Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2([CH3:14])[O:10][CH2:11][CH2:12][O:13]2)=[C:2]([O:1][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:7]=1
Reactant: CC1(c2ccc(Br)cc2O)OCCO1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(c2ccc(Br)cc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solution of 3.11 g (12 mmol) of 2-(2-hydroxy-4-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran were added dropwise successively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4]C(C=C)=[N:6][CH:7]=1.[O-:11][Mn](=O)(=O)=O.[K+].C[C:18]([CH3:20])=[O:19]>O>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:20]([C:18]([OH:11])=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=Cc1cc(C)c(Br)cn1
Agent: [K+]
Solvent: O
Product: Cc1cc(C(=O)O)ncc1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-bromo-4-methyl-2-vinyl-pyridine (7.04 g, 35.5 mmol) in acetone (280 mL) and water (280 mL), KMnO4 (28.81 g, 71.1 mmol) is added. The dark mixture is stirred at rt for 3 days before it is filtered over a glass-filter pad. The colourless filtrate is evaporated to give crude 5-bromo-4-methyl-pyridine-2-carboxylic acid (10.9 g, as potassium salt) as a white solid; LC-MS: tR=0.64 min, [M+1]+=215.90.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[C:24]3[C:37](=S)[NH2:38])=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.C([O-])(=O)C.[NH4+:48]>CC(C)=O.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=[C:24]3[C:37](=[NH:48])[NH2:38])=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(C(=O)NCCc2ccc3c(c2)c(C(N)=S)cn3C(=O)OC(C)(C)C)cc1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CI
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C(=O)NCCc2ccc3c(c2)c(C(=N)N)cn3C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
t-Butyl 5-[2-[4-(3-t-butoxycarbonylaminoprop-1-ynyl)-benzoylamino]ethyl}-3-thiocarbamoyl-indole-1-carboxylate (73 mg, 0.13 mmol, reference example 78) is dissolved in acetone (75 mL) and methyl iodide (5 mL) added. This mixture is heated to reflux. After 15 minutes, the solvent is removed in vacuo giving a yellow residue. MS (ion spray) m/e 591 (M+H+). The residue (80 mg, 0.13 mmol) is dissolved in MeOH (15 mL) and ammonium acetate (0.5 g) added and this mixture heated at reflux for 20 minutes. The solvent is removed in vacuo and the residue partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 and the combined organic layers washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC eluting with 30-70%/15 minutes, giving 22 mg. MS (ion spray) m/z 560 (M+H+).
Reaction SMILES: Cl.C([O:4][C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].N1C=CC=[CH:17][CH:16]=1>>[CH2:16]([CH2:8][N:7]([C:10](=[O:13])[CH2:11][CH3:12])[CH2:6][C:5]([OH:4])=[O:9])[CH3:17]
Reactant: CCOC(=O)CNC
Reactant: c1ccncc1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCCN(CC(=O)O)C(=O)CC
Reaction time: 0.33 h

Procedure:
A 250 mL round-bottomed flask was charged under a flow of nitrogen with pyridine (50 mL) and sarcosine ethyl ester hydrochloride (25 g) and then placed in an ice bath. Propionyl chloride (14.5 mL) was added by syringe over 15 minutes. After stirring for an additional 20 minutes, the ice bath was removed and the mixture was stirred for one hour. The mixture was poured into cold water (175 mL) and extracted with diethyl ether (2×100 mL) and then ethyl acetate (3×100 mL). The combined extracts were stripped on a rotary evaporator and dried under vacuum, yielding a pale yellow liquid (23.5 g). 1H NMR (CDCl3, 500 MHz) δ4.19 (q, J=7Hz, 2 H), 4.13 (s, 2 H), 3.08 (s, 3 H), 2.82 (q, J=7 Hz, 2 H), 1.29 (t, J=7 Hz, 3 H), 1.15 (t, J=7 Hz, 3 H). GC/MS: >99% pure, m/z=173.
Reaction SMILES: [Cl:1]C1C=CC([CH:6](O)[CH2:7][NH:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)=CC=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[ClH:1].[NH:10]1[CH2:11][CH2:12][N:13]2[CH2:6][CH2:7][N:8]=[C:9]12
Reactant: OC(CNC1=NCCN1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C1CN2CCNC2=N1
Product: Cl

