Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C(OC(N1C2=CN=CC([C:37]3[CH:42]=[C:41]([C:43]([O:45][CH3:46])=[O:44])[CH:40]=[CH:39][C:38]=3[C:47]#[N:48])=C2C=C1)=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:46][O:45][C:43](=[O:44])[C:41]1[CH:40]=[CH:39][C:38]([C:47]#[N:48])=[C:37]([C:2]2[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]3[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=23)[CH:42]=1
Reactant: COC(=O)c1ccc(C#N)c(-c2cncc3c2ccn3C(=O)OC(C)(C)C)c1
Reactant: COc1ncc2c(ccn2COCC[Si](C)(C)C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C#N)c(-c2c(OC)ncc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Yield: 68.8 %

Procedure:
A mixture of 4-Bromo-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridine (0.940 g, 2.63 mmol), 4-Cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-benzoic acid methyl ester (Example 140 Step 1 starting material) (0.840 g, 2.93 mmol, 1.1 eq), Bis(di-tertbutyl-(4-dimethylaminophenyl)-phosphine)-di-chloropalladium (II) (0.046 g, 0.066 mmol, 2 mol %), and tribasic potassium phosphate (1.12 g, 5.26 mmol, 2 eq) in a 10:1 mixture of dioxane and water was heated to 80° C. for 2.5 hr. The reaction was cooled to 23° C., the contents decanted into a separatory funnel and the residue in the vial was washed with copious amounts of ethyl acetate. The organic was washed with water, brine, dried (Na2SO4), and concentrated. The crude mixture was further purified by chromatography eluting with 30% EtOAc/Heptane giving 4-Cyano-3-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl]-benzoic acid methyl ester as a yellow amorphous solid (0.790 g, 1.81 mmol, 69%). MS ESI m/z 438.4 (M+H)+. 1NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 6.20 (d, J=3.2 Hz, 1H), 5.54 (d, J=5.0 Hz, 2H), 4.04 (s, 3H), 3.98 (s, 3H), 3.55 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:19][C@H:18]([CH2:20][O:21]C(=O)C3C=CC=CC=3)[C@@H:17]([CH2:30][O:31]C(=O)C3C=CC=CC=3)[CH2:16][C@H:15]2[OH:40])=[C:7]([O:41]CCOC)[N:6]=1.Cl>CO>[OH:31][CH2:30][C@@H:17]1[C@@H:18]([CH2:20][OH:21])[CH2:19][C@@H:14]([N:11]2[CH:10]=[N:9][C:8]3[C:7](=[O:41])[NH:6][C:5]([NH2:4])=[N:13][C:12]2=3)[C@H:15]([OH:40])[CH2:16]1
Reactant: COCCOc1nc(N)nc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(ncn2[C@@H]2C[C@H](CO)[C@@H](CO)C[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
Sodium methoxide (36 mg, 0.67 mmole) was added to a solution of 2-amino-9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-6-(2-methoxyethoxy)-purine (190 mg, 0.33 mmole) in anhydrous methanol (3 ml) under cooling with ice. After stirring the mixture at room temperature for 5 hours, the reaction mixture was neutralized with dilute hydrochloric acid and the solvent was distilled off under reduced pressure. Then, ethyl ether and water were added to the residue, the ethyl ether layer was removed, and water was distilled off. Then, the residue was heated at 100° C. for one hour together with 2N aqueous hydrochloric acid (7 ml). The reaction mixture was neutralized with 1N solution of sodium hydroxide and then purified by Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(hydroxymethyl)-2-hydroxycyclohexyl]-guanine (70 mg, Yield 69%).
Reaction SMILES: COC(=O)CN[C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH2:39]([O:41][C:42]([C:44]1[S:45][C:46]([NH2:49])=[N:47][N:48]=1)=[O:43])[CH3:40]>CCCCCCC.C(OCC)(=O)C>[CH2:39]([O:41][C:42]([C:44]1[S:45][C:46]([NH:49][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[N:47][N:48]=1)=[O:43])[CH3:40]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: CCOC(=O)c1nnc(N)s1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)s1

