Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated using 14.1 g of powdered H-Y at 160° C. After 2 h reaction time the phenol conversion was 11.0%, wherein<0.1 g of phenyl chloroformate and 17.5 g of diphenyl carbonate were formed. The selectivity to give the carbonate was ca. 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:25])[N:7](C3CCN(CC4C=CC=CC=4)CC3)[C:8]2=O)=[CH:4][C:3]=1[S:26]([NH2:29])(=[O:28])=[O:27].O=C1C2C(=CC=CC=2)C(=O)N1.C(O)(=O)C.C(OCC)(=O)C>CO.[Zn]>[ClH:1].[O:25]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[C:3]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:4]=2)[CH2:8][NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccccc3)CC1)C2=O
Agent: O=C1NC(=O)c2ccccc21
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cl
Product: NS(=O)(=O)c1ccc2c(c1)C(=O)NC2

Procedure:
Reduction of the above product (a) 1,3-dioxoisoindole (5.0 g., 0.0107 mole) with zinc and acetic acid according to the method of Example 1(c) and conversion of the free base (partially purified by trituration wih ethyl acetate) to the hydrochloride salt in methanol afforded 6-chloro-2-[1-[(4-chloro-phenyl)phenyl)methyl]-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide hydrochloride as the sesquihydrate, m.p. 256°-260° (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[N:34]1([CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCCN1CCCCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCCN3CCCCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C

Procedure:
A mixture of 2.4 g. (6.06 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, 1.35 g. (6.06 mm.) of δ-piperidinovaleric acid hydrochloride and 1.30 g. (6.30 mm.) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride are stirred at room temperature for 5 hours. The reaction mixture is cooled overnight in the refrigerator and the by-product of dicyclohexylurea removed by suction filration. The mother liquor is evaporated and the residue dissolved in a mixture of methylene chloride/cyclohexane and allowed to stand in the cold for 2 hours. Gravity filtration separates the small amount of solid which appears, and the solvents are removed using a rotary evaporator. Crystallization from methylene chloride/diethyl ether yields the desired product.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:25])/[CH:20]=[C:21](\[CH3:24])/[CH2:22]Br>CN(C=O)C>[CH3:17][O:18][C:19](=[O:25])/[CH:20]=[C:21](\[CH3:24])/[CH2:22][S:14][C:9]1[N:8]=[C:7]([NH2:6])[CH:12]=[C:11]([Cl:13])[N:10]=1
Reactant: Nc1cc(Cl)nc(S)n1
Reactant: COC(=O)/C=C(\C)CBr
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\C)CSc1nc(N)cc(Cl)n1
Reaction time: 15 h

Procedure:
To (E)-4-hydroxy-3-methyl-2-butenoic acid methyl ester (0.75 g, 5.76 mmol) in methylene chloride cooled to -15° C. in a flame dried flask is added dibromotriphenylphosphorane (2.68 g, 6.34 mmol). The reaction is stirred at -15° C.-0° C. for two hours, quenched by addition of ice (10 ml), extracted with methylene chloride (2×10 ml), washed with saline (10 ml), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (95/5). The appropriate fractions are combined and concentrated in vacuo to give (E)-4-chloro-3-methyl-2-butenoic acid methyl ester. 4-Amino-6-chloro-2-mercaptopyrimidine mesylate (0.30 g, 1.16 mmol) is dissolved in DMF (4 ml) and sodium hydride (0.06 g, 2.56 mmol) at ambient temperature followed by the addition of (E)-4-bromo-3-methyl-2-butenoic acid methyl ester (0.22 g, 1.16 mmol). The reaction is stirred for 15 hours, quenched with excess water, extracted with ethyl acetate (3×20 ml). The extracts are combined, washed with saline (20 ml), dried over sodium sulfate, concentrated in uacuo and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (80/20). The appropriate fractions are combined (Rf =0.43, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 134-136° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10](=[N:24][O:25][CH2:26][CH3:27])[CH:11]2[CH:16]3[CH:12]2[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH:6]=[CH:7][C:8]=1[Cl:9].CCCCCC>C(Cl)Cl>[ClH:2].[CH2:26]([O:25][N:24]=[C:10]([CH:11]1[CH:16]2[CH:12]1[CH2:13][NH:14][CH2:15]2)[C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=1)[CH3:27]
Reactant: CCON=C(c1ccc(Cl)c(Cl)c1)C1C2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CCON=C(c1ccc(Cl)c(Cl)c1)C1C2CNCC21
Yield: 200.5 %

