Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH3:28])[CH2:23]1)[CH2:20][CH3:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH3:28])[CH2:23]1)[CH2:20][CH3:21]
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@@H](C)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@H](O)[C@@H]1C[C@@H](C)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
A solution of (3R,5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28f, 2.7 g, 6.8 mmol) in THF (10 mL) was added TBAF (1M in THF, 13.6 mL, 13.6 mmol) and the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:30 to 1:20 EtOAc in petroleum ether) to afford 1.02 g of (3R,5S)-5-[(1S)-1-hydroxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH:18]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)=O.NC1C(=S)NC=CC=1>>[C:11]1([C:8]2([C:5]3[N:4]=[C:3]4[S:17][C:18]([C:20]5[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=5)=[N:1][C:2]4=[CH:7][CH:6]=3)[CH2:10][CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: N#Cc1ccc(C=O)cc1
Agent: Nc1ccc[nH]c1=S
Product: N#Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1

Procedure:
Reaction of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (55.6 mg, 229 μmol) and 4-formylbenzonitrile (29 mg, 218 μmol) according to Reference U and the general procedure for oxidative condensation of 3-aminopyridine-2-thione with aryl aldehydes gave 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzonitrile as a light yellow solid. MS (ESI) m/z: Calculated: 353.1; Observed: 354.1 (M++1).
Reaction SMILES: [CH:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:22]=[CH:21][O:20][N:19]=4)=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9]([OH:24])=[C:8]2[C:25](=[O:36])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>O.C(OCC)(=O)C.CO>[CH:1]1([CH:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:22]=[CH:21][O:20][N:19]=4)=[CH:16][CH:17]=3)[C:10](=[O:23])[C:9]([OH:24])=[C:8]2[C:25](=[O:36])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(-c4ccon4)cc3)C2C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(-c4ccon4)cc3)C2C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a mixture of 5-cyclohexyl-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-4-(4-methoxycarbonylbenzoyl)-1,5-dihydropyrrol-2-one (1.98 g, 4.07 mmol), THF (20 mL) and methanol (13 mL) was added aqueous 2N sodium hydroxide (5.09 mL). The mixture was stirred at 80° C. for 2 hr. To the mixture was added 2N hydrochloric acid (5.09 mL) under ice-cooling conditions, and ethyl acetate and water were added. The mixture was stirred at r.t. overnight. The precipitate was collected by filtration to give 5-cyclohexyl-3-hydroxy-1-(4-isoxazol-3-ylphenyl)-4-(4-carboxybenzoyl)-1,5-dihydropyrrol-2-one (1.70 g, 88%) as yellow crystals.
Reaction SMILES: [BH4-].[Li+].COC1CCCC1.[F:10][C:11]1[CH:12]=[C:13]([C@@H:18]2[CH2:28][CH2:27][C@@H:26]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]2=[O:40])[CH:14]=[C:15]([F:17])[CH:16]=1>>[F:10][C:11]1[CH:12]=[C:13]([C@@H:18]2[CH2:28][CH2:27][C@@H:26]([O:29][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:32])[CH3:33])[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C@H:19]2[OH:40])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)C(=O)c2cccnc21)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: COC1CCCC1
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
Lithium borohydride (0.283 g, 13.01 mmol) was added to a cyclopentyl methyl ether (15 mL) solution of (6S,9R)-6-(3,5-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1.4496 g, 3.25 mmol) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 6 h at room temperature. The reaction was quenched by adding methanol and continued to stir for 0.5 h. The solvent was removed via vacuum and the crude residue was taken up in ethyl acetate, which was washed by water three times. Flash chromatography using ethyl acetate in hexane from 0 to 10% gave the desired product (56%). HPLC tR=3.05 min,
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[N:22]([CH2:26][C:27](O)=[O:28])[C:23](=[O:25])[O:24][C:20]=2[CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[N:22]([CH2:26][C:27]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:7]4[CH:15]=[CH:16][C:4]([F:3])=[CH:5][CH:6]=4)[CH2:10][CH2:11]3)=[O:28])[C:23](=[O:25])[O:24][C:20]=2[CH:19]=1
Reactant: O=C(O)Cn1c(=O)oc2cc(Cl)ccc21
