:3]([CH3:7])[CH2:4][O:5][CH3:6])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][N:9]=[C:14]12
Reactant: O=C1C2=NCCCN2c2ccccc21
Reactant: COCC(C)CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: COCC(C)CC1(O)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-3-methoxy-2-methylpropane (10.02 g) in ether (50 ml) was added dropwise over 20 minutes to magnesium turnings (1.46 g) in ether (10 ml). The mixture was stirred under argon at room temperature for 30 minutes, cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml). The mixture was stirred for 20 minutes and concentrated in vacuo. The aqueous residue was extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound as the free base (2.85 g), m.p. 162°-167° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 244° (dec.).
Reaction SMILES: [N:1]1C2C=CN=CC=2N[C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15](N)C=2C=CC=1.C([OH:26])C>>[N:1]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:15]=[O:26])[C:21]=2[CH:22]=[CH:10][CH:2]=1
Reactant: NC1c2ccccc2-c2c(-c3nc4ccncc4[nH]3)cccc21
Reactant: CCO
Product: O=Cc1cccc2ncccc12

Procedure:
Carry out the procedure as in Example 18, starting from 100 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluorene-9(R,S)-amine, obtained in Example 6, and 59 mg of quinoline-5-carboxaldehyde in 1 ml of ethanol for 3 hours at room temperature, then add 29 mg of sodium hydroborate and stir for 2 hours at room temperature. After purification by HPLC/MS on a Symmetry C18 silica column (5 μm), eluting with a gradient of water 100% (containing 0.07% of TFA) to acetonitrile 100% (containing 0.07% of TFA), we obtain 49.5 mg of trifluoroacetate of N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9(R,S)-yl]-quinolin-5-yl-methylamine, in the form of a pale yellow solid with the following characteristics:
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(Cl)c23)c(C)c1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyridino[2,3-b]-indolizine (0.35 g, 1.04 mmol), and ethylene diamine (0.32 g, 1.04 mmol) in dry NMP (3 mL) at 100° C. for 5 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (30 mL). Wash the combined extract with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 1% ammonium hydroxide) to obtain the title compound as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C([C:38](C2C=CC(NC3C=CC(OC)=CC=3)=CC=2Cl)=[O:39])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:39][CH3:38])=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: COc1ccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)cc1
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: COc1ccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)cc1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 447 (0.08 mmol). The crude product was used without any further purification.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12]([O:19][CH2:20][CH2:21]I)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:12]([O:19][CH2:20][CH2:21][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: ICCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(C=O)cc1OCCOCc1ccccc1
Temperature: 25 °C

Procedure:
20 g isovanillin (Formula IIIa), 41.3 g 2-benzyloxyethyl iodide (Formula IIIb) and 21.8 g potassium carbonate in 200 ml ethyl methyl ketone are stirred for 12 hrs. under reflux. The obtained suspension is cooled to room temperature and the precipitate filtered off, washed with acetone and evaporated. The residue is taken up in ethyl acetate and extracted with H2O (3×) and brine (1×). The organic phase is dried, filtered and evaporated to yield the title compound as an oil.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1COCC1>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]2([OH:26])[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: BrCCCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(CCc2ccc(OCc3ccccc3)cc2)CCCC1
Reaction time: 1 h

Procedure:
To a mixture of magnesium (120 mg) and THF (1.5 mL) was added 1,4-dibromobutane (0.2 mL) at room temperature under nitrogen flow, followed by stirring for 1 hour. The reaction solution was ice-cooled, and a solution of ethyl 3-[4-(benzyloxy)phenyl]propanoate (400 mg) in THF (3 mL) was added dropwise thereto while maintaining an internal temperature of 10° C. or less. The reaction mixture was stirred under ice-cooling for 3 hours, and allowed to stand overnight at room temperature. The reaction liquid was ice-cooled and was adjusted to an acidic pH by adding 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/3-1/1) to obtain 1-{2-[4-(benzyloxy)phenyl]ethyl}cyclopentanol (145 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:38](=[O:47])[C:39]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:40]2[C:41]1=[O:42])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 25 %

Procedure:
In 100 ml of acetonitrile are dissolved 1.7 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2.4 g of ethyl 2-bromo-10-phthalimidodecanoate, and 0.75 g of triethylamine is added to the solution. The mixture is heated at 80° C. for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=3:1 - 2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH2:36][CH:37]([NH2:39])[CH3:38].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH2:36][CH:37]([NH:39][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:38]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CN(C)CCN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 85.2 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.59 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.44 g, 2.59 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (10 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 1.15 g, 85.2% yield. MS: 521.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.43 (s, 1H), 11.31 (d, 1H, J=6.0 Hz), 10.98 (d, 1H, J=7.5 Hz), 8.16 (s, 1H), 8.01 (s, 1H), 7.42-7.35 (m, 2H), 7.20-7.13 (m, 1H), 7.10-7.02 (m, 1H), 6.18 (d, 1H, J=7.2 Hz), 4.16 (m, 1H), 3.95 (t, 2H, J=6.0 Hz), 3.33 (m, 2H), 3.10-2.96 (m, 2H), 2.81 (s, 6H), 1.33 (d, 3H, J=6.3 Hz).
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:23][C@H:22](/[CH:24]=[CH:25]/[P:26](=[O:29])([OH:28])[OH:27])[C@@H:21]([O:30]C(=O)C2C=CC=CC=2)[C@H:20]1[O:39][CH3:40])(=O)C1C=CC=CC=1>[NH4+].[OH-]>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:23][C@H:22]([CH2:24][CH2:25][P:26](=[O:27])([OH:28])[OH:29])[C@@H:21]([OH:30])[C@H:20]1[O:39][CH3:40]
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](/C=C/P(=O)(O)O)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Agent: [NH4+]
Agent: [OH-]
Product: CO[C@@H]1[C@H](O)[C@@H](CCP(=O)(O)O)O[C@H]1n1cnc2c(N)ncnc21
Yield: 93.6 %

