Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:41]=[C:40]2[C:36]([CH2:37][CH2:38][N:39]2[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:35][C:34]=1[O:48][CH3:49]>>[CH3:47][N:45]([CH3:46])[C:43](=[O:44])[CH2:42][N:39]1[C:40]2[C:36](=[CH:35][C:34]([O:48][CH3:49])=[C:33]([NH:32][C:2]3[NH:7][C:6]4=[N:8][CH:9]=[CH:10][C:5]4=[C:4]([NH:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=4[C:24]([NH2:26])=[O:25])[N:3]=3)[CH:41]=2)[CH:37]=[CH:38]1
Reactant: COc1cc2c(cc1N)N(CC(=O)N(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Product: COc1cc2ccn(CC(=O)N(C)C)c2cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Yield: 5.7 %

Procedure:
In a manner analogous to General Protocol III, 2-[(2-{[1-[2-(dimethylamino)-2-oxethyl]-5-(methyloxy)-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.25 g, 0.54 mmol) and 2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-N,N-dimethylacetamide (0.16 g, 0.64 mmol) to afford the title compound (0.016 g, 6% over 3 steps) as a grey solid. LCMS (ESI+) and 1H NMR indicate oxidation of the indoline to the indole. ESIMS (M+H)+=517. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3 H) 2.98 (s, 3 H) 3.80 (s, 3 H) 4.93 (s, 2 H) 6.19-6.20 (m, 1 H) 6.29-6.30 (m, 1 H) 6.82-6.91 (m, 1 H), 6.94-7.01 (m, 1 H) 7.04-7.11 (m, 2 H) 7.25-7.35 (m, 1 H) 7.60 (s, 1 H) 7.98 (s, 1 H) 8.04 (s, 1H) 8.09 (s, 1 H) 8.45 (d, J=8.42 Hz, 1 H) 10.48 (s, 1 H) 11.23 (s, 1 H).
Reaction SMILES: [CH3:1][Si:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:28][C:29](OCC)=[O:30])[CH2:22][C:23](OCC)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[AlH4-].[Li+]>C1COCC1>[CH3:35][Si:2]([CH3:1])([CH3:34])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:22][CH2:23][OH:24])[CH2:28][CH2:29][OH:30])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCOC(=O)CC(CC(=O)OCC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)CCO)c3)ncnc21
Reaction time: 1 h
Yield: 76 %

Procedure:
Diethyl 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol), was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To this mixture, 1.0 M lithium tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction was stirred for 1 h, quenched with ice and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil. The product was purified by FCC on silica gel eluting with an ethyl acetate: methanol gradient to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-1,5-diol as a clear viscous oil (0.51 gm, 76%), LC/MS (M+H)+: 418, 1H NMR (DMSO-d6) 6, 8.85 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 7.45 (d, 1H), 6.83 (d, 1H), 5.73 (s, 2H), 4.91 (m, 1H), 3.75 (m, 2H), 3.59 (m, 2H), 3.45 (m, 2H), 2.18 (m, 4H), 0.95 (m, 2H), 0.1 (s, 9H).
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:14]([C:4]=1[OH:20])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(C)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(C)nc2c1O
Temperature: 25 °C
Yield: 41.4 %

Procedure:
The suspension of 2-[(6-methyl-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester (24.0 g, 86.23 mmol) in diphenylether (300 mL) was heated under refluxing for 3 hrs. After cooling to room temperature, the reaction mixture was poured into nHexane (1000 mL) and the solid was collected by filtration to give 4-hydroxy-6-methyl-[1,5]naphthyridine-3-carboxylic acid ethyl ester (8.3 g, 42%). HR-MS-EI (+) m/e calcd for C12H12N2O3 (M+) 232.0848. found 232.0846.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:23]1([C:17]2[CH:16]=[C:15]([C:13]3[C:12]4[C:11]([CH3:28])=[C:10]([CH3:29])[S:9][C:8]=4[CH:1]=[C:2]4[C:7]=3[CH:6]=[CH:5][CH:4]=[CH:3]4)[CH:20]=[CH:19][C:18]=2[OH:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 78 %

