Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[C:24](OCC)(=O)[C:25]([O:27]CC)=[O:26]>CCOCC>[C:25]([C:24]1[O:23][C:22]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:19]=[CH:20][CH:21]=2)([OH:27])=[O:26]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(O)c1cc(=O)c2c(OCC(O)COc3ccc(Cl)cc3)cccc2o1

Procedure:
A mixture of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-chlorophenoxypropane (13.5 g) and diethyl oxalate (15 ml) was added to a suspension of alcohol-free sodium ethoxide (prepared from sodium 3 g) in absolute ether (200 ml). The mixture was heated under reflux for 1.5 hours during which time a yellow solid separated. The reaction mixture was poured onto ice (100 g) and acidified with a solution of acetic acid (12 ml) in water (80 ml). The ether layer was separated and the aqueous layer extracted with ether (3 × 25 ml). The ether layer was combined with the ether extracts and the solvent was evaporated. Acetic acid (80 ml) and hydrochloric acid (30 ml) were added to the residue and the resulting solution was heated under reflux for 1 hour. On pouring into water a beige gum was precipitated which soon solidified and was filtered. Recrystallization from acetic acid gave crude 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (12.0 g), as a white solid, m.p. 191°-193°. The impure acid (10 g) was heated under reflux for 5 hours with ethanol (100 ml) and concentrated sulphuric acid (10 drops). The solvent was then removed on a rotary evaporator; the residual oil was dissolved in chloroform and washed successively with sodium bicarbonate solution and water. The solvent was removed and a small volume of ether was added to the residual oil which slowly crystallized to give a white solid (8.4 g), m.p. 98°-100°. Recrystallization from aqueous ethanol gave 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (6.6 g) as white fluffy needles, m.p. 98°-100° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=CC(S(O)(=O)=O)=[CH:6][CH:7]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.CC(CCO)=C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[O:17][CH2:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCCC1
Agent: C=C(C)CCO
Solvent: Cc1ccccc1
Product: CC1=CCOC2(CCCC2)C1
Temperature: 115 °C
Yield: 56 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added cyclopentanone (840 g, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provideto 9-methyl-6-oxaspiro[4.5]dec-8-ene (0.851 kg) having a purity of 95% (sum of the isomers) for a total yield of 56%.
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1>C(O)C(C)C>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:4][CH:5]([CH3:8])[CH3:6])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Solvent: CC(C)CO
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(COCC(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Yield: 140.6 %

Procedure:
Reactions similar to those of Reference Example 21 were performed except for using isobutanol instead of ethanol, and from 78 mg (0.10 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, 59 mg of the title compound was obtained as a foam (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:20](=[O:29])[N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccnc2cc(Cl)ccc12
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccnc2cc(Cl)ccc12)c1ccccc1
Yield: 92.7 %

Procedure:
A solution of 7-chloro-4-hydroxyquinoline (0.54 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.87 g, 93% yield) as a colourless oil which solidified upon standing.
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:93])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72]3[CH:76]=[CH:75][S:74][CH:73]=3)[CH:69]=[C:68]([C:77]([N:79]3[CH2:83][CH2:82][C:81]([F:85])([F:84])[CH2:80]3)=[O:78])[CH:67]=2)[C:54]=1[CH2:86][CH2:87][C:88]([O:90]CC)=[O:89])C.[OH-].[Na+]>CCO>[C:88]([CH2:87][CH2:86][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72]3[CH:76]=[CH:75][S:74][CH:73]=3)[CH:69]=[C:68]([C:77]([N:79]3[CH2:83][CH2:82][C:81]([F:84])([F:85])[CH2:80]3)=[O:78])[CH:67]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:93])=[O:47])([OH:90])=[O:89]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 91.4 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[3-(3,3-difluoro-pyrrolidine-1-carbonyl)-5-thiophen-3-yl-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (71 mg, 0.11 mmol) and 1.0 N aqueous NaOH (1.1 mL) in EtOH (5 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[3-(3,3-difluoro-pyrrolidine-1-carbonyl)-5-thiophen-3-yl-phenoxy]-hexyl}-phenoxy)-butyric acid (64.7 mg, 91%) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:15]([O:17][C@@H:18]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[N:21]=2)[CH3:19])=[O:16])=[CH:4][C:3]=1[OH:26].[C:27](O)(=O)[CH:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]3[N:1]=[C:27]([CH:28]([CH3:30])[CH3:29])[O:26][C:3]=3[CH:4]=[C:5]([C:15]([O:17][C@@H:18]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)[CH3:19])=[O:16])[CH:6]=2)=[CH:9][CH:10]=1
Reactant: CC(C)C(=O)O
Reactant: Cc1noc([C@@H](C)OC(=O)c2cc(O)c(N)c(-c3ccc(F)cc3)c2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1noc([C@@H](C)OC(=O)c2cc(-c3ccc(F)cc3)c3nc(C(C)C)oc3c2)n1
Temperature: 150 °C
Yield: 28.8 %

