Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH2:11]1[O:21][C:20]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=2[O:12]1.[OH-].[Na+]>CO>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]3[O:21][CH2:11][O:12][C:13]=3[CH:14]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1ccc(O)cc1

Procedure:
4-Hydroxy acetophenone, 1 (2.7 g, 20 mmol), 3,4-methylenedioxy benzaldehyde, 6 (3 g, 20 mmol) and 50% aqueous sodium hydroxide (5 mL) in methanol (40 mL) were reacted under reflux as in 7 to yield 11. Yield 3.5 g (65%); mp 191-193° C.; MS (FAB) 269 (M++1); IR (KBr) 3410, 1646; 1H NMR (200 MHz, CDCl3) δ 9.15 (s, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.72 (d, J=15.5 Hz, 1H), 7.37 (d, J=15.5 Hz, 1H), 7.16 (s, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.82 (d, J=7.9 Hz, 1H), 6.02 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:4]([C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: c1ccccc1
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-methoxy-4-chlorobenzoic acid (1.0 g, 0.0054 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 0.00507 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=3.74 (s, 3H), 7.00 (d, J=1.77 Hz, 1H) 7.05 (dd, J=8.08, 1.77 Hz, 1H), 7.32 (d, J=8.08 Hz, 1H), 7.41-7.48 (m, 2H), 7.54-7.60 (m, 1H), 7.74-7.83 (m, 2H). MS (ES+): m/z 246.83 (100)[MH+]. HPLC: tR=3.66 min (Open Lynx polar—5 min).
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][NH2:13])=[O:11])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:16]([NH:13][NH:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][C:6]([OH:5])=[CH:7][CH:8]=1)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=Cc1ccccc1)NNC(=O)c1ccc(O)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
To 100 ml of acetic acid were added 5.0 g of p-hydroxybenzoylhydrazine and 5.5 g of cinnamoyl chloride, and the mixture was stirred at 20° C for 3 hours. The reaction mixture was then poured into 2 liters of water, and the produced precipitate was collected and washed with water. The so obtained product was then recrystallized twice from acetic acid and dried under reduced pressure to yield 3.1 g of N-cinnamoyl-N'-(p-hydroxybenzoyl)hydrazine as white crystals, m.p. 263°-264.5° C. Analysis: Calculated for C16H14N2O3 : C, 68.08%; H, 5.00 %; N, 9.92%, Found: C, 68.15%; H, 4.87%; N, 9.98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:39])[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:36]2[CH2:35][CH2:34][N:33]([C:31](=[O:32])[N:30]([CH3:29])[CH3:39])[CH2:38][CH2:37]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Product: CN(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid and piperazine-1-carboxylic acid dimethyl amide. White solid. MS (m/z): 527.3 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[CH2:3][C:4](=[O:10])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[CH3:1][C@@H:2]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[CH2:3][C:4](=[O:10])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C[C@H](CC(=O)N1CCCC1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CC(=O)N1CCCC1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-amide (125 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added TFA (0.5 mL, 6.49 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylenediamine (0.4 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h then quenched with water. The resultant precipitate was collected via filtration and washed with water and EtOAc. The solid was dissolved in 10% MeOH/CH2Cl2 and washed with water. The aqueous layer was back-extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated to afford 64 mg (66%) of 2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-amide as an off-white solid. MS: (M+H)+=466; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.07 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 7.97 (d, J=1.1 Hz, 1H), 7.28 (dd, J=8.7, 1.5 Hz, 1H), 4.36-4.54 (m, 1H), 4.16 (s, 3H), 3.40 (t, J=6.6 Hz, 2H), 3.10-3.25 (m, 2H), 2.52-2.76 (m, 2H), 1.61-1.90 (m, 4H), 1.38 (d, J=6.8 Hz, 3H).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([Br:16])=[CH:12][C:13]=1[O:14]C)=[O:8].O>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([Br:16])=[CH:12][C:13]=1[OH:14])=[O:8]
Reactant: COC(=O)c1sc(Br)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1sc(Br)cc1O
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
BBr3 (26 mL, 1.0 M in heptane, 25.9 mmol, 3.0 Eq.) was added dropwise to a stirred solution of 5-Bromo-3-methoxy-thiophene-2-carboxylic acid methyl ester (2.17 g, 8.62 mmol, 1.0 Eq.) in anhydrous DCM (100 mL) at −10° C. under nitrogen. After 1.5 hours, water (40 mL) was added and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (50% Petroleum ether/DCM) to give the sub-title compound as a white solid (1.67 g, 7.04 mmol, 81%); 1H NMR (400 MHz, CDCl3) δ 3.90 (3H, s), 6.80 (1H, s), 9.68 (1H, br s).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[O:28]=[C:29]1[N:35]2[CH2:36][CH2:37][C@H:34]2[C:33]2=[C:38]([C:41]([NH:43][NH2:44])=[O:42])[N:39]=[CH:40][N:32]2[C:31]2[CH:45]=[CH:46][S:47][C:30]1=2>CN(C)C=O>[O:11]=[C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]1[CH2:12][C:13]([NH:44][NH:43][C:41]([C:38]1[N:39]=[CH:40][N:32]2[C:31]3[CH:45]=[CH:46][S:47][C:30]=3[C:29](=[O:28])[N:35]3[CH2:36][CH2:37][C@H:34]3[C:33]=12)=[O:42])=[O:15]
