Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[P:2]([O:6][CH2:7][C@H:8]1[O:12][C@@H:11]([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[C@H:10]([OH:23])[C@@H:9]1[OH:24])([O-:5])([O-:4])=[O:3].[Na+].[NH+]1C=CC=C[CH:27]=1.C(N(CCCC)CCCC)CCC.IC>O.CO>[P:2]([O:6][CH2:7][C@H:8]1[O:12][C@@H:11]([N:13]2[C:22]3[N:21]=[CH:20][N:19]([CH3:27])[C:17](=[NH:18])[C:16]=3[N:15]=[CH:14]2)[C@H:10]([OH:23])[C@@H:9]1[OH:24])([OH:5])([OH:4])=[O:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)([O-])[O-])[C@@H](O)[C@H]1O
Reactant: c1cc[nH+]cc1
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CCCCN(CCCC)CCCC
Product: Cn1cnc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c1=N
Temperature: 25 °C
Reaction time: 20 h
Yield: 23 %

Procedure:
Adenosine-5′-monophosphate sodium salt (10 g, 24.7 mmol) was dissolved in water (50 mL). The resulting solution was applied to a Dowex 50WX8 column (200 mL) in the pyridinium form. Subsequently the column was washed with 600 mL water-methanol (1:1). The eluate was directly collected into a cold, stirred solution of tri-n-butylamine (17.6 mL, 74.1 mmol) in methanol. The solvent was evaporated to dryness, dissolved again in methanol and re-evaporated twice. This procedure was repeated twice more with anhydrous DMF (700 mL) using an oil pump. The residue was dissolved in 700 mL anhydrous DMF. Iodomethane (50 mL, 803 mmol) was then added and the reaction mixture was stirred at room temperature for 20 hours. The solution was evaporated to dryness. The residue was dissolved in water (1000 mL) and the pH of the solution was adjusted from 1.2 to 7.5 with 1M triethylammonium bicarbonate (pH 11.0). Purification by ion exchange chromatography yielded the product (2.1 g, 23%) as a sodium salt, and was used in the next steps without further purification: MS (ES) m/z 362 [M+H]+, 360 [M+Na]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:32])([F:31])[C:5]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)(O)[OH:6].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CO>[F:31][C:4]([F:3])([F:32])[CH:5]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH:16]=[C:15]([CH3:30])[CH:14]=2)=[CH:11][N:12]=1)[OH:6]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)(O)C(F)(F)F)s2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C(F)(F)F)s2)c1
Reaction time: 3 h
Yield: 90.9 %

Procedure:
Sodium borohydride (41.6 mg, 1.099 mmol) was added to the product of Step 1 (450 mg, 0.999 mmol) in MeOH (3.3 mL) at 0° C. After stirring for 3 h, the reaction was poured into a separatory funnel containing ethyl acetate and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography to give 2,2,2-trifluoro-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (394.6 mg, 0.908 mmol, 91% yield) as a white solid. APCI: [M+H]+ m/z 435.1. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.84 (d, J=4.9, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.86 (d, J=6.0, 1H), 7.48 (s, 1H), 7.29 (d, J=4.9, 1H), 7.22 (s, 1H), 5.52 (dd, J=6.7, 13.1, 1H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]([F:21])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccccc1
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24j (124.9 mg, 0.50 mmol) was added 1.25 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (225 μL, 2.5 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (40 μL, 0.5 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warning, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 114.8 mg of a mixture of 24j and 25j as an off-white solid. FTIR (film) 1849.3 cm−1.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([O:19][C@H:20]1[C@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:35]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:34][CH:21]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:12]([O:19][C@H:20]1[C@H:36]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:35]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:34][C@H:21]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([F:1])=[N:3][C:4]=2[NH2:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1nc(F)nc2nc[nH]c12
Reactant: O=C(OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