Procedure:
3.4 parts of p-chloro-α-(2-imidazoline-2-ylaminomethyl)benzyl alcohol are added to 30 parts of sulfuric acid 80% while stirring and cooling in an ice-bath. Upon completion, the whole is stirred for 2 hours at room temperature. The reaction mixture is poured onto crushed ice, alkalized with a concentrated sodium hydroxide solution and the product in base form is extracted with methylene chloride. The extract is dried, filtered and evaporated. The residue is dissolved in 2-propanol. The solution is filtered over diatomaceous silica and the filtrate is acidified with an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off, washed with acetone and dried, yielding 5-p-chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole hydrochloride, m.p. 266.1°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22]CC(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:60]=[CH:59][C:51]([C:52]([O:54]C(C)(C)C)=[O:53])=[CH:50][CH:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:31][CH3:32])[C:20]([NH:22][C:48]2[CH:60]=[CH:59][C:51]([C:52]([OH:54])=[O:53])=[CH:50][CH:49]=2)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(C(=O)O)cc1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl 4-aminobenzoate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:7].O.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[Cl:7][C:1]1[CH:6]=[CH:5][C:4]([C@H:1]2[CH2:6][CH2:5][C@H:4]([CH2:3][CH2:2][C@H:1]3[CH2:6][CH2:5][C@H:12]([CH:13]=[O:9])[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: c1ccccc1
Reactant: Cl
Solvent: O
Product: O=C[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C

Procedure:
A solution of 18.1 g of 4-chloro-1-[trans-4-{2-(4-methoxymethylidene)cyclohexyl)ethyl]cyclohexyl]benzene in 90 ml of tetrahydrofuran is treated with 22.5 ml of 2N hydrochloric acid and boiled at reflux for 30 minutes while stirring and gassing with nitrogen. Subsequently, the reaction mixture is cooled to room temperature, poured into 400 ml of water and extracted with methylene chloride. The organic phases are washed with water, dried over sodium sulphate, filtered and concentrated. The residue is dissolved in 150 ml of tert.-butyl methyl ether. The solution is evaporated to a large extent and then treated with 200 ml of methanol. Crystallization at -25° C. and recrystallization of the colourless, crystalline precipitate gives pure trans-4-[2-(trans-4-(4-chlorophenyl)cyclohexyl)ethyl]cyclohexanecarboxaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])=[CH:13][C:12]([C:23]([N:25]2[CH2:29][CH2:28]SC2=S)=[O:24])=[CH:11][C:10]=1[C:31]([N:33]1[CH2:37][CH2:36][S:35][C:34]1=[S:38])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40]CCN.CO>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([C:15]([N:17]2[CH2:21][CH2:20][S:19][C:18]2=[S:22])=[O:16])=[CH:13][C:12]([C:23]([NH:25][CH2:29][CH2:28][O:40][CH3:39])=[O:24])=[CH:11][C:10]=1[C:31]([N:33]1[CH2:37][CH2:36][S:35][C:34]1=[S:38])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1)N1CCSC1=S
Reactant: COCCN
Solvent: CO
Solvent: ClCCl
Product: COCCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1

