Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:3]1.[C:17]1([S:23]Cl)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:15][N:14]([S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](=[O:13])[O:11][C:8]1[C:9]2[O:10][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: ClSc1ccccc1
Solvent: c1ccncc1
Product: CN(Sc1ccccc1)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 11 g of carbofuran in 50 ml of pyridine was added to 14.5 g of benzenesulfenyl chloride and the mixture was allowed to stand overnight at room temperature. The mixture was filtered, 250 ml of dry ether was added to the filtrate and the mixture refiltered. The filtrate was concentrated under reduced pressure. The residue was washed by stirring with 50 ml of water for one hour at room temperature. When the oily product was stirred with 200 ml of hexane, about 80% dissolved. The hexane solution was decanted, washed six times with water, then with saturated aqueous sodium chloride solution, then dried over sodium sulfate. The dried solution was concentrated under reduced pressure and the residue distilled to give a colorless liquid, b.p. 168°-174° at 0.005 mm. Redistillation gave 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (methyl)(phenylthio)carbamate, b.p. 168° at 0.005 mm, nD25 1.5758. This compound crystallized upon standing, m.p. 66°. The n.m.r. spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[F:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7]>>[F:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:2]([CH3:3])[CH3:1])[C:6]=1[NH2:7]
Reactant: Nc1ccccc1F
Reactant: C=CC
Product: CC(C)c1cccc(F)c1N

Procedure:
2-fluoro-6-isopropyl aniline was prepared by the method of Example 2 using an H-Y zeolite catalyst for the condensation of 2-aniline and propylene. In this reaction 2-fluoroaniline and propylene were fed to a reactor in a 1:5 mole ratio and LHSV of 0.25 based on 2-fluoroaniline. The reaction was conducted at 255° C. and 879 psig. The effluent product stream was analyzed by gas chromatography. Conversion of 2-fluoroaniline was 71.2%.
Reaction SMILES: C1(C#C)C=CC=CC=1.[CH:9]1([CH2:15][CH2:16][C:17]#[CH:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:18]=[C:17]([CH2:16][CH2:15][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#CCCC1CCCCC1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(CCC3CCCCC3)nn2)sc1C(=O)NCc1ccccc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with 4-cyclohexylbutyne to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 22% yield: mp 82-84° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.37-7.33 (m, 5H), 6.19 (br s, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.68 (s, 3H), 1.78-1.56 (m, 5H), 1.30-1.16 (m, 5H), 0.99-0.71 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.7, 153.3, 149.9, 137.5, 128.8, 127.8, 123.8, 118.2, 44.3, 37.0, 36.5, 33.1, 26.5, 26.2, 22.9, 17.4; MS (ES+) m/z 410.4 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13].[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])=[N:24][NH:25][CH:26]=2)=[CH:18][CH:17]=1>CN(C=O)C>[N:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])=[N:24][N:25]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:26]=2)=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c(-c2cccc(C#N)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
Cesium carbonate (8.34 g, 25.6 mmol) and (2-chloromethoxy-ethyl)-trimethyl-silane (1.71 g, 10.24 mmol) were added to a solution of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (2.10 g, 8.54 mmol) in dry DMF (70 ml) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 24 h. A further addition of (2-chloromethoxy-ethyl)-trimethyl-silane (0.57 g, 3.41 mmol) was required to affect reaction completion; the solvent was then removed under reduced pressure and the residue was taken up with DCM (50 ml). The organic layer was washed with a saturated NaHCO3 solution (1×50 ml), brine (1×50 ml), dried over Na2SO4. The filtrate was evaporated to dryness to give a brown oil, which was purified by flash chromatography, over silica gel, using DCM/MeOH/NH4OH (9.8:0.2:0.1) as eluent, to afford 3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzonitrile (2.57 g, 6.82 mmol, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17](B(O)O)[C:18]([F:21])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.C([O-])(=O)C.[K+].C(O)C.O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:21][C:18]1[N:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:16][C:17]=1[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