A mixture of 2-fluoroadenine (0.50 g), 2,3,5-tri-O-benzyl-1-α-D-arabinofuranosyl chloride (freshly prepared from 2.22 g of 2,3,5-Tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose) and N,N-diisopropylethylamine (0.56 mL) in anhydrous N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 3 days under a nitrogen atmosphere. The mixture was then concentrated under high vacuum and the residue was partitioned between dichloromethane (200 mL) and water (25 mL). The organic phase was washed sequentially with saturated NaCl (50 mL), 1M H3PO4 (50 mL) and saturated NaCl (25 mL), and was then dried over MgSO4 and decolorizing carbon. The dried solution was filtered and concentrated under vacuum. The residue was purified by silica gel chromotography with 1% methanol in dichloromethane as eluant. The appropriate fractions were combined and recrystalized from ethanol/toluene to obtain 0.39 g of the title compound. This material was identical by IR and TLC with an authentic sample.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:18][C:4]=2[N:5]=[C:6]([NH:8]C(=O)CCCCCCC)[N:7]=1.Cl[CH2:28][C:29]1[C:34]([CH3:35])=[C:33]([O:36][CH3:37])[C:32]([CH3:38])=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[N:18]([CH2:28][C:29]3[C:34]([CH3:35])=[C:33]([O:36][CH3:37])[C:32]([CH3:38])=[CH:31][N:30]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CCCCCCCC(=O)Nc1nc(Cl)c2cc(CN3CCCC3)[nH]c2n1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2c(CN3CCCC3)cc3c(Cl)nc(N)nc32)c1C
Temperature: 45 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A suspension of the crude octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (330 mg, 0.87 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (162 mg, 0.87 mmol) and K2CO3 (121 mg, 0.87 mmol) in dry DMF (1 mL) was heated to 45° C. overnight. After work-up (EtOAc) and evaporation, the residue was taken up in 6N methanolic HCl (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc (10 mL×3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) yielded 4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (4.1 mg, yield 1.0%). HPLC Rt: 6.092 min. 1H-NMR (CDCl3): δ 8.09 (s, 1H), 6.31(s, 1H), 5.55(s, 2H), 4.85(s, 2H), 3.77 (s, 3H), 3.52(brs, 2H), 2.43 (m, 4H), 1.76–1.71 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[N:12][OH:13].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[N:12][O:13][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCCC1
Reactant: ON=Cc1c(Br)ccc2c1OCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1C=NOCCN1CCCC1)OCO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-bromo-1,3-benzodioxole-4-carbaldehyde oxime (0.244 g, 1 mmol) in dry DMF (15 ml), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.207 g, 1.22 mmol) and NaH (0.138 g, 3.45 mmol, 60% dispersion in oil) were added. The reaction mixture was stirred at ambient temperature for 5 minutes and then heated at 80° C. overnight. Then the reaction mixture was cooled to ambient temperature and quenched with methanol (4 ml). After evaporation of the solvent in vacuo, water (25 ml) was added to the residue, and the mixture was extracted with dichloromethane (2×25 ml). The combined organic phases were dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography with a mixture of chloroform:ethyl acetate (10:1) as the eluent. After the isolation of the unreacted starting material, the eluent was changed to ethyl acetate:isopropanol:cc. NH3 (9:1:0.5). The crude product was digerated with water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)cc3)CC1)O2
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)cc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-[2-(4-Chloro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (200 mg, 0.433 mmol) was suspended in DCM (10 ml). TEA (0.09 ml, 0.6 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-chloro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (130 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the requisite hydroxamic acid as a light yellow solid (89 mg, hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[N:14](C=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:18])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CC(C)=O.CCO>[Cl:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:18])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1c2c(Cl)cccc2Sc2cccc(Cl)c21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Clc1cccc2c1Nc1c(Cl)cccc1S2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of the crude 1,9-dichloro-10H-phenothiazine-10-carbaldehyde was dissolved in acetone (8 mL) and a solution of KOH (330 mg, 5.88 mmol) in EtOH (5.0 mL) was added. The mixture was stirred for 12 h at room temperature and then was evaporated to dryness to give a residue. The residue extracted with EtOAc and washed with 1M H3PO4. The organic layers were combined and dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give 300 mg of a light yellow solid. LC/MS confirmed M+1=269.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].N#N.CCOC(C)=O>C1COCC1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:20]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][CH2:13]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(OCCN2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1OC