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
A solution of 5.8 g (19 mmol) of N-phthaloylglycine in 30 ml of dimethylformamide was treated at room temperature with 3.2 g (19.75 mmol) of 1,1'-carbonyldiimidazole and the mixture was subsequently heated to 50°. After 30 minutes the mixture was cooled to room temperature, 5.6 g (19.63 mmol) of (S)-8-oxo-11,11 a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide were added thereto and the mixture was stirred at room temperature for 12 hours. The suspension obtained was filtered and the colour-less powder obtained was washed with ethanol and diethyl ether. There were obtained 8.7 g (96%) of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-11,11a-dihydro-8H,10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide of m.p. >260°.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:26])C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O.C(O)(=O)C>[CH:33]1([N:32]2[C@@H:28]3[C@@H:27]([CH2:31][CH2:30][CH2:29]3)[C:25]([OH:26])=[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:14])(=[O:15])[N:12]=3)[C:17]2=[O:18])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C1CCCC1NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(C3CCCC3)C1=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 1.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-cyclopentylamino-cyclopentanecarboxylic acid ethyl ester (0.068 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (63.7 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.4 mg, 0.315 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-[3-(1-cyclopentyl-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (2.5 mg, 0.005 mmol, 1.7%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.51-2.11 (13H, m), 3.06 (3H, s), 3.84-4.03 (1H, m), 4.52-4.67 (1H, m), 7.49-7.57 (3H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C21H26N4O6S2 494.13, found 495.5 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH3:25])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH3:25])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2ccn(C)c2c1
Yield: 78.9 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(1-methyl-1H-indol-6-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.076 g; 0.184 mmol), sodium hydroxide 10N (0.184 mL; 1.838 mmol) in methanol (1.8 mL) to afford 0.058 g (75%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([S:23][C:24]2[NH:28][C:27]([CH2:29][O:30]CC3C=CC(OC)=CC=3)=[N:26][C:25]=2[CH:40]([CH3:42])[CH3:41])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C.CN(C)C=O>[Cl:22][C:20]1[CH:19]=[C:18]([S:23][C:24]2[N:28]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:27]([CH2:29][OH:30])=[N:26][C:25]=2[CH:40]([CH3:42])[CH3:41])[CH:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: ClCCCCCc1ccccc1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(CO)n(CCCCCc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
To dimethylformamide was added 92 mg of 1-chloro-5-phenylpentane and 152 mg of potassium iodide under ice-cooling, the mixture was allowed to warm up to room temperature and stirred for 20 minutes. Then, 200 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b)was added, followed by addition of 126 mg of potassium carbonate. Then the mixture was warmed up to 50° C. and allowed to react for 6 hours. After completion of the reaction, the mixture was diluted with water, extracted with diethyl ether, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To thus-obtained oil were added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1)to give 120 mg of Compound I-124 (yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([OH:14])[C:8]=1[CH3:15])=O>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[CH:16][C:3]=1[CH2:4][NH:6][C:7]1[C:8]([CH3:15])=[C:9]([OH:14])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: Cc1ccc(O)c(C)c1NC(=O)c1cc(-c2cccc(F)c2)ccc1F
Solvent: C1CCOC1
Product: Cc1ccc(O)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)benzamide (400 mg, 1.13 mmol, 1.0 eq) in THF under N2 was added dropwise a solution of BH3 (5.65 mL, 1M in THF, 5.65 mmol, 5.0 eq). The reaction mixture was heated to 60° C. and stirred under N2 for 3 h. After cooling, the resulting mixture was quenched by addition of 1 M HCl and water and the aqueous layer extracted with EtOAc. The organic extract was dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title product as yellow oil (340 mg, 89%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][N:12]3[Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:27][CH2:28][C:29]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:19])[CH3:20])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Nc3ccccc3)cccc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N(C(=O)CCl)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.6 %

Procedure:
To a 0° C. solution of phenyl-(1-triisopropylsilanyl-1H-indol-4-yl)-amine XXI (1.09 g, 3 mmol) and TEA (1.35 ml, 9.7 mmol) in DCM (20 ml) was added 2-chloroacetyl chloride (773 μl, 9.7 mmol). The mixture was stirred for 5 minutes and then refluxed for 3 hours. The reaction was cooled to room temperature and partitioned between H2O and DCM. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 2-chloro-N-phenyl-N-(1-triisopropylsilanyl-1H-indol-4-yl)-acetamide XXII as an off-white solid (775 mg, 59% yield).
