Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30]([CH2:32][C:33]([O:35]C)=[O:34])=[O:31])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[OH2:31].[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30]([CH2:32][C:33]([OH:35])=[O:34])=[O:31])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CS(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O
Product: O=C(O)CS(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 185 %

Procedure:
A mixture of methyl [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl)hexyl]sulfinyl]acetate (1.06 g, 2.1 mmol), 3 N sodium hydroxide solution (2.1 mL, 6.3 mmol) and methanol (50 mL) was heated at reflux for 10 minutes. The methanol was evaporated, the residue acidified to pH=5 with IN HCl and extracted with dichloromethane (3x). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to afford [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl)hexyl]sulfinyl]acetic acid hydrate (0.98 g, 95%) as a white foam; m.p. =132.5°-134.5° C. MS(CI): m/e =443 (MH+ --CO2).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC(C)C)(C)C.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:10]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[CH2:9])[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C[C@H](NC1CCCC1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: C=C[C@@H](c1ccccc1)N(Cc1ccccc1)C1CCCC1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of N-[(1S)-1-phenylprop-2-en-1-yl]cyclopentanamine (24 mg) and diisopropylamine (18 mg) in DCM (2.5 ml) at RT under N2 was added benzoyl chloride (20 mg). This mixture was stirred for 1 h. The reaction was evaporated and purified by flash chromatography (2% EtOAc/hexane) to afford the title compound (15 mg, 44%) as a pale oil. 1H NMR (300 MHz, CDCl3) δ 1.22-2.27 (m, 8H), 3.57 (bs, 1H), 5.28-5.60 (m, 3H), 6.23 (bs, 1H), 7.00-7.71 (m, 10H). MS APCI, m/z=306 (M+1), LC/MS, 2.83 min. Chiral HPLC was used to determine ee % by comparing this sample to a known sample of the racemic compound N-benzyl-N-(1-phenylprop-2-en-1-yl)cyclopentanamine. 14.99 min (97.89%) and 17.52 min (2.11%) or 96% ee. Chiral HPLC method: Chiral Technologies 10 μm Chiralpak AD column 4.6 mm×250 mm. Solvents: A=IPA, B=Hexane. Isocratic Method 7% A/B over 30 minutes at 0.6 ml/mn.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[CH2:36](O)[CH2:37][OH:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([O:38][CH2:37][CH2:36][O:35]2)[CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(NC(C)=O)C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(CCc1ccc(C2(CCCCc3ccccc3)OCCO2)cc1)(NC(C)=O)C(=O)OCC

Procedure:
A solution of diethyl 2-acetamido-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}malonate (13.5 g), ethylene glycol (3.1 ml) and p-toluenesulfonic acid (0.53 g) in benzene (135 ml) was refluxed under heating for 20 hours, while dehydrating with Dean-Stark trap. The reaction mixture was treated with triethylamine (2.4 ml) and ethyl acetate (200 ml) was added thereto. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a pale yellow oily substance (15.9 g). The obtained pale yellow oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=1:1) to give diethyl 2acetamido-2-{2-[4-(1,1-ethylenedioxy-5-phenylpentyl)phenyl]ethyl}malonate (14.1 g) as a colorless transparent oily substance.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:11].[Cl-].[Mg+2].[Cl-].[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:9])[CH2:27][C:26]([O:25][CH2:29][CH3:28])=[O:11])=[CH:7][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccncc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg+2]
Product: CCOC(=O)CC(=O)c1ccncc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1′-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700 ml), and the resulting solution was stirred for 1.5 hr at 50° C. After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50° C. for 6 hr. The solvent was removed under reduced pressure and the residue was quenched by the addition of dilute acetic acid. The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=2/1 to 1/1) and recrystallization from hexane-ethyl acetate gave 41.52 g (74%) of the title compound.
Reaction SMILES: [Cl-:1].[K+:2].[P:3](=[O:7])([OH:6])([OH:5])[OH:4].[P].[K]>>[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[K+:2].[K+:2].[K+:2].[ClH:1]
Reactant: [Cl-]
Reactant: O=P(O)(O)O
Agent: [K+]
Agent: [K]
Agent: [P]
Product: Cl
Product: O=P([O-])([O-])[O-]