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OCCN2CCN(CCCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1OC
Yield: 73 %

Procedure:
To a solution of 1-{4-[2-(3,4-dimethoxy-phenoxy)ethyl]-piperazin-1-yl}-6,6-bis-(4-fluoro-phenyl)-hexan-1-one (0.7 g, 1.2 mmol) in THF (15 ml), was added LiAlH4 (100 mg, 2.4 mmol). The mixture was stirred at room temperature overnight (under N2). EtOAc was added and then washed with wate (2×10 ml), saturated NaCl (3×5 ml), dried over MgSO4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica (CH2Cl2:MeOH 10:1) to give the desired product in 73% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CC(C)=O>[OH:15][CH:14]([C:13]([OH:17])=[O:16])[NH:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: O=CC(=O)O
Reactant: Cc1cc(C)cc(C(N)=O)c1
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)cc(C(=O)NC(O)C(=O)O)c1

Procedure:
A mixture of 3,5-dimethylbenzamide (22.6 g, 0.15 mol) and glyoxylic acid monohydrate (15.3 g, 0.17 mol) in acetone (120 ml) is heated under nitrogen atmosphere at reflux for 6 h. The solvent is evaporated in vacuo to give 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine. To a solution of 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine in methanol (350 ml) is added concentrated sulfuric acid (4.6 ml) at room temperature. The mixture is stirred for 2 days and then concentrated in vacuo. The residue is diluted with ethyl acetate, washed with two portions of saturated sodium bicarbonate solution and with two portions of brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give 2-methoxy-N-(3,5-dimethyl benzoyl)glycine methyl ester.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:23]1([CH:22]=[C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)[C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc2[nH]c(C(=CC3CCCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 81.2 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclohexyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.24 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 12 h. The mixture was then diluted with ethyl acetate (150 mL) and washed with a saturated aqueous ammonium chloride solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclohexyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (80 mg, 82.6%) as a white solid: LC/MS m/e calcd for C23H26N2O3S [M+H]+ 411.54, observed 411.2.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:22][CH2:23][CH:24]([OH:31])[CH2:25][S:26][CH2:27][C:28]([OH:30])=[O:29])[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])[CH3:9]>C1C=CC=CC=1>[CH3:1][O:29][C:28](=[O:30])[CH2:27][S:26][CH2:25][CH:24]([OH:31])[CH2:23][S:22][C:13]1[CH:12]=[C:11]([C:8]([CH3:7])([CH3:9])[CH3:10])[C:16]([OH:17])=[C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])[CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)c1cc(SCC(O)CSCC(=O)O)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: COC(=O)CSCC(O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (3 ml) was added to a solution of the compound of Example 41 (2.3 g) in benzene (50 ml) and stirred for 3 hours at room temperature. The reaction volume was reduced and methyl alcohol (100 ml) added. After evaporation of the solvents, the product (an oil) was purified by chromatography on silica.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:33]1[C:34]([C:42]2([CH2:57][OH:58])[C:50]3[C:45](=[N:46][CH:47]=[CH:48][CH:49]=3)[N:44]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:43]2=[O:56])=[CH:35][C:36]2[O:40][CH2:39][O:38][C:37]=2[CH:41]=1>C1COCC1>[CH2:51]([N:44]1[C:45]2=[N:46][CH:47]=[CH:48][CH:49]=[C:50]2[C:42]2([C:34]3=[CH:35][C:36]4[O:40][CH2:39][O:38][C:37]=4[CH:41]=[C:33]3[O:58][CH2:57]2)[C:43]1=[O:56])[CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cccnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a mixture of triphenylphosphine (2.61 g, 9.95 mmol) and diethyl azodicarboxylate (1.73 g, 9.95 mmol) in anhydrous THF (100 mL) was added slowly a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.85 