Reaction SMILES: Br[CH:2]1[CH2:9][CH2:8][C:7]2[C:10](=[O:14])[CH2:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Sn](CCCC)(CCCC)CCCC.[F-].[NH4+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ag]=O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:2]1[CH2:9][CH2:8][C:7]2[C:10](=[O:14])[CH2:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1F
Reactant: O=C1CC=CC2=C1CCC(Br)CCC2
Agent: O=[Ag]
Agent: [Pd]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=C1CC=CC2=C1CCC(c1ccccc1F)CCC2
Temperature: 120 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
In 10 ml of dimethylformamide were dissolved 2.0 g (7.9 mmol) of 8-bromo-l-benzocyclooctanone, 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine) palladium and 2.0 g (8.6 mmol) of silver oxide, 4.6 g (11.9 mmol) of o-fluorophenyltributyl tin was added thereto, and the mixture was stirred under an argon atmosphere at 120° C for 2 hours. After cooling, an aqueous solution of ammonium fluoride was added to the reaction solution, and then stirred at room temperature for 12 hours. The reaction solution was filtered through celite, washed with ethyl acetate and water, and then extracted. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then separated and purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (9:1)]to obtain 0.84 g (40%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][C@H:26]([OH:27])[CH2:28][NH:36][CH3:35])=[CH:22][CH:23]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CO
Product: CCOCc1nc(-c2ccc(OC[C@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B2) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
2-Chloropyridine4-carbonyl chloride (0.143 g) was added to a stirred mixture of N-(3-amino4-methylphenyl)-2-morpholinopyridine4 carboxamide (0.211 g), triethylamine (0.164 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained the title compound (0.276 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.24 (d, 2H), 7.34 (d, 1H) 7.81 (s, 1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.26 (d, 1H), 8.6 (d, 1H); Mass Spectrum M+H+ 452 and 454.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].Cl[Si:19]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:20][Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>N1C=CC=CC=1>[OH:3][C@@H:2]1[C@@H:4]2[O:5][Si:19]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:34])[CH3:33])[O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[O:8][CH2:7][C@H:6]2[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
Uridine (15, 100.0 g, 409.5 mmol) was co-evaporated to dryness with anhydrous pyridine (600 mL) and re-suspended in anhydrous pyridine (700 mL). To this stirred fine suspension was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (135.7 g, 482.5 mmol) over 60 min at ambient temperature. After stirring the fine suspension for 17 h at ambient temperature, the reaction was quenched by adding methanol (20 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (1.5 L) and water (2 L). The organic layer was further washed with 5% hydrochloric acid (2×1 L), brine (500 mL), dried over solid sodium sulfate (50 g), filtered and concentrated under reduced pressure to the crude product, ca 250 g. The residue was subjected to a filtration column using silica gel (1.75 kg) and a gradient of ethyl acetate in hexanes 20-65%. The pure product fractions as judged by a homogenous TLC (Rf 0.55 in 1:1 hexanes-ethyl acetate) were combined and concentrated under reduced pressure and dried (40° C., 0.2 mm Hg, 24 h) to afford 145.5 g (76%) of 16 as a white foam solid. An additional fraction (35 g) of slightly impure 16 was also collected. 1H NMR (DMSO-d6) δ (ppm) 11.35 (s, 1H, NH), 7.66 (d, 1H, J=7.6 Hz, H-6), 5.57 (d, 1H, J=4.8 Hz, 2′-OH), 5.50-5.49 (m, 2H, 1′-H and H-5), 4.14-4.18 (m, 3H, 2′, 3′, 4′-H), 3.97-3.87 (m, 2H, 5′-Ha and Hb), 1.02-0.95 (m, 28H, CH(CH3)2).