Procedure:
To (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone (4.8 g, 11.7 mmol) in anhydrous methylene chloride (70 mL) at −78° C. under nitrogen was added dropwise over a period of 20 min boron tribromide (3.6 mL, 37.6 mmol). The reaction mixture was then allowed to stir at room temperature for 22 h. The solution was poured onto a mixture of ice and water (600 mL) and extracted with diethyl ether (800 mL). The diethyl ether layer was washed twice with water (500 mL) and once with brine (500 mL). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3) gave the title compound as a white solid (3.4 g, 78%): mp 156-158° C.; (DMSO-d6): δ9.48 (s, 1H), 8.42 (s, 1H), 7.93 (d, 1H), 7.46-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.00 (s, 1H), 6.95-6.90 (m, 2H), 3.38-3.28 (m, 1H), 2.39 (s, 3H), 1.99-1.90 (m, 2H), 1.68-1.47 (m, 6H), 1.60 (s, 3H); MS(EI): [M+] 372; Anal. Calc. for C25H24OS: C, 80.60; H, 6.49; N, 0.00. Found: C, 80.39; H, 6.43; N, 0.04.
Reaction SMILES: [CH:1]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([C:27]1[N:28]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[S:56](=[O:59])(=[O:58])[NH2:57])=[CH:46][CH:45]=2)[C:29](=[O:42])[N:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[N:31]=1)[CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1>>[CH2:23]([C:27]1[N:28]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[S:56](=[O:59])(=[O:58])[NH:57][C:8]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:10])=[CH:46][CH:45]=2)[C:29](=[O:42])[N:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)C1CCCCCC1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C2CCCCCC2)cc1

Procedure:
The title compound was prepared from cycloheptanecarboxylic acid (2.0 equivalents), CDI (2.0 equivalents), 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) (1.0 equivalent), and DBU (2.0 equivalents) according to the procedure of Example 7, to give a 69% yield of the desired material after flash chromatography, as a glassy solid, mp 146°-149° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 655 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3[N:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:18][CH:17]=4)=[CH:15][C:6]=3[C:5]=2[CH:4]=1)#[CH:2].[N:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N+:30]=[N-:31]>CN(C)C=O.C(Cl)Cl.CO.[Cu]I>[CH2:32]([N:29]1[CH:2]=[C:1]([C:3]2[N:11]=[CH:10][C:9]3[NH:8][C:7]4[N:12]=[CH:13][C:14]([C:16]5[CH:17]=[CH:18][C:19]([CH2:22][N:23]6[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]6)=[CH:20][CH:21]=5)=[CH:15][C:6]=4[C:5]=3[CH:4]=2)[N:31]=[N:30]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(Cn2cc(-c3cc4c(cn3)[nH]c3ncc(-c5ccc(CN6CCCCC6)cc5)cc34)nn2)cc1
Temperature: 60 °C
Yield: 20 %

Procedure:
A mixture of 6-ethynyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (90 mg, 0.2 mmol), copper (I) iodide (4.7 mg, 0.02 mmol), and azidomethyl-benzene (36 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) was heated at 60° C. for 2 h. The cooled reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by preparative HPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as an off-white solid (20 mg, 20%). 1H NMR (DMSO-D6, 400 MHz): 12.30 (s, 1H), 9.16 (d, J=2.2 Hz, 1H), 8.93 (s, 2H), 8.91 (s, 1H), 8.61 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.40 (m, 7H), 5.69 (s, 2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.57-1.46 (m, 4H), 1.40 (m, 2H). LCMS (Method D): RT=9.35 min, M±H+=500.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccccc1S
Product: Clc1ccc(-c2nc3ccccc3s2)cc1

Procedure:
2-Aminothiophenol (12.5 g, 0.1 mole) and 14.1 g (0.1 mole) p-chlorobenzaldehyde were combined in an Erlenmeyer flask at room temperature. The aldehyde dissolved in the mixture which became cloudy after a few minutes. Heat was evolved and the mixture gradually solidified. The product was recrystallized from ethanol yielding 18.0 g (73%) pale yellow crystals, mp. 85°-87°.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9](Br)[C:10]([O:13][CH:14](F)F)=[N:11][CH:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[NH:18]1[CH:22]=[CH:21][C:20](B(O)O)=[N:19]1>>[CH3:14][O:13][C:10]1[C:9]([C:21]2[CH:22]=[N:18][NH:19][CH:20]=2)=[CH:8][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:12][N:11]=1
Reactant: FC(F)Oc1ncc(Cn2cncn2)cc1Br
Reactant: OB(O)c1cc[nH]n1
Product: COc1ncc(Cn2cncn2)cc1-c1cn[nH]c1