g, 7.69 mmol) in anhydrous THF (50.0 mL) at 0° C. The brown reaction solution was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (50.0 mL). The organic solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (100 mL). The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to give the title compound (1.45 g, 54%), which was triturated from ether and hexane to give a colorless solid: mp 126-127° C.; 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, 1H), 7.54 (dd, 1H), 7.01 (dd, 1H), 6.666 (s, 1H), 6.25 (s, 1H), 5.89 (d, 1H), 4.71 (ABq, 2H), 3.68 (t, 2H), 1.70-1.60 (m, 2H), 1.32-1.22 (m, 4H), 0.82 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.9, 156.8, 156.0, 149.0, 147.9, 142.3, 132.0, 126.7, 119.3, 119.2, 103.4, 101.9, 93.8, 79.7, 57.4, 39.3, 28.9, 27.1, 22.2, 14.3; MS (ES+, m/z) 353 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(OCCO)C.C(OCC)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][N:17]=[C:4]2[OH:5]
Reactant: N=CN
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CCOCCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: Oc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Preparation D12, Step 1: A mixture of 2-amino-5-bromobenzoic acid (5.7 g, 24.78 mmol) and formamidine acetate (5.2 g, 49.5 mmol) in 2-ethoxyethanol (50 mL) was heated at reflux for 4 h. The reaction was cooled to room temperature, allowed to stand overnight, then diluted with diethyl ether (20 mL) to further precipitate the product. The solids were collected by filtration, rinsed with 2-ethoxyethanol (10 mL), diethyl ether (2×50 mL), and air dried to yield 4.4 g of 6-bromoquinazolin-4-ol as a tan solid. MS (ES+)=225/227 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C@@H:7]([NH:21][CH2:22][P:23]([O:27]C)([O:25]C)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl.C[Si](Br)(C)C>CO>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([NH:21][CH2:22][P:23]([OH:27])([OH:25])=[O:24])[CH:6]=[CH:5][C:4]([OH:29])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=C[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(OC)OC
Agent: C[Si](C)(C)Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)C=C[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-5-(Biphenyl-4-yl)-4-[(dimethylphosphonomethyl)-amino]-2-pentenoic acid ethyl ester (536 mg, 1.28 mmol) is dissolved in methanol (1 mL) and treated with 1N sodium hydroxide (2 mL, 2 mmol). The reaction mixture is stirred for 3 hours at room temperature, then 1N hydrochloric acid (5 mL) is added. The carboxylic acid is extracted in methylene chloride (20 mL). The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is suspended in methylene chloride (2 mL) under nitrogen and treated with trimethylsilyl bromide (0.424 mL, 3.21 mmol). The clear solution is stirred at room temperature for 18 hours, then concentrated in vacuo. The residue is triturated with water (5 mL) and the precipitate is filtered off and then dissolved in 1N sodium hydroxide (5 mL). 1N Hydrochloric acid (8 mL) is added to precipitate the product which is filtered and washed with water (10 mL). The solid is suspended in ethanol (5 mL) and stirred for 20 minutes with propylene oxide (2 mL). Concentration in vacuo yields (S)-5-(biphenyl-4-yl)-4-(phosphonomethylamino)-2-pentenoic acid as a white solid; m.p.: 231°-233°.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(O)[C:4]=2[CH:3]=1.Cl>C(O)(=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[C:17]4[C:16]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccccc2-c2ccccc2)c2ccccc2-c2ccc(Br)cc21
Agent: Cl
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2

Procedure:
47.0 g of 2-bromo-9-(biphenyl-2-yl)fluoren-9-ol were refluxed for 2.5 hours in 114 ml of 99.8% acetic acid with addition of 1.5 ml of conc. HCl.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][NH:7][CH3:6])=[CH:17][CH:16]=1
Reactant: CN(CCCc1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-propyl]-methyl-carbamic acid tert-butyl ester (0.417 g, 1.560 mmol) in 3 mL of dichloromethane, was added trifluoroacetic acid (3 mL). After stirring at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in 20 mL of ethyl acetate and the resulting solution was washed with NaOH solution (1N) and brine, and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure provided the title compound as a colorless oil (0.189 g, 72% yield), which was used directly in the next step (Step d of Specific Scheme 7) without further purification. GC-MS: tR=5.6 min; m/z 167 (M+).