Procedure:
To a slurry of the trithiazolide 17 (31.0 g, 0.05 mol) in dichloromethane (600 mL), a solution of 2-methoxyethylamine (0.38 g, 5 mmol) in dichloromethane (30 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in methylene chloride). The desired product was obtained as yellow, thick oil; yield 2.1 g (73% based on the methoxyethylamine). 25.8 g of unreacted starting trithiazolide was also recovered during the separation.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=O)[CH:26](Br)[CH2:27]C)C.COCCCC.C[O-].[Na+]>O.C(O)(=O)C>[CH2:26]([C:25]([CH2:15][C:14]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(Br)CC
Reactant: COc1ccc(C=O)cc1OCCOCc1ccccc1
Agent: CCCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)Cc1ccc(OC)c(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
24 g of the product of step (ii) 21.5 g bromobutyric acid ethyl ester and 30 ml t.butyl methyl ether are added dropwise over 50 mins. at 5° C. to a pre-prepared suspension of sodium methylate in 25 ml t.butyl methyl ether. The reaction mixture is stirred for 45 mins. at ca. 5° C. and then stirred for 12 hrs. at room temperature. The pH is adjusted to 5 by addition of glacial acetic acid and the obtained suspension diluted with H2O and extracted 3× with t.butyl methyl ether. The organic phase is extracted with NaHCO3 (1×) and brine (1×), and evaporated to ca. 100 ml. 13.5 ml 50% aqueous NaOH are added drop-wise and the whole stirred for 2 hrs. at 40° C., diluted with 50 ml. H2O and stirred for a further 30 mins. at room temperature. The organic phase is separated and the aqueous phase adjusted to pH 1 at max. 40° C. with 15 ml conc. HCl. The reaction mixture is stirred at 40° C. for a further 1.5 hrs., cooled to room temperature and extracted with toluene. The organic phase is washed with NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to yield the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:3]=1[C:16](=[O:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].[N+:25]([C:28]1[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=1)([O-:27])=[O:26]>CS(C)=O.O.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][O:12][C:4]1[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=[C:2]([O:1][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[C:3]=1[C:16](=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cc(OCOC)c(C(C)=O)c(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
To a stirred suspension of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]ethanone (78 g, 298 mmol) and K2CO3 (45.3 g, 328 mmol) in DMSO (500 mL) and water (40 ml) was added 4-nitro-1-fluorobenzene (46.3 g, 328 mmol, 1.1 eq). After stirring for 15 min. at room temperature, the resulting suspension was heated for 6 hours at 55° C. After cooling, the dark solution was diluted with ethyl acetate (2000 mL) and thoroughly washed with 10% citric acid solution, then with brine and dried over Na2SO4. The solvent was removed and the residue was columned over silica gel eluting with cyclohexane/ethyl acetate 3/1, to provide the title compound (56 g, 52% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][CH:27]=[CH2:28])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].P(C)(C)C>C1COCC1.O.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][CH:27]=[CH2:28])[C@@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N=[N+]=[N-])C(=O)OCc1ccccc1
Agent: CP(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-2) (101 mg, 0.262 mmol) in THF (3.9 mL) and H2O (0.4 mL) was added Me3P (0.29 mL, 0.29 mmol, 1 M sol. in THF) and stirring was continued at 23° C. for 3 h. The reaction mixture was diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over Na2SO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 1:1 (+small amount of Et3N) to give (1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-2) (47 mg, 50%) as a light brown oil. 1H-NMR (250 MHz, CDCl3) □1.24 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 1.93 (2H, bs), 1.99 (1H, m), 2.07-2.18 (2H, m), 2.31 (1H, dd, J=12.5, 7 Hz), 3.45 (1H, bt, J=8 Hz), 3.93 (2H, bd,J=6 Hz), 4.12 (2H, q, J=7.1 Hz), 5.10-5.35 (4H, m), 5.78 (1H, m), 7.28-7.38 (5H, m); MS[ISP] 360 [(M+H)+ ]; □D20 -10.67° (c=1.00, CHCl3).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:39]=[CH:38][CH:37]=[CH:36][C:15]=1[NH:16][C:17]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:18]=1[C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20]>>[F:13][C:14]1[CH:39]=[CH:38][CH:37]=[CH:36][C:15]=1[N:16]1[C:17]2[C:18](=[CH:30][C:31]([F:35])=[C:32]([F:34])[CH:33]=2)[C:19](=[O:20])[N:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:1]1=[O:2]
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 48.5 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.9 g, 30 mmol) and crude 2-(2-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example Y, 5.6 g, 15 mmol) provided 2.9 g of the title compound as a solid, mp 204-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([NH:8][NH2:9])[CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.O>ClCCl>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:10])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cc(Cl)ccc1F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)=NNc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
(5-Chloro-2-fluoro-phenyl)-hydrazine (22.5 g, 140 mmol) was dissolved in dichloromethane (80 mL). Ethyl pyruvate (16.3 mL, 140 mmol) was added slowly to this solution at room temperature. The mixture was stirred for another 1 h at room temperature, added to water and extraxcted with dichloromethane. Organic phases were pooled, washed subsequently with hydrochloric acid (1 N) and brine and dried with MgSO4. Solvents were removed in vacuo and the residue was triturated with n-hexane to yield the title product as beige solid (22.8 g, 62.9%), ISP-MS: m/e=259.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH:31]=[CH:30][C:29]([O:33][CH3:34])=[O:32])=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
5-Bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, (1.0 g, Example 1 part c)), methyl acrylate (0.95 ml), tri-o-tolylphosphine (0.128 g), palladium acetate (0.047 g) and triethylamine (4 ml) in acetonitrile (20 ml) were stirred in a pressure tube at 70° C. for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by flash silica chromatography eluting with a gradient of 0-1% ethanol in dichloromethane to give the sub-title compound as a brown foam (0.90 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][C:23](O)=[O:24].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:23](=[O:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(NC(=O)Cc2ccc(Cl)cc2Cl)c1