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (commercially available, CAS RN 64837-53-2) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Yellow solid (67%). MS (ESI): m/z=652.12 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH3:11])(=[O:5])=[O:4].[Li]CCCC.[O:18]1[CH2:20][CH2:19]1>O1CCCC1>[OH:18][CH2:19][CH2:20][C:9]1[N:8]=[C:7]([CH3:11])[N:6]([S:3]([N:2]([CH3:12])[CH3:1])(=[O:4])=[O:5])[CH:10]=1
Reactant: C1CO1
Reactant: Cc1nccn1S(=O)(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CCO)cn1S(=O)(=O)N(C)C
Temperature: -78 °C
Yield: 43.1 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N,N,2-trimethyl-1H-imidazole-1-sulfonamide (compound 282.1, 6.4 g, 33.8 mmol) in tetrahydrofuran (50 mL). This was followed by the addition of n-BuLi (2.5M in hexane) (16.3 mL, 40.6 mmol) dropwise with stirring at −78° C. The reaction mixture was stirred for 1 h at −78° C. Oxirane (12.1 mL, 242.89 mmol) was added dropwise at −30° C. The reaction mixture was stirred for 2 h at room temperature, then quenched with 10 mL of water. The aqueous phase was extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc:MeOH (40:1) as the eluent to yield 3.4 g (43%) of the title compound as a white solid.
Reaction SMILES: C(OC(=O)[CH:5]([CH:8]1[CH2:14][N:13]2[CH2:15][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:6]#[N:7])C.[Na:17].C([O:23][N:24]=O)CC(C)C>C(O)C>[Na:17].[N:13]12[CH2:15][CH:9]([CH:8]([C:5](=[N:24][OH:23])[C:6]#[N:7])[CH2:14]1)[CH2:10][CH2:11][CH2:12]2
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C(C#N)C1CN2CCCC1C2
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)C1CN2CCCC1C2
Temperature: 50 °C

Procedure:
Ethyl(1-azabicyclo[3.2.1]octan-6-yl)cyanoacetate (36 g, 0.16 mol) in abs. ethanol (100 ml) was added to a solution of sodium (4 g, 0.21 mol) in abs. ethanol (100 ml). Isoamylnitrite (25 ml, 0.19 mol) was added over 0.5 h, and the mixture was heated at 50° C. for 4 h. Evaporation of the reaction mixture gave crude sodium salt of the title compound, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH:11]=[N:12][C:13]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]3[C:14]=2[CH2:15][NH:16][C:17]3=[O:23])[CH:7]=1.B(Br)(Br)Br.CO.ClCCl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]2[C:7]=1[CH:11]([NH:12][C:13]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]3[C:14]=1[CH2:15][NH:16][C:17]3=[O:23])[C:10]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:9][C:8]2([CH3:30])[CH3:29]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cc(F)cc2c1CNC2=O)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cc(F)cc3c2CNC3=O)c2c(F)ccc(O)c21
Reaction time: 1 h
Yield: 2.5 %