Reactant: Fc1ccc(CN2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)oc2cc(Cl)ccc21)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
In a 4 mL vial was added 1-(4-fluoro-benzyl)-piperazine dihydrochloride (13) (51 mg, 0.22 mmol, 1.0 equiv), (6-chloro-2-oxo-benzooxazol-3-yl)-acetic acid (50 mg, 0.22 mmol, 1.00 equiv), DIEA (153 μL, 0.88 mmol, 4.0 equiv), HATU (100 mg, 0.26 mmol, 1.20 equiv) and 1.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at room temperature overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-chloro-3-{2-[4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (14): HPLC retention time, 1.05 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 403.8, found, 404.5.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25].[OH-].[Na+]>C(O)C.O>[OH:26][C:24]1[CH2:23][CH:22]([C:15]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[CH3:13])[CH2:2][C:3](=[O:4])[CH:25]=1
Reactant: CC(=O)C=Cc1c(C)cc(C)cc1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C2CC(=O)C=C(O)C2)c(C)c1

Procedure:
Diethyl malonate (10.1 g; 60 mmole) was added to a solution of sodium metal (1.4 g; 60 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(2,4,6-trimethylphenyl)but-1-en-3-one (11.4 g; 61 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (7.3 g; 180 mmole in 100 ml of water) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was extracted twice with ethyl acetate (100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product, 3-hydroxy-5-mesitylcyclohex-2-en-1-one, was obtained as a pale yellow solid (10.9 g; 77.4%), mp 165° C. Proton magnetic resonance spectrum (dimethylsulfoxide; δ in ppm): 2.0-4.1 (14H, m); 5.2 (1H, s); 6.8 (2H, s); 11.2 (1H, br.s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][C:2]1([C:12]([O:14]CC)=[O:13])[C:7]([O:9]CC)=[O:8].[OH-].[Na+:18].O1CCOC1>>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][C:2]1([C:7]([O-:9])=[O:8])[C:12]([O-:14])=[O:13].[Na+:18].[Na+:18]
Reactant: CCOC(=O)C1(C(=O)OCC)OCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCO1
Product: O=C([O-])C1(C(=O)[O-])OCCCO1
Yield: 102.6 %

Procedure:
Hydrolysis of 9.0 g (0.039 mol) of diethyl 1,3-dioxane-2,2-dicarboxylate with 6.8 g of 50% aqueous sodium hydroxide as described in Example 2 for the dioxolane analog yielded 8.4 g (0.04 mol) 98% of the title compound as a white free flowing solid.
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C[O:24][C:25]([C@@H:27]1[CH2:29][C@H:28]1[CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([C:37]2[C:41]3[S:42][CH:43]=[CH:44][C:40]=3[O:39][N:38]=2)[CH2:33][CH2:32]1)=O.CN1CCOCC1.[CH2:52]([C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1)[CH3:53]>CN(C)C=O>[CH2:52]([C@H:54]1[CH2:59][CH2:58][C@H:57]([NH:60][C:25]([C@@H:27]2[CH2:29][C@H:28]2[CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[C:41]4[S:42][CH:43]=[CH:44][C:40]=4[O:39][N:38]=3)[CH2:33][CH2:32]2)=[O:24])[CH2:56][CH2:55]1)[CH3:53]
Reactant: COC(=O)[C@@H]1C[C@H]1CN1CCC(c2noc3ccsc23)CC1
Reactant: CC[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCC(c3noc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add TOTU (415 mg, 1.06 mmol) to a solution of trans-2-(4-thieno[2,3-d]isoxazol-3-yl-piperidin-1-ylmethyl)-cyclopropanecarboxylic acid methyl ester (Example 22b) (300 mg, 1.0 mmol), in dimethylformamide (approximately 10 mL), and allow the reaction to stir at ambient temperature for 0.5 h. Add N-methylmorpholine (107 mg, 1.26 mmol) and trans-4-ethylcyclohexylamine (254 mg, 2.0 mmol), and stir for 6 h. Add additional equivalents of N-methylmorpholine and TOTU and continue to stir for overnight. I think again I didn't write it down Concentrate the reaction and purify the residue by column chromatography over silica gel (dichloromethane/MeOH, gradient 0→30%) to obtain 270 mg (65%), LC/MS, m/z=416 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:25])[N:3]=[CH:4]2)=[CH:12][CH:13]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccc(F)cc1
Reactant: O=C(O)c1ccncc1
Product: NC(=O)c1c(NC(=O)c2ccncc2)ncn1Cc1ccc(F)cc1
Yield: 65 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 19, using 2.0 g (8.5 mmol) of 4-amino-1-(4-fluorobenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 58 and isonicotinic acid instead of cyclopentylacetic acid to obtain 1.87 g of 1-(4-fluorobenzyl)-4-(4-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 65%).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH:14]([O:19]C(=O)NC(C2C=CC=CC=2)C)[C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C=CC=CC=1.[NH4+].[Cl-]>[O:1]([C:8]1[N:13]=[C:12]([C@@H:14]([C:15]([F:18])([F:16])[F:17])[OH:19])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O[C@@H](c1cccc(Oc2ccccc2)n1)C(F)(F)F