Procedure:
The title compound was prepared in a manner analogous to Example 4, from Intermediate 13 and the appropriate pyrazole boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.07 (s, 1H), 8.01 (q, J=2.3 Hz, 2H), 7.99 (s, 1H), 5.37 (s, 1H), 3.94 (s, 3H), 2.52 (s, 1H). [M+H]=257.26.
Reaction SMILES: [NH2:1][C@H:2](C(O)=O)[CH2:3]C1C=C2C(C=CC=C2)=CC=1.[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][C:25]2=O)=[CH:20][CH:19]=1.Cl>C1COCC1>[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH2:22][CH2:23][CH2:24][C:25]2=[CH:3][C:2]#[N:1])=[CH:20][CH:19]=1
Reactant: O=C1CCCc2ccc(F)cc21
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: N#CC=C1CCCc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.6 eq. of Nal are suspended in 130 ml of anhydrous THF under a nitrogen atmosphere in a 250 ml three-necked flask. The mixture is cooled in a bath of ice/salt and 1.6 eq. of diethyl cyanomethylenephosphonate in 40 ml of THF are added dropwise. The reaction mixture is stirred for 45 minutes and then, whilst still cold, 1 eq. of the compound obtained in Step E, in 70 ml of THF, is added dropwise. The mixture is stirred for 4 hours and is then poured onto a mixture of ice/water, acidified with 3M HCl solution and extracted 3 times with ethyl ether. The organic phase is dried over MgSO4 and evaporated under reduced pressure; the residue obtained is recrystallised.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][OH:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CCNC(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [H-]
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)n(CCNC(=O)OC(C)(C)C)c2c1
Yield: 97.6 %

Procedure:
To a solution of methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (450 mg, 0.89 mmol) in methanol (4 ml) was added borosodium hydride (50.0 mg, 1.32 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-hydroxymethylphenyl)-1H-indole-6-carboxylate (440 mg, yield 97%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[OH2:13]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[CH:2]=[C:3]([C:4]([NH2:5])=[O:13])[N:7]=[N:6]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: O
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 82 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzylazide (9,22 g), 2-chloroacryonitrile (6,68 g) and water is stirred at about 82° C. for about 24 hours. 2-Chloroacrylnitrile is distilled off by raising the external temperature to about 113° C. excess. The mixture is cooled to about 40° C. and toluene (10 ml) is added. Within about 40 minutes at about 80° C. sodium hydroxide (5,5 ml—30%) is added the amide being crystallized. By raising the external temperature to 112° C., toluene is distilled off. The suspension is cooled to 20° C. and the product is isolated by filtration, washed with water (200 ml) and dried at about 60° C. in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[C:13]1([CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1

Procedure:
To a solution of 36.6 g (0.3 mol) of 4-hydroxybenzaldehyde in 100 ml of ethanol were added dropwise, one after another, a solution of 12.0 g (0.3 mol) of sodium hydroxide in 100 ml of water and a solution of 36.5 ml of (0.307 mol) of benzylbromide in 100 ml of ethanol and the mixture was then kept for 1 hour at 50° C. The ethanol was extensively distilled off, finally in vacuo, the remaining aqueous emulsion was divided between water and ethyl acetate. The ethyl acetate phase was dried over sodium sulphate and evaporated down in vacuo. The residue remaining crystallised on trituration with petroleum ether and was recrystallised from diisopropylether. 48.0 g (75.4% of theory) of colourless crystals of melting point 118-122° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[C:15]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)C1(c2ccc(O)cc2)CC1
Product: COC(=O)C1(c2ccc(OCCC(=O)OC(C)(C)C)cc2)CC1
Temperature: 110 °C
Yield: 54 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (7.0 g, 3.6 mmol) in acrylic tert-butyl ester (50 mL) was added Na (42 mg, 1.8 mmol) at room temperature. The mixture was heated at 110° C. for 1 h. After cooling to room temperature, the resulting mixture was quenched with water and extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (6.3 g, 54%) and unreacted start material (3.0 g). 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 3.62 (s, 3H), 2.69 (t, J=6.6 Hz, 2H), 1.59-1.56 (m, 2H), 1.47 (s, 9H), 1.17-1.42 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])=[CH:5][N:6]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH3:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])=[CH:5][N:6]=1
Reactant: Cc1ncc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1