Procedure:
Accordingly, in one aspect of the present invention, there is provided a process for the production of potassium phosphate, which comprises (a) reacting potassium chloride with phosphoric acid in a molar feed ratio of phosphorus to potassium in the range of at least about 1.3:1 at a temperature of about 130° to about 200° C. to form potassium phosphate and by-product hydrogen chloride; (b) removing the hydrogen chloride from the reaction mixture by passing air through the reaction mixture during a first portion of the period for the reaction of the potassium chloride and by passing steam through the reaction mixture during the remainder of the period of the reaction of the potassium chloride; and (c) recovering the stripped hydrogen chloride in the form of hydrochloric acid having a concentration of at least about 20 wt. % HCl.
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:34])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C>C(O)(C)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:15]2[CH:14]([CH2:13][CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=3)[OH:34])[C:17](=[O:18])[N:16]2[C:19]2[CH:26]=[CH:25][C:22]([C:23]([NH:3][OH:2])=[NH:24])=[CH:21][CH:20]=2)=[CH:32][CH:31]=1
Reactant: [NH3+]O
Reactant: N#Cc1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N=C(NO)c1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
279 mg of hydroxylammonium hydrochloride were added to a solution of 280 mg of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-fluorophenyl)-4-oxoazetidin-1-yl]benzonitrile (11) and 0.65 ml of triethylamine in 15 ml of isopropanol. The mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 451.48 (C25H23F2N3O3); MS (ESI): 452.10 (M+H+).
Reaction SMILES: [OH:1]O.[NH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[CH2:12][CH2:11][CH2:10]3)[C:5](=[O:15])C1=O.[OH-].[Na+].Cl>O>[NH2:3][C:14]1[C:6]([C:5]([OH:15])=[O:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: O=C1Nc2c(ccc3c2CCC3)C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (5 mL) in water (44 mL) to a solution of 1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione (3.80 mg, 20.3 mmol) and sodium hydroxide (5.03 g, 126 mmol) in water (97 μL) over a period of 30 minutes, stir the mixture at room temperature for 1 h. Acidulate with 1N hydrochloric acid, filter the solid, wash with water and dry to afford 4-Amino-indan-5-carboxylic acid (3.13 g, 87%). Dissolve 4-Amino-indan-5-carboxylic acid (3.07 g, 17.3 mmol) in ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl) diazomethane (17.3 mL, 34.6 mmol, 2M in hexanes) at room temperature and stir the solution for 1 hour. Remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (2.50 g, 76%). 1H NMR (MeOD, 300 MHz) δ 2.12 (quintuplet, J=7.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 3.83 (s, 3H), 6.53 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH:11][C:12]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=S)=[CH:9][N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.C(O)C>[Hg]=O.CN(C)C(=O)C>[CH:1]1([N:4]2[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:11][C:10]3[C:5]2=[N:6][CH:7]=[N:8][CH:9]=3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cncnc2NC2CC2)CC1
Agent: O=[Hg]
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cncnc3n2C2CC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A mixture of 15.7 parts of ethyl 4-[[[[4-(cyclopropylamino)-5-pyrimidinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate, 20 parts of mercury(II) oxide, 40 parts of ethanol and 135 parts of N,N-dimethylacetamide was stirred overnight at 80° C. The reaction mixture was filtered over diatomaceous earth while hot. The filtrate was poured into water and the product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (14.1%) of ethyl 4-[(9-cyclopropyl-9H-purin-8-yl)amino]-1-piperidinecarboxylate; mp. 177.0° C. (compound 17).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: COc1cccc(B(O)O)c1
Product: COC(=O)c1c(O)c2ccc(-c3cccc(OC)c3)cc2sc1=O

Procedure:
4-Hydroxy-7-(3-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 3-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.10 (M−1).
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C:6]1=[O:25])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[CH:15][C:14]=1[CH2:13][CH2:12]3)C.[C:26]1(C)C=CC=CC=1.C[Li].Cl>CCOCC.O>[CH:4](=[C:5]1[CH2:10][C@H:9]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C:6]1=[O:25])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[CH:15][C:14]=1[CH2:13][CH2:12]3)[CH3:26]
Reactant: Cc1ccccc1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C(=CN(C)C)C[C@@H]12
Agent: Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC=C1C[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]2(C)C1=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A solution of 5 g. of 16-dimethylaminomethylene-3-methoxy-1,3,5(10)-estratrien-17-one in 150 ml. of toluene is combined dropwise at -10° C. with 28.5 ml. of a 5% solution of methyllithium in ether. After this dropwise addition, the mixture is agitated for 15 minutes at -10° C.; then about 10 ml. of water is gently added in drops, and the reaction solution is poured into about 200 ml. of 0.5 N hydrochloric acid. The organic phase is separated, dried over sodium sulfate, and concentrated under vacuum. After crystallization of the residue from ethyl acetate/ether, 3.9 g. of 16-ethylidene-3-methoxy-1,3,5(10)-estratrien-17-one is obtained, m.p. 139°-140° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+]([O-])=O)=[C:9](/[CH:11]=[CH:12]/[N:13](C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[C:1]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][C:6]=1[NH2:19])[NH:13][CH:12]=[CH:11]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)/C=C/c1cc(C(C)(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2cc[nH]c2cc1N
Temperature: 25 °C
Yield: 11.8 %