Yield: 81 %

Procedure:
A stirred solution of 1.28 g (3.08 mmol) of the [S-(R*,S*)] carbamate from Step A, 0.52 ml (380 mg, 3.7 mmol) of triethylamine, and 0.34 ml (460 mg, 3.4 mmol) of trichlorosilane in 12 ml of toluene under a nitrogen atmosphere was heated at 60° C. for 2 hours. The reaction mixture was then diluted with 50 ml of saturated aqueous NH4Cl and extracted with ether (3×25 ml). After being dried (MgSO4), the combined organic extracts were concentrated under reduced pressure and chromatography of the residue on 20 g of silica gel with 1:15 ethyl acetate/hexane afforded 667 mg (81%) of the title compound as a white solid melting at 51.5°-53.5° C.: [α]D22 =+2.0° (CHCl3, c 1.00) and [α]36522 =+4.8° (CHCl3, c 1.00). The spectral and chromatographic properties of this material were identical to those of racemic material prepared in Example 1 (Step C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([O:31]CC)=O)[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[O:31])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]([CH3:27])[CH2:23][CH2:24][O:25][CH3:26])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)CCOC)c1=O
Product: COCCN(C)C(=O)Cn1c(=O)c(C(=O)NCC(F)(F)F)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(2-{methyl[2-(methyloxy)ethyl]amino}-2-oxoethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2,2,2-trifluoroethylamine employing methods similar to those described in Example 9 and was recrystallized from a mixture of DMSO and EtOH. The product was obtained as a white solid: 1H NMR (d6-DMSO) mixture of rotamers δ 10.53 (1H, m), 8.55 (1H, s), 7.77 and 7.59 (1H, s), 7.29 (2H, m), 7.12 (2H, br t, J=8 Hz), 5.20 and 5.16 (2H, s), 4.27 (2H, br), 4.12 (2H, s), 3.63 and 3.57 (2H, br m), 3.40-3.20 (2H, m), 3.33 and 3.22 (3H, s), 3.16 and 2.81 (3H, s); AP+ MS: 525 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH2:17])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=1)[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(N2CCCCC2)ccc1NC(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
Subsequently, crude 2-amino-5-piperidin-1-yl-benzoic acid ethyl ester (compound A) (1.3 g) was dissolved in anhydrous methylene chloride (100 ml). Triethylamine (5.6 ml) and 3,4-dimethoxy-benzoyl chloride (compound B) (1.8 g) were added at 0° C., and the mixture was stirred at room temperature for 24 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-chloroform system to give 2-(3,4-dimethoxy-benzoylamino)-5-piperidin-1-yl-benzoic acid ethyl ester (960 mg, yield 52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[N:7]=[N:8][N:9]([C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:10]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C(=O)N([Br:38])C(=O)C1>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([Br:38])[C:6]1[N:7]=[N:8][N:9]([C:11]([CH3:19])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[N:10]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1nnn(C(C)(C)c2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)c1nnn(C(C)(C)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
A solution of [2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-acetic acid ethyl ester (Norman, D. P. G. et al JOC 1999, 64, 9301-9306) (2.53 g, 9.23 mmol) in THF (50 mL) stirring at −78° C. under N2 is treated with a 1 M soluion of NaHMDS in THF (9.23 mL) followed by NBS (1.64 g, 9.23 mmol). After 15 min, the reaction mixture is quenched by the slow addition of water and diluted with EtOAc. The organic layer is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The reaction mixture is purified by flash column chromatography eluted with 9:1 hexanes:EtOAc, then 2:1 hexanes:EtOAc, and finally flushed with EtOAc. The desired product, bromo-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-acetic acid ethyl ester, is recovered contaminated with 30% dibromide.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=C[CH:8]=1)([CH3:6])=[O:5])#[N:2].C(N=S(C1C=CC(N2C(=O)C3C(=CC=CC=3)C2=O)=NC=1)(C)=O)#[N:16]>>[C:1]([N:3]=[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[N:16][CH:8]=1)([CH3:6])=[O:5])#[N:2]