Procedure:
HCl (g) was bubbled through a solution of tert-butyl 6-((3,4-dichlorophenyl)(ethoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.25 mmol) obtained in step-2 of example 1 in dry DCM (5 mL). After the completion of the reaction as confirmed by TLC, the reaction mixture was purged with excess of nitrogen. The solvent was removed in vacuo to afford a gummy solid which was titurated with hexane to afford hydrochloric acid salt of 3-azabicyclo[3.1.0]hexan-6-yl(3,4-dichlorophenyl)methanone O-ethyl oxime (75 mg, 86%) as a white solid as a mixture of isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CC>>[CH2:21]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: COc1cscc1OC
Reactant: CCCCCCCCCCCC[C@H](O)CO
Product: CCCCCCCCCCCCC1COc2cscc2O1

Procedure:
Chiral 2-n-dodecyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with (S)-1,2-tetradecanediol and purified to a purity of 98.01% as described in INVENTION EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited a specific rotation of −65° at 25° C. and 436 nm in hexane.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].O.O.Cl[Sn]Cl>O.Cl>[ClH:15].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])[NH2:1]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(C(=O)O)c1
Temperature: -3 °C
Reaction time: 2 h
Yield: 123.1 %

Procedure:
A solution of 2.11 g of NaNO2 in 40 ml of water is added over 30 minutes to a suspension, cooled to −2° C., of 5 g of 5-amino-2-chlorobenzoic acid in 50 ml of concentrated HCl. The solution is stirred for 2 hours at −3° C. and cooled to −10° C., and a solution of 23 g of SnCl2.2H2O in 20 ml of concentrated HCl and 20 ml of water is added over 30 minutes. The mixture is stirred for one and a half hours at 0° C. and filtered, and the precipitate is dried to obtain 4 g of expected product.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:31]1[N:35]=[C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:1][C@H:3]3[CH2:5][C@@:4]3([CH2:12][N:13]([CH3:23])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:38][CH2:37]2)[O:33][N:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@@H]1C=O)S(=O)(=O)c1ccccc1
Product: CN(C[C@@]1(c2ccccc2)C[C@@H]1CN1CCC(c2nc(Cc3ccccc3)no2)CC1)S(=O)(=O)c1ccccc1

Procedure:
N-{[(1S,2S)-2-formyl-1-phenylcyclopropyl]methyl}-N-methylbenzenesulfonamide and 4-(3-benzyl-1,2,4-oxadiazol-5-yl)piperidine (incorporating by reference as needed WO 00/39125) were reacted as per Preparation 10 to give the title compound. 1H NMR (300 MHz, DMSO-de) δ 7.69-7.54 (m, 5H), 7.35-7.20 (m, 10H), 4.06 (s, 2H), 3.55 (d, J=13.8 Hz, 1H), 2.97-2.85 (m, 1H), 2.78 (d, J=13.8 Hz, 1H), 2.64-2.59 (m, 1H), 2.53 (s, 3H), 2.27-2.21 (m, 1H), 2.02-1.88 (m, 4H), 1.75-1.61 (m, 2H), 1.48-1.41 (m, 1H), 1.17 (m, 1H), 1.07-1.02 (m, 1H), 0.93-0.89 (m, 1H). ES-LCMS m/z 557.1 (M+H).
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([OH:19])(=[O:18])[C:15]([CH3:17])=O.[OH-:20].[Na+]>O>[O:11]1[CH2:12][CH2:13][N:8]([C:2]2[CH:7]=[CH:6][C:5]([C:15]([C:5]3[CH:6]=[CH:7][C:2]([N:8]4[CH2:13][CH2:12][O:20][CH2:10][CH2:9]4)=[CH:3][CH:4]=3)([CH3:17])[C:14]([OH:19])=[O:18])=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: [OH-]
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: CC(=O)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)(c1ccc(N2CCOCC2)cc1)c1ccc(N2CCOCC2)cc1
Yield: 66 %