Procedure:
A solution of (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-N,N-dimethylethen-amine (5.3 g, 18 mmol) and tin (II) chloride dihydrate (37 g, 0.18 mol) in ethanol (200 mL) was heated at reflux overnight. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residual slurry was diluted with water (500 mL) and was basifed with 10% aq. Na2CO3 to pH 8. The resulting suspension was extracted with ethyl acetate (3×100 mL). The ethyl acetate extract washed with water and brine, dried over Na2SO4, and concentrated. The residual solid washed with CH2Cl2 to afford a yellow powder, which was purified by column chromatography to give 5-tert-butyl-1H-indol-6-amine (0.40 g, 12%). 1H NMR (DMSO-d6) δ 10.34 (br s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 6.14 (s, 1H), 4.43 (br s, 2H), 2.48 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].O.C(OCC)C.Cl[CH:22]1[C:27](=O)[CH2:26][CH2:25][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:23]1.[CH:34]([NH2:36])=O>C(O)CCC>[CH2:32]([O:31][C:29]([N:24]1[CH2:25][CH2:26][C:27]2[N:36]=[CH:34][S:2][C:22]=2[CH2:23]1)=[O:30])[CH3:33]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC=O
Reactant: CCOC(=O)N1CCC(=O)C(Cl)C1
Solvent: O
Solvent: CCCCO
Solvent: CCOCC
Product: CCOC(=O)N1CCc2ncsc2C1
Reaction time: 8 h

Procedure:
Phosphorus pentasulfide (500 g) was suspended in formamide (3,000 ml) with ice cooling, and the suspension was stirred overnight. Water and diethyl ether were added to the reaction mixture, and an organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow oil. After the oil was dissolved in n-butanol (350 ml), and 3-chloro-1-ethoxycarbonylpiperidin-4-one (150 g) synthesized according to the process described in literature (Tetrahedron, 1983, Vol. 39, p. 3767) was added to the solution, the resultant mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was filtered through Celite. The resultant filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane-ethyl acetate:hexane=1:2) to obtain the title compound (79.0 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.O[CH2:13][CH2:14]/[CH:15]=[CH:16]/[P:17](=[O:26])([O:22][CH:23]([CH3:25])[CH3:24])[O:18][CH:19]([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:13][CH2:14]/[CH:15]=[CH:16]/[P:17]([O:22][CH:23]([CH3:24])[CH3:25])([O:18][CH:19]([CH3:20])[CH3:21])=[O:26])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)OP(=O)(/C=C/CCO)OC(C)C
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(/C=C/CCn1cnc2c(Cl)nc(N)nc21)OC(C)C
Temperature: 0 °C
Yield: 35.2 %

Procedure:
To a mixture of 2-amino-6-chloropurine (0.6 g, 3.81 mmol) , diisopropyl (E)-4-hydroxybut-1-enylphosphonate (0.90 g, 3.81 mmol) and triphenyl phosphine (2.00 g, 7.62 mmol) in dry N,N-dimethylformamide (30 ml) stirred at 0° C. under dry nitrogen was added diethyl azodicarboxylate (1.33 g, 7.62 mmol). The mixture was allowed to warm to room temperature and stirred for 1.3 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (9:1) to afford (E)-2-amino-6-chloro-9-[4-(diisopropoxyphosphoryl)but-3-enyl]purine as a light brown gum (0.52 g, 35%), m.p. 150° C.; λmax (EtOH) 311 (6,760), 249 (5,420) and 224 (24,320)nm; υmax (KBr) 3385, 3320, 3208, 1635, 1615, 1560, 1520, 1410 and 1240 cm-1 ; δH [(CD3) 2 SO] 1.08 (6H, d, J 6 Hz, CH(CH3)2), 1.16 (6H, d, J 6 Hz, CH(CH3)2), 2.77 (2H, m, CH2), 4.27 (4H, m, CH2N and CH(CH3)2), 5.69 (1H, dd, J 17 Hz and 21Hz, PCH=CH), 6.52 (1H, ddt, J 6 Hz, 17 Hz and 22 Hz PCH=CH), 6.89 (2H, br.s, D2O exchangeable, NH2), 8.11 (1H, s, H-8) (Found: MH+ 388.1288. C15H23ClN5O3P requires MH+ 388.1305).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C@@H:26]([CH3:30])[C:27](O)=[O:28].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)[O:35]1)CC>CC#N>[CH2:1]([N:8]([CH2:9][C@@H:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[C:27](=[O:28])[C@@H:26]([OH:35])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Cl)C(=O)O
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Reactant: O[C@H](CNCc1ccccc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](O)C(=O)N(Cc1ccccc1)C[C@@H](O)C(F)(F)F