Reactant: CS(=O)(=NC#N)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Reactant: CS(=O)(=NC#N)c1ccc(CN)cc1
Product: CS(=O)(=NC#N)c1ccc(CN)nc1

Procedure:
The title compound is prepared in analogy to preparation 6d, substituting 2-(4-(N-cyano-S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione with 2-(5-(N-cyano-S-methylsulfonimidoyl)pyridin-2-yl)-isoindole-1,3-dione (preparation 16d). ESI mass spectrum: [M+H]+=211; r.t. HPLC: 0.23 min (Z011_S03).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:23]([CH3:24])[C:22](=O)[N:21]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([Br:33])=[CH:28][C:27]=4[CH3:34])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:10][CH2:9]1)=O)C.Cl.[OH-].[Na+]>O1CCCC1.CO>[Br:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:26]([N:21]2[C:16]3[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([N:11]4[CH2:12][CH2:13][CH:8]([CH2:6][OH:5])[CH2:9][CH2:10]4)[C:15]=3[C:23]([CH3:24])=[CH:22]2)=[C:27]([CH3:34])[CH:28]=1
Reactant: CCOC(=O)C1CCN(c2nc(C)nc3c2C(C)C(=O)N3c2c(C)cc(Br)cc2C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a solution of lithium borohydride (2.61 g) in tetrahydrofuran (60 mL) was added a solution of 1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid ethyl ester (6.0 g) in a mixture of tetrahydrofuran (60 mL) and methanol (3 mL) dropwise over 10 minutes under ice-cooling. The reaction mixture was warmed up to room temperature and stirred for 3 hours. After cooling with an ice-bath, 6 M HCl aqueous solution (30 mL) was added and stirred at room temperature for 1 hour. The solution was made to alkaline (pH=9) with 6 M NaOH aqueous solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=1:1) to give {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Yield: 75 %

Procedure:
According to the general procedure as outlined above for the synthesis of intermediate 43, f 5-chloroisatin, compound VIII, (10.0 g, 55.07 mmol) was reacted with potassium carbonate (9.89 g, 5.03 mmol) and tert-butyl bromoacetate (8.95 ml, 60.58 mmol) in N,N-dimethylformamide (100 ml) to give the title compound (12.14 g, 75%) as orange solid (HPLC purity: 99%) after precipitation from water. MS (ESI−): 294.2
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3([CH3:24])OCC[O:20]3)[CH:14]=2)[O:10][CH:11]=1)=[O:6].Cl.O>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:20])[CH3:24])[CH:14]=2)[O:10][CH:11]=1)=[O:6]
Reactant: COC(=O)c1coc(Cc2cccc(C3(C)OCCO3)c2)n1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1coc(Cc2cccc(C(C)=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-oxazole-4-carboxylic acid methyl ester (383 mg, 1.26 mmol) in THF (21.5 mL) was treated with 1N HCl (3.4 mL) and the reaction mixture was stirred at rt overnight. Water was added and the reaction mixture was extracted twice with EA (25 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.88 min, [M+AcCN+H]+=301.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.[Br:14]Br>C(OCC)C>[Br:14][CH:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[C:11]1=[O:12]
Reactant: O=C1CCCOc2cc(Br)ccc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2ccc(Br)cc2OCCC1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (1.2 g, 5 mmol) in diethyl ether (20 mL) at 0° C. was added bromine (257 μL, 5 mmol) dropwise under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, allowed to warm up to RT and stirred for 3 h. Further bromine (50 μL, 0.97 mmol) was added and stirring was pursued for 16 h. The solvent was removed in vacuo and the resultant residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to give the title compound as a white solid (1.55 g, 97%). 1H NMR (CDCl3): 7.62 (1H, m), 7.26 (2H, m), 4.94 (1H, dd, J=7.7, 6.7 Hz), 4.43 (1H, ddd, J=12.7, 5.6, 4.8 Hz), 4.25-4.15 (1H, m), 2.97-2.86 (1H, m), 2.51 (1H, ddt, J=14.7, 7.7, 4.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][CH2:14][C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16])[CH3:12]
Reactant: Nc1nc2ccccc2s1
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Aminobenzothiazole (4.5 g) is dissolved in pyridine (100 ml) and thereto is added dropwise ethoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, dried and recrystallized from a mixed solvent of diethyl ether/n-hexane to give the title compound (4.5 g) having the following physical properties.