A mixture of 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (655 mg, 1.931 mmol), 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (586 mg, 2.317 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich) (25.6 mg, 0.097 mmol) and potassium acetate (285 mg, 4.83 mmol) in ethanol (6.00 mL, 103 mmol) and H2O (1.00 mL, 55.5 mmol) was heated at 80° C. for 2 h. After cooling, the reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (pure hexanes to 50% ethyl acetate in hexane) to give the tert-butyl 4-((6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate as a pale yellow foam (0.877 g, 89%). LCMS (API-ES) m/z 512 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:10][CH2:11][CH:12]=[CH2:13])=[C:6]([OH:9])[CH2:7][CH3:8])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.CCOC(C)=O>[CH2:11]([O:10][CH:5]([CH:6]([OH:9])[CH:7]=[CH2:8])[CH2:4][OH:3])[CH:12]=[CH2:13]
Reactant: C=CCOC(C(=O)OCC)=C(O)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(CO)C(O)C=C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-allyloxy-3-hydroxy-pentenoic acid ethyl ester (200 mg, 1.00 mmol) in THF (5 mL) was added LiAlH4 (151 mg, 4.00 mmol). The resulting solution was stirred at ambient temperature for 15 min. H2O (10 mL) was added and the mixture was diluted with EtOAc (50 mL×2), washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 50% EtOAc-hexane
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([F:16])[F:15])=[CH:10][CH:9]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:24]=[C:23]([C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[F:31])[CH:22]=[CH:21][C:20]=1[OH:32].C(N(CC)CC)C>C(#N)C.O>[F:15][CH:14]([F:16])[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][CH:2]([N:28]3[CH2:29][CH2:30][C@@H:25]([C:23]4[CH:22]=[CH:21][C:20]([OH:32])=[C:19]([F:18])[CH:24]=4)[C@H:26]([F:31])[CH2:27]3)[C:3]2=[O:17])=[CH:9][CH:10]=1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Reactant: O=C1C(Br)CCN1Cc1ccc(C(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C1C(N2CC[C@@H](c3ccc(O)c(F)c3)[C@H](F)C2)CCN1Cc1ccc(C(F)F)cc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 47.5 %

Procedure:
A stirred mixture of 3-bromo-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (100 mg, 0.328 mmol, intermediate 2a), 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (70 mg, 0.328 mmol, from example 114, step E), and triethylamine (0.137 mL, 0.985 mmol) in acetonitrile (2 mL) was heated at 120° C. in a CEM microwave for one hour. The reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine solution, dried over sodium sulfate, and evaporated under reduced pressure to give a crude residue. The crude residue was purified via preparative LC/MS (column: Waters Xbridge C18, 19×150 mm, 5 μm; guard column: Waters XBridge C18, 19×10 mm, 5 μm; mobile phase A: 5:95 methanol:water with 10 mM NH4OAc; mobile Phase B: 95:5 methanol:water with 10 mM NH4OAc; Gradient: 15-50% B over 25 min, followed by a 10 min hold at 50% B and 5 min hold at 100% B; flow: 15 ml/min) to afford 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (68 mg, 46%). The diastereomeric mixture was separated by preparative chiral SFC (column=Chiralpak AD-H (250 mm×21 mm, 5 μm); isocratic solvent=40% methanol (w/0.25% DEA) in CO2, 100 bar; temp=25° C.; flow rate=75 g/min; injection volumn=1.1 mL (˜6 mg/mL in MeOH); λ=220 nM; Peak 1=3.2 min, Peak 2=5.0 min) to afford the titled compounds of example 117 (18 mg of peak-1, and 20 mg of peak-2). Data for example 117, P-1: LC-MS m/z 437 (M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 7.55 (d, J=8.03 Hz, 2H) 7.42 (s, 2H) 6.97-7.04 (m, 1H) 6.62-6.95 (m, 3H) 4.48-4.68 (m, 3H) 3.76 (t, J=8.78 Hz, 1H) 3.50 (dt, J=3.31, 1.64 Hz, 0H) 3.25-3.31 (m, 0H) 3.11-3.18 (m, 0H) 2.99-3.05 (m, 0H) 2.41-2.71 (m, 3H) 2.16-2.26 (m, 1H) 2.08 (dq, J=12.91, 8.79 Hz, 1H) 1.78-1.91 (m, 2H). Data for example 117, P-2: LC-MS m/z 437 (M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 7.55 (d, J=8.03 Hz, 2H) 7.41 (d, J=8.28 Hz, 2H) 7.00 (dd, J=12.39, 1.91 Hz, 1H) 6.62-6.93 (m, 3H) 4.47-4.70 (m, 3H) 3.69-3.77 (m, 1H) 3.38-3.55 (m, 1H) 3.24-3.30 (m, 1H) 3.15 (dt, J=3.31, 1.64 Hz, 1H) 2.74-2.83 (m, 2H) 2.52-2.72 (m, 2H) 2.44 (td, J=10.02, 4.80 Hz, 1H) 2.03-2.27 (m, 2H) 1.76-1.90 (m, 2H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=O)[CH3:5].[K+].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH:28](C(O)=O)[CH2:27][CH2:26][N:25]2[C:33]([O:35][CH3:36])=[O:34])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[CH2:29][C@H:28]([C:9](=[O:11])[CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:12])[CH2:27][CH2:26][N:25]2[C:33]([O:35][CH3:36])=[O:34])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 9.4 %