Procedure:
To a solution of (R)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (4-2, 5 g, 22.81 mmol) in CH3CN (200 ml) was added DIEA (12 ml, 68.7 mmol), (S)-2-chloropropionic acid (2.4 ml, 27.4 mmol), then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (16.3 ml, 27.4 mmol) slowly at rt. After 2.5 hr the mixture was concentrated. The material was taken up in EtOAc and washed with saturated NaHCO3, H2O, and brine. The organic layer was filtered through a pad of silica gel washing with ethyl acetate then concentrated to afford (S)—N-benzyl-2-hydroxy-N—((R)-3,3,3-trifluoro-2-hydroxypropyl)propanamide (4-3) as a clear oil which was sufficiently pure for use in the next step.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:20]>CN(C)C=O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[NH:20][CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]1=2
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CCC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCC2
Temperature: 100 °C

Procedure:
To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g, 157 mmol) in ethyl alcohol (500 mL) under nitrogen at ambient temperature was added acetyl chloride(56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hyroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in N,N-dimethylformamide (225 mL) was heated at 100° C. under nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo , and the residue triturated with ether to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1h. After cooling in an ice bath, the mixture was acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid. m.p. 269-270° C.
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[C:4]=1[O:5][CH2:6][C@H:7]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:8][O:9][S:10]([CH3:13])(=[O:12])=[O:11].B(Br)(Br)Br.O>ClCCl>[OH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:3]([OH:2])[C:4]=1[O:5][CH2:6][C@H:7]([O:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH2:8][O:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: COc1cccc(OC)c1OC[C@@H](COS(C)(=O)=O)OS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC[C@H](COc1c(O)cccc1O)OS(C)(=O)=O
Temperature: 0 °C
Yield: 88.7 %

Procedure:
Methanesulfonic acid (S)-3-(2,6-dimethoxy-phenoxy)-2-methanesulfonyloxy-propyl ester (3.08 g, 8.00 mmol) in) in dichloromethane (40 ml) was cooled to 0° C. and stirred under nitrogen atmosphere. Boron tribromide (1 M solution in dichloromethane, 18 ml, 18 mmol) was added in 15 min. The mixture was stirred at +25° C. for 4 h, and poured on mixture of ice (10 g) and water (15 ml), and the layers were separated. Organic phase was recovered and water layer was extracted twice with dichloromethane (15 ml). Organic phase and dichloromethane extracts were combined and washed with water (15 ml) and saturated sodium chloride solution (15 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness to give 2.53 g of the title compound.
Reaction SMILES: CC([CH:5]1[CH2:11][N:10](C([O-])=O)[CH2:9][C:8]2[CH:15]=[C:16]([C:19]3[CH:20]=[C:21]4[NH:27][C:26]([NH:28][C:29]([O:31]CC5C=CC=CC=5)=[O:30])=[N:25][C:22]4=[N:23][CH:24]=3)[CH:17]=[CH:18][C:7]=2[O:6]1)(C)C.[ClH:39]>CO.O1CCOCC1>[ClH:39].[C:8]1([CH2:9][N:28]([C:26]2[NH:27][C:21]3[C:22]([N:25]=2)=[N:23][CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:7]4[O:6][CH2:5][CH2:11][NH:10][CH2:9][C:8]=4[CH:15]=2)[CH:20]=3)[C:29](=[O:30])[OH:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:7]=1
Reactant: CC(C)(C)C1CN(C(=O)[O-])Cc2cc(-c3cnc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)ccc2O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)N(Cc1ccccc1)c1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Temperature: 55 °C
Yield: 76 %

Procedure:
To the solution of 1,1-dimethylethyl-7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-imidazo[4,5-b]pyridine-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (4.5 g, 8.73 mmol) in methanol (20 ml) was added 4 N HCl in dioxane at room temperature. Then the reaction mixture was heated to 55° C. for 3 hours. After cooling to room temperature, the precipitate collected by filtration, washed with a minimum of methanol and dried to give phenylmethyl[6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (3.0 g, 76% yield). 1HNMR (400 MHz, CD3OD): 8.59 (m, 1H), 8.51 (s, 1H), 7.85 (m, 1H), 7.79-7.75 (m, 1H), 5.37 (s, 2H), 4.53 (s, 2H), 4.37-4.32 (m, 2H), 3.67-3.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[S:13]([OH:16])(=O)=[O:14].S([O-])([O-])=O.[Na+].[Na+].[CH3:23]I>>[CH3:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:10]([S:13]([CH3:23])(=[O:16])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: CI
Reactant: O=S(=O)(O)Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
in stage b) 4-chloro-2-methylbenzoic acid is reacted with chlorosulfonic acid, sodium sulfite and methyl iodide to give 2-methyl-4-chloro-5-methylsulfonylbenzoic acid,