Procedure:
To a solution of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl 6-amino-4′-fluoro-5-hydroxybiphenyl-3-carboxylate (10.0 mg, 28.0 μmol), and isobutyric acid (4.94 mg, 56.0 μmol) and solid support triphenylphosphine (75% by weight; 29.4 mg, 84.0 μmol) in acetonitrile (0.28 mL) was added trichloroacetonitrile (5.63 μL, 56.0 μmol). The mixture was heated in a microwave reactor for 10 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (3.3 mg). HRMS [M+1] found=409.1683.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1.[N+](C1C=C(O)C=CC=1)([O-])=O.[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]>C1(C)C=CC=CC=1>[CH2:35]([C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:17]=2)=[O:47])=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: COc1cc2nccc(Oc3cccc([N+](=O)[O-])c3)c2cc1OC
Agent: O=[N+]([O-])c1cccc(O)c1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=O)Nc2cccc(Oc3ccnc4cc(OC)c(OC)cc34)c2)cc1
Yield: 32 %

Procedure:
6,7-Dimethoxy-4-(3-aminophenoxy)quinoline (51 mg), which was obtained, analogously to Example 49, by reducing 6,7-dimethoxy-4-(3-nitrophenoxy)quinoline obtained in the same manner as described in Example 48, except that 3-nitrophenol was used in place of 4-nitrophenol, was dissolved in toluene (3 ml) with heat, 4-n-butylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 50 minutes. The resulting residue was purified by chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 26 mg of the title compound (yield: 32%).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][O:13][C:14]([CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=O)=[O:15].C1C=CC2N(O)N=NC=2C=1.[N:32]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:41]([O:40][C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:18](=[O:20])[C@H:17]([OH:21])[CH2:16][C:14]([O:13][CH3:12])=[O:15])[CH2:34][CH2:33]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)C[C@@H](O)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 32.9 %

Procedure:
EDCI (3.6 g, 19 mmol) was added to a solution of (R)-3-(methoxycarbonyl)-2-hydroxypropanoic acid (2.8 g, 19 mmol) and HOBt (2.6 g, 19 mmol) in DMF (200 mL). After stirring this mixture for 5 min, benzyl piperazine-1-carboxylate (4.2 g, 3.6 mL, 19 mmol) and triethylamine (2.6 mL, 19 mmol) were added and stirred for 3 days at room temperature. The reaction mixture was poured into water and extracted with EtOAc. After washing the organic layers with brine and water, drying over Na2SO4 and concentrating, purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 gave 4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylic acid benzyl ester as an oil (2.19 g, 33%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m, 5H), 5.15 (s, 2H), 4.79-4.74 (m, 1H), 3.95 (d, J=8.0 Hz, 1H), 3.79-3.74 (m, 1H), 3.74 (s, 3H), 3.71-3.44 (m, 7H), 2.62 (d, J=5.8 Hz, 2H) ppm.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:13][CH2:14][C:15]1[N:16]([CH2:29][CH2:30][OH:31])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([O:13][CH2:14][C:15]1[N:16]([CH2:29][CH:30]=[O:31])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1)[CH3:12]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CC=O
Temperature: 25 °C