Procedure:
380 mg (0.832 mmol) of 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}6-fluoro-2,3-dihydroisoindol-1-one is mixed at room temperature with 8.3 ml of a 1 M solution of BBr3 in dichloromethane and stirred for one hour at ice bath temperature. The working-up of the batch is carried out as described in Example 4. After chromatography of the crude product on a Flashmaster (amine phase; mobile solvent methanol/dichloromethane), 9.2 mg (2.7%) of the desired compound is obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13].[C:14]([Cu])#[N:15]>CN1C(=O)CCC1>[Cl:13][C:3]1[C:4]2[N:8]=[C:7]([CH2:9][CH3:10])[NH:6][C:5]=2[CH:11]=[CH:12][C:2]=1[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Solvent: CN1CCCC1=O
Product: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Temperature: 220 °C
Yield: 35.5 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1H-benzimidazole (0.050 g, 0.192 mmol) and CuCN (0.030 g, 0.576 mmol) were combined in NMP (3 mL) and heated to 220° C. for 20 min in a microwave. The cooled mixture was partitioned between Et2O and water. The organic portion was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.014 g): MS (ESI) m/z 206 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:28]=[CH:27][C:14]([O:15][CH:16]3[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>CO>[NH:18]1[CH2:17][CH:16]([O:15][C:14]2[CH:27]=[CH:28][C:11]([CH2:10][N:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:12][CH:13]=2)[CH2:19]1
Reactant: CC(=O)N1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCN(Cc2ccc(OC3CNC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Intermediate 23A (1.5 g, 2.7 mmol) was dissolved in MeOH (20 mL), a 4.0 M solution of HCl in MeOH (2 mL) was added and the reaction mixture was stirred at RT for one hour. The mixture was concentrated and the residue was co-evaporated with EtOH several times. The residue was triturated with THF and then DCM (50 mL) and aqueous K2CO3 (5 g dissolved in 5 mL water) were added. After phases were separation, the organic phase was dried (Na2CO3) and the solvent was removed by evaporation. There was obtained 0.55 g (71%) of 23B.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:21])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:3][N:4]([CH3:21])[C:5]1[CH:10]=[C:9]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:7][C:6]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cc(N)ccc1-c1nc2ncccc2[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cc(NS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
An amount of 0.49 gm 2-(2'-dimethylamino-4'-aminophenyl)-imidazo[4,5-b]pyridine dihydrochloride was dissolved in 10 ml of pyridine, 0.38 gm of methanesulfonyl chloride were added dropwise, and the mixture was stirred for two days at ambient temperature. The reaction mixture was poured onto water, and the solution obtained was extracted with ethyl acetate. The ethyl acetate phases were washed with common salt solution and concentrated by evaporation. The residue was triturated with 2N acetic acid, subjected to filtration, and washed with water.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(Oc4ccccc4)c3)c2cc1OC
Temperature: 139 °C
Yield: 77.8 %

Procedure:
A mixture of 0.248 g (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.204 g (1.1 mmol) of 3-phenoxyaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 3 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.309 g (78%) of the desired product as cream crystals. MP 253-254° C.; mass spectrum (electrospray, m/e,): 397.0(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:5]=[CH:6][C:7]=1OS(C(F)(F)F)(=O)=O.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[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>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:5]=[CH:6][C:7]=1[C:21]#[N:22]
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#N)c(Cl)c1
Temperature: 80 °C
Reaction time: 34 h
Yield: 37 %

Procedure:
To a stirred solution of methyl 2-(3-chloro-4-(trifluoromethylsulfonyloxy)-phenyl)acetate (4.419 g, 13.283 mmol) in dimethylformamide were added zinc cyanide (1.6 g, 13.681 mmol) and tetrakis(triphenylphosphine) palladium (1.5 g, 1.3283 mmol). The reaction mixture was stirred for 34 h at 80° C., then cooled to room temperature and diluted with ethyl acetate. The mixture was filtered using celite pad. The filtrate dissolved in ethyl acetate and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to give methyl 2-(3-chloro-4-cyanophenyl)acetate (1.044 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(CCCCCCN(CCc2ccccc2)C(=O)C(F)(F)F)C(=O)C(F)(F)F)cc1N
Reaction time: 4 h
Yield: 55.2 %

Procedure:
N-[2-(3-Amino-4-methoxyphenyl]ethyl]-2,2,2-trifluoro acetamide (2.62 g., 0.01 moles) in dry dimethylformamide (50 ml) was added dropwise with stirring to sodium hydride (0.3 g., 80% oil dispersion, 0.01 moles) in dry dimethylformamide (50 ml) under nitrogen. The solution was warmed at 60° for 30 min then cooled and N-(6-bromohexyl)-2,2,2-trifluoro-N-(2-phenylethyl)acetamide (3.80 g., 0.01 mole) was added. The solution was stirred for 4 hours then quenched with water and extracted with ethyl acetate. The extracts were washed with water dried and evaporated to give crude N-[2-(3-amino-4-methoxyphenyl)ethyl]-N'-(2-phenylethyl)-1,6-hexanediylbis (2,2,2-trifluoroacetamide) (3.1 g) as a pale brown oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[N:4]=1.Br>C(O)(=O)C>[CH3:28][C:11]1[N:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[CH:17]=1
Reactant: COc1nc(N2CCCC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(N3CCCC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Yield: 94.2 %