Procedure:
A solution of tert-butyl 4-{1-[(2-methyl-1,3-thiazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (715 mg; compound B20) in DCM (15 ml) is reacted with trifluoroacetic acid (3 ml) according to the procedure described in example B43 to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13](Cl)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][NH:17][CH2:18][CH2:19][CH2:20][P:21](=[O:24])([OH:23])[OH:22].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(OCC)C.O.CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:17]([CH2:18][CH2:19][CH2:20][P:21](=[O:22])([OH:24])[OH:23])[OH:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CNC(=O)OCc1ccccc1
Reactant: O=P(O)(O)CCCNO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C(NCC(=O)N(O)CCCP(=O)(O)O)OCc1ccccc1
Yield: 32.7 %

Procedure:
A solution of N-benzyloxycarbonylaminoacetyl chloride (2.85 g) in ethyl ether (5 ml) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (985 mg) and sodium bicarbonate (1.51 g) in a mixture of water (20 ml) and methanol (20 ml) with stirring under ice-cooling. During the period, the reaction mixture was adjusted to pH 7-8 with 5% aqueous sodium bicarbonate solution. The stirring was continued for an hour, whereafter the mixture was adjusted to pH 10 with 1 N aqueous sodium hydroxide solution and stirred at the same temperature for 45 minutes. The resultant mixture was adjusted to pH 7 and methanol was distilled off under reduced pressure. The resultant aqueous solution was adjusted to pH 2 with 10% hydrochloric acid and washed with ethyl acetate (30 ml), whereafter the solution was adjusted to pH 1 with 10% hydrochloric acid and then extracted twice with n-butanol (30 ml). The combined n-butanol layer was concentrated under reduced pressure to give a residue, which was crystallized from ether to give 3-[N-(N-benzyloxycarbonylaminoacetyl)N-hydroxyamino]propylphosphonic acid (720 mg) in the form of crystals MP: 101°~105° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)=[O:12].Cl[Si](C)(C)C.[Cl:40][CH2:41][CH2:42]OS(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[CH2:18])[CH:16]([CH2:42][CH2:41][Cl:40])[C:15](=[O:19])[NH:14]1)=[O:12]
Reactant: O=S(=O)(OCCCl)C(F)(F)F
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C1C(CCCl)C(=O)NC1(C(=O)OC)C(O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Lithium diisopropylamide solution (0.67 M solution in tetrahydrofuran, 0.09 ml, 0.06 mmol, 1.0 equiv) was added dropwise via syringe to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (23 mg, 0.06 mmol, 1.0 equiv) in tetrahydrofuran (1.5 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (8 μl, 6.8 mg, 0.06 mmol, 1.0 equiv) was added and the resultant solution was stirred at −78° C. for 2.5 h. Another equiv of lithium diisopropylamide solution (0.67 M solution in tetrahydrofuran, 0.09 ml, 0.06 mmol, 1.0 equiv) was added dropwise at −78° C. The reaction mixture was stirred −78° C. for 30 min. A stock solution of trifluoro-methanesulfonic acid 2-chloro-ethyl ester in toluene (2.45 M, 0.1 ml, 0.24 mmol, 4.0 equiv) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 50 min. A buffer solution (pH=7, 5 ml) was added at −78° C. The organic layer was separated, washed with brine solution (5 ml), dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to furnish 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-4-(2-chloro-ethyl)-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (16 mg, 59%) along with recovered starting material (5 mg, 22%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C@H:3]2[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:2]12.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([N:5]1[C:1](=[O:11])[C@H:2]2[CH2:10][CH:9]=[CH:8][CH2:7][C@H:3]2[C:4]1=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1[C@H]2CC=CC[C@H]2C(=O)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
30.2 g of cis-1,2,3,6-tetrahydrophthalimide was dissolved in 200 ml of N,N-dimethylformamide. After adding 38.7 g of potassium carbonate and 30.4 g of benzyl chloride, the resulting mixture was stirred at 50° C. for 3 hours and further at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were ground and washed with diisopropyl ether and n-hexane followed by filtration. Thus 39.1 g of the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:24])=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:24])[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1-c1cccc(OC)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1cc(CCl)ccc1-c1cccc(OC)c1
Reaction time: 8 h

Procedure:
To a stirred solution of T13.2 (530 mg, 1851 μmol) in DCM (15 mL) at 23° C. was added thionyl chloride (270 μL, 3702 μmol). The resulting mixture was stirred overnight and was then concentrated and then purified by silica gel chromatography (0 to 10% EtOAc/hexanes) to provide T13.