Procedure:
To a solution of 1.1 g 3-Amino-4-methoxy-benzoic acid methyl ester and 1 g (2,4-Dichloro-phenyl)-acetic acid in 15 ml CH2Cl2, 2.7 ml NEt3 and 1.24 g BOP-Cl and 10 mg DMAP were added. After stirring over night the solvent was removed under reduced pressure and the residue directly purified by chromatography on silica with ethyl acetate/heptane 1:5→1:1 to yield the ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C@:10]3([C@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[N:12]([CH2:24][CH2:25][CH2:26]Cl)[C@@H:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][O:33][CH:34]([Si](C)(C)C)[CH3:35].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.FC(F)(F)C(O)=O>>[CH3:25][CH2:24][N:12]([CH:11]([CH3:10])[CH3:28])[CH:13]([CH3:14])[CH3:32].[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:35][C:34](=[O:33])[N:12]([CH2:24][CH2:25][CH2:26][N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: C=C(C)[C@H]1N(CCCCl)C(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C1N(CCCN2CCCCC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: CCN(C(C)C)C(C)C
Yield: 23.1 %

Procedure:
In a manner similar to the method described in example 60b, (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 123a (0.12 g, 0.20 mmol) was reacted with piperidine (2 mL), trifluoroacetic acid (1 mL) and then N,N′-diisopropylethylamine (1.5 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-(3-piperidin-1-yl-propyl)spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as a yellow solid (Yield: 40 mg, 23.1%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].Br[CH2:14][O:15][CH3:16].CN([CH:20]=[O:21])C>>[CH3:14][O:15][CH2:16][O:1][C:2]1[CH:7]=[C:6]([O:21][CH3:20])[CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)C=O
Reactant: COCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [H-]
Agent: [Na+]
Product: COCOc1cc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of hydroxynitrobenzene (21.2 g, 0.125 mol) in DMF (250 ml) was added sodium hydride (4.5 g, 0.188 mol) at 0° C. under argon. The mixture was allowed to stir at 0° C. for 1 h, then bromomethyl methylether (22 ml, 0.150 mol) was added. After stirring for 18 h at rt the reaction was quenched with water. The mixture was extracted with ethyl acetate (3×30 ml) and the combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduce pressure gave the title compound as a brown oil (23.4 g, 88%).
Reaction SMILES: Br[CH2:2][C:3](=[O:15])[C:4]([CH3:14])([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:5].[P:16]([O:21]C)([O:19][CH3:20])[O:17][CH3:18]>C1(C)C=CC=CC=1>[CH3:18][O:17][P:16]([CH2:2][C:3](=[O:15])[C:4]([CH3:14])([O:6][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:5])([O:19][CH3:20])=[O:21]
Reactant: COP(OC)OC
Reactant: CC[Si](CC)(CC)OC(C)(C)C(=O)CBr
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)OC(C)(C)C(=O)CP(=O)(OC)OC
Yield: 90 %

Procedure:
A solution of 14 (1.55 g; 5.25 mmol) and trimethyl phosphite (514 μl; 782 mg; 6.31 mmol) in toluene (20 ml) was refluxed for 3 days. The mixture was purified by column chromatography (5-15% 2-propanol/hexane) to give 1.54 g (4.75 mmol; 90% yield) of 2. 1H NMR (400 MHz, CDCl3) δ 0.65 (6H, q, J=7.9 Hz), 0.98 (9H, t, J=7.9 Hz), 1.36 (6H, s), 3.40 (2H, d, JH—P=20.7 Hz) 3.80 (6H, d, JH—P=11.2 Hz); 13C NMR (101 MHz, CDCl3) δ 6.4, 6.9, 26.8, 33.7 (d, JC—P=137.8 Hz), 52.8 (d, JC—P=6.7 Hz) 80.0, 207.1 (d, JC—P=6.0 Hz); MS (EI) m/z 324 ([M−Et]+, 98), 238 (65), 211 (61), 173 (100); exact mass calculated for C11H24O5PSi ([M−Et]+) 295.1126. found 295.1126.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[CH3:29][C:26]1([CH3:30])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:18][C:17](=[O:33])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:3]=[C:2]([NH:1][C:44]([NH:43][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:45])[CH:36]=[CH:35][CH:34]=4)[CH2:20]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccccc5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.057 g) in dichloromethane (2 ml) was treated with phenyl isocyanate (0.020 g) and the mixture stirred under nitrogen at 20° C. for 2 h. Isopropanol (5 ml) was added to quench excess isocyanate, and the mixture stirred for 30 min before leaving to stand for 15 h. The solvents were removed in vacuo to give a residue which was purified by SPE. Elution with a stepped gradient of eluants from cyclohexane to cyclohexane-EtOAc (9:1) and onwards to EtOAc followed by solvent evaporation in vacuo gave the title compound (0.062 g). LCMS RT=3.70 min, ES+ve 618 (MH)+.