Procedure:
Magnesium chloride (5.38 g, 56.51 mmol) and potassium 3-ethoxy-3-oxopropanoate (9.62 g, 56.51 mmol) were suspended in methyl THF (100 mL) and heated to 50° C. under nitrogen for 18 h using an oversized stirring bar, then cooled to room temperature (flask 1). In a separate flask was to a suspension of 2-(4-tert-butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (9.5 g, 29.74 mmol) (reference compound 15) in methyl THF (100 mL) added di(1H-imidazol-1-yl)methanone (7.23 g, 44.62 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 4 h (flask 2). Then, the contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). Resulting suspension stirred at room temperature for 18 h. 3.8 M HCl was added (ca. 150 mL) and the resulting biphasic mixture stirred vigorously for 2 h. The phases were separated. The organic phase was washed with water, satd NaHCO3 and brine, then dried over MgSO4 and evaporated. The residue was purified via Biotage in two equal portions (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 2-(4-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.09 g, 9.4%) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.31 (s, 9H), 1.50-1.99 (m, 4H), 2.50-2.96 (m, 2H), 3.47 (s, 2H), 3.74 (s, 3H), 4.08-4.23 (m, 3H), 5.46-5.71 (m, 1H), 7.09-7.16 (m, 2H), 7.34-7.40 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([N:9]2[C:13]3=[C:14]4[CH:20]=[CH:19][NH:18][C:15]4=[N:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:21])[CH2:4]1.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC(Cl)C>[O:21]=[C:10]1[N:9]([C@H:5]2[CH2:6][CH2:7][CH2:8][C@H:3]([CH:2]=[O:1])[CH2:4]2)[C:13]2=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=[C:12]2[NH:11]1
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@H]1CCC[C@H](CO)C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 1-[trans-3-(hydroxymethyl)cyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (180 mg) in dichloroethane (2 ml) was added 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (293 mg) at 4° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture were added chloroform, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium thiosulfate. The organic layer was separated and extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform:methanol=100:0-85:15 to give trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][N:18]=1.[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: Cc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncn1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Lithium bis(trimethylsilyl)amide 1.0 M in THF (4.25 L, 4.25 mol) was cooled to −70° C. with stirring under nitrogen. 4-methylpyrimidine (250 g, 2.66 mol) was added followed by Methyl 4-chlorobenzoate (453.2 g, 2.66 mol). The cooling bath was removed and the mixture was allowed to warm to room temperature and stir for 16 h. Water (3 L) and ethyl acetate (3 L) were added followed by acetic acid (200 mL). The layers were separated and the organic layer was washed with brine and dried over magnesium sulfate. The mixture was then concentrated to 800 mL and hexanes (250 mL) were added. The product was filtered, washed with hexanes, and air dried to provide a yellow solid. (388.1 g, 64%): mp 110.4-110.5° C. 1H NMR (acetone-d6/300 MHz) 14.9 (bs, 1H), 8.8 (s, 1H), 8.4 (m, 1H), 7.7 (d, 2H, J=8.7 Hz), 7.3 (d, 2H, J=8.7 Hz), 6.9 (m, 1H), 5.9 (s, 1H).
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:32]2[CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (855.1.1 mg, 8.45 mmol, 1.178 mL) and para-chlorobenzylamine (543.36 mg, 3.84 mmol, 0.467 mL) resulting in the formation of a white precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the resultant precipitate recrystallised (EtOAc, petrol) to give the title product as a fine white crystalline solid (1.191 g, 3.20 mmol, 83%). 1H NMR: (300 MHz, DMSO) δ ppm 4.23 (d, 1H, J=15.59, H9) 4.45 (d, 1H, J=15.62H9′) 7.25 (m, 9H, H1-H5, H10-H13) 7.56 (m, 2H, H6-H7) 7.76 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.09 (N—CH2), 90.55 (O—C—N), 122.98, 123.19, 128.02, 128.39, 128.57, 129.76, 130.21, 130.66, 131.60, 133.07, 133.15, 137.44, 139.33, 149.52 (Ar), 167.16 (C═O). Mp: 156.2-156.9° C. IR: 1467, 1661, 3184 cm−1.