Procedure:
Into 12 ml of 6N--HCl solution was dissolved 4.65 g of N-phenylmorpholine. To the solution was added 1.5 g of pyruvic acid and the mixture was heated with reflux for 20 hours. The reaction mixture was, after cooled, diluted with 100 ml of water and adjusted to pH 6 with addition of 20% aqueous solution of sodium hydroxide. The precipitated crystal was collected by filtration which was 3.75 g (yield 66%) of 2,2-bis(4-morpholinophenyl)propionic acid, having a melting point of 217°~223° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccccc1CC(=O)N(C)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 8a in dichloromethane (0.1 M) at 0° C. under nitrogen was added triethylamine (3.5 eq) and acetyl chloride (1.1 eq). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane) to afford the product. (70%) 1H NMR (400 MHz, CDCl3) δ 6.98-7.43 (m, 10H), 6.06 (m, 1H), 5.29 (m, 1H), 4.38 (m, 2H), 3.70-4.02 (m, 2H), 3.03-3.27 (m, 1H), 2.89 (s, 2H), 2.80 (s, 1H), 2.58-2.78 (m, 3H), 2.50 (br s, 1H), 1.92 (s, 3H), 1.81 (m, 1H), 1.75 (m, 3H). Mass Spectral Analysis m/z=394.3 (M+H)+ tR=3.43 min (99%)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH:3]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([NH:1][C:23]([NH2:22])=[S:24])[NH:6][N:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of 5-amino-3-(2-chlorophenyl)pyrazole (3.8 g, 19.6 mmol) in THF (150 mL) was added dropwise benzoyl isothiocyanate (2.9 mL, 21.56 mmol). The reaction mixture was stirred at room temperature for 4 hours, then 4 N aqueous solution of NaOH (8 mL) was added, and the reaction mixture was further stirred at room temperature for 17 hours. The reaction mixture was neutralized to pH 7 with 1 N aqueous HCl, and extracted with EtOAc (3×). The combined organic layers were directly purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 3.47 g (72 % yield) of [5-(2-chloro-phenyl)-2H-pyrazol-3-yl]-thiourea as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(Cl)ncc2Br)CC1
Yield: 63 %

Procedure:
Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidine was reacted with tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate to provide the title compound in 63% yield. 1H NMR (CDCl3, 400 MHz) 8.43 (s, 1H), 4.32 (d, 2H), 4.18 (m, 2H), 2.76 (m, 2H), 2.03 9 m, 1H), 1.80 (m, 2H), 1.46 (s, 9H), 1.34-1.26 (m, 2H); MS (ESI) m/z: Calc: 405.1 (M+). Found. 307.9 (M+-Boc+2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([O:8][CH3:15])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Br)cc1N1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ncc(Br)cc1N1CCOCC1
Product: Cn1cc(Br)cc(N2CCOCC2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-morpholinopyridin-2(1H)-one (1.0 equiv.) in DMF (0.2 M) was added potassium carbonate (2.0 equiv.), followed by iodomethane (1.0 equiv.). The solution was stirred at room temperature for 3 hours. The solution was partitioned between water and ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude material was a mixture of N-methylated and O-methylated products (90:10). The material could be used for the next step without further purification as a mixture of isomers or it could be purified via silica gel column chromatography eluting with 0-100% ethyl acetate in heptanes to afford 5-bromo-1-methyl-3-morpholinopyridin-2(1H)-one in 71% yield LCMS (m/z) (M+H)=273/275, Rt=0.55 min and 4-(5-bromo-2-methoxypyridin-3-yl)morpholine in 10% yield. LCMS (m/z) (M+H)=273/275, Rt=0.82 min.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([CH3:44])=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([CH3:44])=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 17.9 %