Procedure:
To dichloromethane (10 mL) at −78° C. was added dimethylsulfoxide (0.37 mL, 5.17 mmol) and oxalyl chloride (0.33 mL, 3.79 mmol). After several minutes, a solution of 2-[8-(ethoxymethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]ethanol (prepared as described in U.S. Pat. No. 6,797,718, 1.00 g, 3.44 mmol) in dichloromethane (40 mL) was added dropwise followed by triethylamine (1.5 mL, 10.3 mmol). The mixture was allowed to warm to room temperature and more dichloromethane (80 mL) was added. The solution was transferred to a separatory funnel and washed with saturated aqueous potassium carbonate, water, and brine. The aqueous layers were combined and back-extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the product [8-(ethoxymethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]acetaldehyde as a tan solid (0.86 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.Cl>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1CCN(c2ccnc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To a solution tert-butyl 1-(2-(trifluoromethyl)pyridin-4-yl)piperidin-4-ylcarbamate (314 mg, 0.91 mmol) in dichloromethane (4.5 mL) was added HCl (2 M in diethylether, 2.27 mL, 4.55 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethylether and dried to afford the title compound (201 mg, 90%) as an off white solid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[CH:22]=[C:23]([C:33](O)=[O:34])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[N:25]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[N:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1ccc(-n2nc(C)cc2C(=O)O)cc1
Product: Cc1ccc(-n2nc(C)cc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-Methyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=1.27 min; [M+H]+=475.2.
Reaction SMILES: [Cl:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([C:18]3[NH:22][N:21]=[CH:20][CH:19]=3)[C:15]([NH:23][CH2:24][CH:25]([OH:29])[CH2:26][CH2:27][OH:28])=[N:14][CH:13]=2)=[CH:6][CH:5]=1>CCCCCCC.CCO.CO>[Cl:1][C:2]([F:31])([F:32])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([C:18]3[NH:22][N:21]=[CH:20][CH:19]=3)[C:15]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][CH2:27][OH:28])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCC(O)CCO)c(-c2ccn[nH]2)c1
Solvent: CCCCCCC
Solvent: CO
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NC[C@@H](O)CCO)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared by chiral separation (Preparative chiral HPLC, ChiralPak® AS, 20 μm 50×500 mm, mobile phase: n-heptane/EtOH/MeOH (85:10:5)+0.05% DEA, flow rate 68 mL/min, wavelength: 210 nm) of a racemic mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-((2,4-dihydroxybutyl)amino)-5-(1H-pyrazol-5-yl)nicotinamide (Example 97), slower eluting isomer (Peak 2, tR=12.52 min). Or alternatively, in an analogous fashion to that described in Example 97 using (S)-benzyl(2,4-dihydroxybutyl)carbamate (Stage 98.1) as chiral starting material. HPLC chiral (Chiralpak® AS-H, eluent: n-heptane/EtOH/MeOH (80:12:8)+0.05% DEA, flow rate:1 mL/min, temperature: RT, DAD 300 nm.): tR=9.31 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)([Cl:34])=[O:33]>ClCCl.C1(C)C=CC=CC=1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:32]([Cl:34])=[O:33])[CH2:17][C:16]=3[CH:22]=2)=[CH:8][CH:7]=1
Reactant: c1c[nH]c(-c2ccc(-c3ccc4c(c3)CNCCO4)cn2)n1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine as obtained in step 3 was dissolved in dichloromethane (2 mL), diisopropylethylamine (0.12 mL, 0.65 mmol) was added, followed by addition of phosgene (0.07 mL of a 20% solution in toluene, 0.13 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated to afford crude 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[Li]C(C)(C)C.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20](=[O:21])[C:18]1=[O:19])[CH3:13].[NH4+].[Cl-]>C1COCC1>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]1[C:27]2[C:22](=[C:23]([Br:28])[CH:24]=[CH:25][CH:26]=2)[C:20]([OH:21])([C:2]2[CH:6]=[CH:5][O:4][CH:3]=2)[C:18]1=[O:19])[CH3:30]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccoc2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To 3-bromofuran (95.1 mg, 2.1 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added t-BuLi (0.38 mL, 2.1 eq, 1.7 M in pentane) at −78° C. (bath temperature). Stirring was continued for 1 hour after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red coloured solution was stirred at −40° C. for 8 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 2% MeOH in CHCl3) to give the title compound as a yellow solid (103.3 mg, 85%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([C:63]1[CH:92]=[CH:91][CH:90]=[CH:89][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:68])=[N+:61]=[N-:62].C(#N)C>O.O1CCCC1>[N:60]([C:63]1[CH:92]=[CH:91][CH:90]=[CH:89][C:64]=1[CH2:65][O:66][C:67]([NH:69][CH2:70][CH2:71][CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:86])([CH3:87])[CH3:88])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:68])=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 14.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (46.3 mg, 0.073 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk41) (134 mg, 0.291 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (14 mL), and the mixture was stirred at room temperature for 1.75 hours. Acetonitrile (0.6 mL) was added and the mixture was stirred at the same temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk42) (11.1 mg, 15%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:41]([O-:44])(=[S:43])[CH3:42].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:41]([S:43][CH2:25][C@H:13]1[N:12]([CH2:11][CH:10]([C:5]2[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=2[CH3:28])[OH:27])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)(=[O:44])[CH3:42]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Reactant: CC([O-])=S
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(O)c1ccc(F)c(C#N)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S)-tert-butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (synthesis described above, 0.090 g, 0.23 mmol) was dissolved in THF (2.3 mL) and cooled to 0° C. Triethylamine (0.038 mL, 0.274 mmol) was added followed by addition of Ms-Cl (0.020 mL, 0.252 mmol), and DMAP (2.79 mg, 0.023 mmol). The ice bath was removed and stirring was continued for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting material was re-dissolved in DMSO (2 mL) and treated with potassium thioacetate (0.035 g, 0.306 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight and then heated at 45° C. for 2 h. The mixture was diluted with ethyl acetate and washed with water (3 times) and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (100% hexane to 80% EtOAc/Hexane) to give the desired product LC/MS: M+1=452.3.