Procedure:
Compound 21.6 (37 mg, 95% yield) was synthesized from compound 21.3 (62 mg, 0.11 mmol) by treating 21.3 with concentrated NH4OH (10 ml) at 45° C. for 30 min. 1HNMR (D2O, 300 MHz) δ 8.17 (s, 1H), 8.05 (s, 1H), 6.4 (m, 1H), 6.02-5.87 (m, 2H), 4.65(bs, 2H), 4.37 (m, 2H), 3.32(s, 3H). 31PNMR (D2O, 300 MHz) δ 11.001 ppm. LRMS (ESI) MH+ C12H16N5O6P requires 358.1. Found 358.0.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N+:7]([O-:18])=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(Br)ccc1F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)ccc(Br)[n+]1[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 95.5 %

Procedure:
A solution of 6-bromo-3-fluoro-2-methylpyridine (2.84 g, 14.94 mmol, 1 eq.) was dissolved in DCM (250 ml) and cooled to 0° C. Then mCPBA (7.34 g, 29.89 mmol, 2 eq.) was added by portions and the reaction was warmed to r.t. and stirred for 48 h. A sat. aqueous solution of NaHCO3/Na2S2O3 (1/1) was added and stirring allowed for 5 min. Then DCM was added and the layers separated. The aqueous layer was extracted with DCM then the organics were combined, dried over MgSO4 and concentrated. 6-bromo-3-fluoro-2-methylpyridine 1-oxide (2.94 g, 89%) was obtained as a white solid.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][N:33]=3)=[CH:38][C:39]2=[O:55])=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 4-(5-chloro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:14][CH2:13]3)[C:9]2=[NH:12])=[CH:4][CH:3]=1.O=[C:16]([CH3:20])[C:17](=[S:19])[NH2:18]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([C:9]42[NH:18][C:17](=[S:19])[C:16]([CH3:20])=[N:12]4)[CH2:14][CH2:13]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: N=C1c2cc(Br)ccc2CCC12CC2
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CCC21CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
7′-Bromo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-naphthalen]-1′-imine (Intermediate 11, 717 mg, 2.87 mmol) and 2-oxopropanethioamide (970 mg, 9.40 mmol) were dissolved in dry MeOH (25 mL) and heated at 60° C. under argon for 24 h. After standing at r.t. overnight the formed precipitate was filtered and washed with MeOH. Drying in vacuo afforded the title compound (688 mg, 65% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.27-0.35 (m, 1 H), 0.35-0.45 (m, 2 H), 0.47-0.53 (m, 1 H), 1.69-1.79 (m, 1 H), 2.03-2.12 (m, 1 H), 2.27 (s, 3 H), 2.90 (t, 2 H), 6.73 (d, 1 H), 7.24 (d, 1 H), 7.47 (dd, 1 H), 12.28 (s, 1 H); MS (ES+) m/z 335.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg]I.[Mg].CI.Cl>CCOCC>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[CH:5]=1)([CH3:17])[CH3:2]
Reactant: C[Mg]I
Reactant: CC(=O)c1ccc(-c2ccccc2)c(C)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: Cc1cc(C(C)(C)O)ccc1-c1ccccc1

Procedure:
A solution of 4-acetyl-2-methylbiphenyl (12.8g, 0.061 mole) in dry ether (340me) was added over 30 minutes to methyl magnesium iodide, (from magnesium, 1.8g, methyl iodide, 5.1ml, and ether 61 ml). The mixture was stirred under reflux for 5 hours, stirred overnight at room temperature and finally decomposed by the dropwise addition of hydrochloric acid (2N; 170ml). The product was isolated in ether washed with aqueous sodium thiosulphate and water, dried, evaporated, and distilled. The product solidified on standing and was recrystallized from light petroleum (b.p. 40°-60° C) to give 4-(1-hydroxy-1-methylethyl)-2-methylbiphenyl, m.p. 60°-64° C. A solution of this (5g) in ethyl acetate (50ml) containing concentrated sulphuric acid (3 drops) was hydrogenated over palladium-charcoal (10%, 0.5g) for 8 hours. The mixture was filtered and the filtrate was concentrated by evaporation. The residue was dissolved in ether (50ml), washed with aqueous sodium hydrogen carbonate, dried, evaporated and distilled to give 4-isopropyl-2-methylbiphenyl, b.p. 93°-94° C/0.3mm.