Procedure:
Prepared in 17.9% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(prop-1-en-2-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.3 Hz, 1H), 7.22-7.12 (m, 3H), 5.98 (br. s., 1H), 5.43 (s, 1H), 4.89 (s, 1H), 4.61 (br. s., 1H), 3.83 (t, J=11.2 Hz, 1H), 3.63 (t, J=11.0 Hz, 1H), 3.44 (d, J=12.1 Hz, 4H), 3.20-3.11 (m, 1H), 2.66 (d, J=11.0 Hz, 1H), 2.32 (s, 3H), 2.15 (s, 3H), 1.91-1.59 (m, 9H), 1.52 (br. s., 1H), 1.19 (s, 3H), 1.17 (s, 9H), 1.06 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 684.4.
Reaction SMILES: [C:1]1([CH:7]2[N:12]3[C:13](=[O:19])[NH:14][C:15]4=[CH:16][CH:17]=[CH:18][C:10](=[C:11]34)[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>CC(O)=O>[Br:20][C:18]1[C:10]2[O:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]3[C:13](=[O:19])[NH:14][C:15]([C:11]=23)=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CO3
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of 4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (400 mg, 2 mmol) and N-bromosuccinimide (310 mg, 1.7 mmol) in AcOH (10 mL) was stirred at room temperature for 2 h. The reaction mixture was allowed to cool and was concentrated to remove AcOH. The residue was taken up in EtOAc and was washed with water saturated NaHCO3, brine, dried over magnesium sulfate, filtered and concentrated to give crude product. The product was purified by flash column chromatography on a Biotage system eluting with a hexane: EtOAc gradient (0-40%) to give 7-bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as an amber oil (0.30 g, 60%). LCMS calc. for C15H12BrN2O2 (M+H)+: m/z=331.1, 333.1. found: 331.0, 333.0. 1H NMR (300 MHz, CD3OD) δ 7.42-7.23 (m, 3H), 7.23-7.09 (m, 3H), 6.70 (d, J=8.4 Hz, 1H), 5.46 (dd, J=2.6 Hz, 1H), 4.66 (dd, J=11.6, 2.4 Hz, 1H), 4.47 (dd, J=11.6, 3.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1C=C[CH:40]=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C.[CH:52]([N:55]([CH:63]([CH3:65])[CH3:64])[P:56](Cl)[O:57]CCC#N)([CH3:54])[CH3:53]>C(Cl)Cl.C(OCC)(=O)C>[C:38]([CH2:39][CH2:40][PH:56]([O:36][C@@H:23]1[C@@H:22]([CH2:21][NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:26][C@@H:25]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)([N:55]([CH:52]([CH3:53])[CH3:54])[CH:63]([CH3:64])[CH3:65])[OH:57])#[N:37]
Reactant: c1ccncc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O[PH](O)(CCC#N)N(C(C)C)C(C)C)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
0.15 g (0.31 mmol) of 5'-tritylamino-5'-deoxy-thymidine [prepared as described in step (a) above] was dried by azeotropic distillation with pyridine and then dissolved in 2 ml of methylene chloride. 0.23 ml (1.2 mmol) of N,N-diisopropyl-N-ethylamine was then added to the resulting solution, after which 0.08 ml (0.36 mmol) of 2-cyanoethyl N,N-diisopropylchlorophosphoramidite was added over a period of 2 minutes in a stream of nitrogen. The resulting mixture was then stirred at room temperature for 60 minutes. At the end of this time, it was confirmed that the starting compound had disappeared by thin layer chromatography, and the reaction mixture was diluted with 30 ml of ethyl acetate. The resulting organic solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was through a 1PS (trade mark) filter paper (Whatman), and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through 15 g of silica gel (70-230 mesh), using ethyl acetate as the eluent, to give 0.19 g (yield 89%) of the title compound as a foamy substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][N:15]=[CH:16][C:9]=23)[CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:14]1[C:10]2=[N:11][CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[C:4]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])[CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:7]=3)=[C:9]2[CH:16]=[N:15]1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C#N)c1cc(Br)cc(-c2ccnc3[nH]ncc23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C#N)c1cc(-c2ccccc2)cc(-c2ccnc3[nH]ncc23)c1
Temperature: 150 °C
Yield: 34.2 %

Procedure:
A mixture of 2-(3-bromo-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-methylpropanenitrile (50 mg, 0.147 mmol) and phenyl boronic acid (26.76 mg, 0.220 mmol) were placed in a microwave vial. Ethylene glycol dimethyl ether (1.5 ml) was then added followed by sodium carbonate (269.0 mg, 243.9 μL of 2 M, 0.488 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.2 mg, 0.012 mmol). The reaction mixture was heated under microwave irradiation at 150° C. for 60 minutes. The reaction mixture was allowed to cool down to room temperature and was diluted with ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (17 mg, 34% yield).