Reaction SMILES: O[CH:2]1[C:8]2=[C:9]([CH3:16])[C:10](=[O:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C@:7]32[O:17][C@:4]([CH3:18])([CH2:5][O:6]3)[CH2:3]1.[H][H].S(=O)(=O)(O)O>Cl(O)(=O)(=O)=O.CO>[OH:15][C:10]1[C:9]([CH3:16])=[C:8]2[C:7](=[C:12]([CH3:13])[C:11]=1[CH3:14])[O:17][C@:4]([CH3:18])([CH2:5][OH:6])[CH2:3][CH2:2]2
Reactant: CC1=C(C)[C@]23OC[C@](C)(CC(O)C2=C(C)C1=O)O3
Reactant: [H][H]
Agent: O=S(=O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CO)O2
Reaction time: 15 h
Yield: 111.3 %

Procedure:
A mixture of 0.59 g of (3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one, 0.7 g of palladium-on-barium sulfate (5% by weight) and 3 drops of concentrated perchloric acid in 20 ml of methanol was hydrogenated with ca 120 ml of hydrogen under normal pressure. Subsequently, 2 ml of 2-N sulfuric acid were added and air was conducted into the mixture for 15 hours. The reaction mixture was again hydrogenated with ca 25 ml of hydrogen. After removal of the catalyst by filtration over Hyflo, the filtrate was treated with dilute sodium bicarbonate solution and extracted with ether. The combined organic phases were dried over magnesium sulfate. After distillation of the solvent on a rotary evaporator, there were obtained 0.62 g of brown crystals, which, for purification, was chromatographed on Kieselgel with acetic ester/toluene (1/1 parts by volume). The resulting (S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol crystallized from methylene chloride/hexane at a yield of 487 mg; melting point 126.5°- 128.5°.
Reaction SMILES: C([O:4][CH2:5][CH:6]([NH:12][C:13](=[O:71])[C:14]1[C:19]([I:20])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:17]([I:29])=[C:16]([C:30](=[O:69])[NH:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:68])[C:37]2[C:42]([I:43])=[C:41]([NH:44][C:45](=[O:51])[CH2:46][O:47]C(=O)C)[C:40]([I:52])=[C:39]([C:53](=[O:66])[NH:54][CH:55]([CH2:61][O:62]C(=O)C)[CH2:56][O:57]C(=O)C)[C:38]=2[I:67])[C:15]=1[I:70])[CH2:7][O:8]C(=O)C)(=O)C.O.N>CO>[OH:24][CH2:23][C:22]([NH:21][C:18]1[C:17]([I:29])=[C:16]([C:30]([NH:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:68])[C:37]2[C:42]([I:43])=[C:41]([NH:44][C:45](=[O:51])[CH2:46][OH:47])[C:40]([I:52])=[C:39]([C:53](=[O:66])[NH:54][CH:55]([CH2:56][OH:57])[CH2:61][OH:62])[C:38]=2[I:67])=[O:69])[C:15]([I:70])=[C:14]([C:19]=1[I:20])[C:13]([NH:12][CH:6]([CH2:7][OH:8])[CH2:5][OH:4])=[O:71])=[O:28]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCCCNC(=O)c2c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c2I)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: N
Solvent: CO
Solvent: O
Product: O=C(CO)Nc1c(I)c(C(=O)NCCCNC(=O)c2c(I)c(NC(=O)CO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude Acetic acid 3-acetoxy-2-[3-{3-[3-(2-acetoxy-1-acetoxymethyl-ethylcarbamoyl)-5-(2-acetoxy-acetylamino)-2,4,6-triiodo-benzoylamino]-propylcarbamoyl}-5-(2-acetoxy-acetylamino)-2,4,6-triiodo-benzoylamino]-propyl ester (1.5 g) was dissolved in methanol (10 ml) and water (10 ml) was added. Concentrated aqueous ammonia (3 ml) was added and the solution stirred at ambient temperature for 18 h. The reaction was evaporated to dryness, the residue dissolved in water and purified by preparative hplc to give the title product as a white solid after freeze drying.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH3:32][NH2:33]>C(O)C>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:33][CH3:32])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CN
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Solvent: CCO
Product: CN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1

Procedure:
Prepared according to the method of example 33(b), using N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 35(a)) (0.2 g) and 8M methylamine in ethanol (3 mL) to afford the title compound (0.063 g).