Procedure:
A solution of 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidine (0.1 g, 0.22 mmol) in acetic acid (3 mL) was treated with HBr (0.1 mL, 0.90 mmol) and heated at 90° C. for 6.5 h. The mixture was cooled to RT, quenched with ice water, neutralized with NaHCO3 to pH=8 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated to dryness, the resulting material treated with MeCN and the solid was collected via filtration to afford 5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one (89 mg, 91%). 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 8.73 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.31 (m, 1H), 8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.52 (m, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.61 (d, J=5.6 Hz, 1H), 3.85 (s, 3H), 3.50 (m, 4H), 2.35 (s, 3H), 1.91 (m, 4H); MS (ESI) m/z: 430.2 (M+H+).
Reaction SMILES: ClC1N=C(C2C=CC=CC=2)N=C(OCCC(C)C)C=1.ClC1C=C(Cl)N=C(C2C=CC=CC=2)N=1.Cl[C:35]1[CH:40]=[C:39]([Cl:41])[N:38]=[C:37]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[N:36]=1.[CH2:52]([CH:54]([CH2:57][CH2:58][CH2:59][CH3:60])[CH2:55][OH:56])[CH3:53]>CC(C)CCO>[Cl:41][C:39]1[N:38]=[C:37]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[N:36]=[C:35]([O:56][CH2:55][CH:54]([CH2:52][CH3:53])[CH2:57][CH2:58][CH2:59][CH3:60])[CH:40]=1
Reactant: CCCCCCCCCCc1nc(Cl)cc(Cl)n1
Reactant: CCCCC(CC)CO
Agent: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: Clc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC(C)CCO
Product: CCCCCCCCCCc1nc(Cl)cc(OCC(CC)CCCC)n1

Procedure:
The compound of Example 25 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-decylpyrimidine and 3-methylbutanol by 2-ethylhexanol.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:37])(=[O:36])[N:13]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[C:27]=2[CH3:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:35][C:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[S:30][C:26]=1[N:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=1)[S:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)(=[O:36])=[O:37]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2sc3ccccc3c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)N2CCC(C(=O)O)CC2)sc2ccccc12
Yield: 43.2 %

Procedure:
To a solution of compound 5-A (27 mg, 0.049 mmol), dissolved in MeOH (1.0 mL), was added 3N NaOH (24 μL, 0.073 mmol) and the reaction mixture was refluxed for 18 hours. The reaction was cooled and the solvent evaporated under reduced pressure. The residual solid was partitioned between H2O and EtOAc, the organic layer collected, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude material was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 50% MeCN—H2O (0.1% TFA) to 70% MeCN—H2O (0.1% TFA) gradient to afford 11.2 mg of compound 10 as a white solid. 1H-NMR (CD3OD, 400 MHz): δ 7.71-7.86 (m, 1H), 7.54-7.61 (m, 1H), 7.29-7.42 (m, 4H), 7.10-7.23 (m, 2H), 4.72-4.85 (br s, 2H), 3.63-3.79 (m, 2H), 2.95-3.11 (m, 2H), 2.44-2.61 (m, 1H), 1.99 (s, 3H), 1.87-1.96 (m, 2H), 1.60-1.81 (m, 2H); MS (method 2): m/z 528.9 (MH+); HPLC (method 1): Rt 6.68 minutes.
Reaction SMILES: [CH2:1]([S:8][CH:9]([S:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][C@@H:11]([C@H:20]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:21]C(=O)C1C=CC=CC=1)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CCCCCC.C(OCC)(=O)C>ClCCl.CO>[CH2:40]([S:39][CH:9]([S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C@@H:11]([C@H:20]([CH2:30][O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:21])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 4-O-benzoyl-3,5-di-O-benzyl-2-deoxy-L-threopentose dibenzyl dithioacetal (88.8 g, 137 mmol) in dichloromethane (500 ml) was added a solution of sodium methoxide (11.1 g, 206 mmol) in methanol (205 ml) dropwise, with stirring, at 0° C. The reaction mixture was then allowed to warm to room temperature over a period of 3 hours. At the end of this time TLC (hexane-ethyl acetate [4:1]) revealed complete conversion to a slower moving component (Rf 0.31). The mixture was then poured into a 5% solution of NaH2PO4 and extracted with dichloromethane. The dichloromethane extracts were then washed with a 5% solution of sodium hydrogen carbonate and water, dried (magnesium sulphate) and evaporated. The crude title product was applied to a silica gel column eluted with hexane-ethyl acetate (4:1). Combination of the appropriate fractions gave the title product as a clear colourless syrup.