Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S)C.C[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:19][C:20]([OH:22])=[O:21])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCC(CC(=O)O)CC(=O)O)cc1
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C(O)CC(CCc1ccc(O)cc1)CC(=O)O
Temperature: 25 °C
Yield: 88 %

Procedure:
To a suspension of 57% sodium hydride-paraffin (2.2 g) in dry dimethylformamide (70 ml) in an atmosphere of nitrogen is slowly added ethanethiol (4.0 ml). The mixture is stirred at room temperature until a clear solution results. To this solution is added a solution of 3-[2-(4-methoxyphenyl)ethyl]-glutaric acid (1.2 g) in dry dimethylformamide (10 ml) and the mixture is heated with stirring in a bath at 165° C. for 6.0 hours. The mixture is then evaporated to dryness in vacuo and the resulting residue is dissolved in water (50 ml), extracted with ether (two 50 ml portions) and the ether extract is discarded. The aqueous solution is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried with anhydrous magnesium sulfate, and evaporated to a residue. Crystallization of this from chloroform-hexane affords 1.0 g of the title compound, melting point 142°-144° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: NC=O
Product: Oc1ncnc2cc(F)ccc12
Temperature: 25 °C
Yield: 78 %

Procedure:
2-Amino-4-fluorobenzoic acid (1.55 g, 10 mmol) in formamide (5 mL) was heated to 150° C. for 6 h. The mixture was cooled to room temperature with stirring. The precipitate was filtered out and washed with ethyl ether to give 1.3 g of 7-fluoroquinazolin-4-ol (78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1.[C:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:28]([O:27][C:25]([N:32]1[CH2:37][CH2:36][CH:35]([O:23][C:22]([C:7]2[CH:6]=[C:5]3[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]4[C:4]3=[CH:3][C:2]([Cl:1])=[C:19]3[C:14]=4[N:15]=[CH:16][CH:17]=[CH:18]3)=[CH:9][CH:8]=2)=[O:24])[CH2:34][CH2:33]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccc3c(c2)-c2cc(Cl)c4cccnc4c2NS3(=O)=O)CC1
Yield: 47.7 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), 1-Boc-4-piperidinol (0.11 g, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), TEA (0.12 ml, 0.11 mmol) and DMF (1 ml) gave the title compound (70 mg, 46%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:18])[CH2:17][CH2:16][CH2:15][CH:14]2[CH:10]1[CH2:11][NH:12][CH2:13]2.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29](O)=[O:30])=[CH:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:18])[CH2:17][CH2:16][CH2:15][CH:14]2[CH:10]1[CH2:11][N:12]([C:29](=[O:30])[CH2:28][C:21]1[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=1)[CH2:13]2
Reactant: COc1ccccc1C1(O)CCCC2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCCC2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 1.5 g of (3aRS,4RS,7aSR)-4-(2-methoxyphenyl)-4-perhydroisoindolol and 1.27 g of 3-indoleacetic acid in 40 cm3 of dichloromethane, cooled to 0° C., are added 0.08 g of 1-hydroxybenzotriazole and 1.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture is stirred for 18 hours at room temperature and the organic phase is then washed with twice 80 cm3 of water and then with 80 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 40 cm3 fractions. Fractions 24 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.21 g of (3aRS,4RS,7aSR)-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-4-perhydroisoindolol are obtained in the form of an off-white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>CCOC(C)=O.O>[CH3:27][S:24]([C:20]1[CH:19]=[C:18]([C:15]2[S:14][C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)[N:9]=[C:10]([C:28]([F:31])([F:30])[F:29])[CH:11]=3)=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: OB(O)c1cccnc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Br)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3-c3cccnc3)s2)c1
Temperature: 75 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a 50 mL round bottom flask attached with condenser was added 1-(2-Bromo-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole (prepared following the described in Example 1c) (110 mg, 210 μmol), 3-pyridylboronic acid (31 mg, 525 μmol), PdCl2dppf (25 mg, 10 mol %), K2CO3 (58 mg, 410 μmol), 1,4-dioxane (8 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 75° C. for 20 hrs. The reaction solution was diluted with EtOAc (150 mL) and transferred to a separator), funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 45 mg (41% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (m, 1H), 7.99 (m, 2H), 7.51-7.90 (m, 8H), 7.24 (s, 1H), 7.17-7.23 (m, 2H), 6.87 (d, 1H), 3.28 (s, 3H); 19F NMR (400 MHz, DMSO-d6) δ −61.2 ppm. MS (ES) 526.5 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:3][CH2:2]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:23]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[CH2:5][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1[nH]c2nccc(NC3CCNCC3)c2c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1[nH]c2nccc(NC3CCN(Cc4ccccc4)CC3)c2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
358 (60 mg, 0.20 mmol) and benzaldehyde (0.03 mL, 0.26 mmol) were suspended in DCE (4 mL), and stirred for 2 h at room temperature. NaBH(OAc)3 (130 mg, 0.61 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with 1NHCl and the crude material was purified directly via HPLC to provide 361 (22 mg, 28% yield) as a solid. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]([CH2:16][CH2:17][C:18](O)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][C:20]([CH3:22])=[CH2:21])[C:12](=[O:15])[O:13]C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]3[CH2:16][CH2:17][C:18]([CH2:19][C:20]([CH3:22])=[CH2:21])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:13][C:12]3=[O:15])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)C1(c2ccc(Br)cc2)CC1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(Br)cc3)CC2)C(=O)O1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of methyl 1-(4-bromophenyl)cyclopropyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate (58.8 mg, 0.129 mmol) in dry THF (10 mL) was added NaH (60% in mineral oil, 10 mg, 2 equiv). The mixture was heated to reflux for 2 h. LC-MS found the reaction was complete. The mixture was cooled to rt, quenched with satd aq NH4Cl (3 mL), diluted with EtOAc (30 mL), washed with 1% aq HCl (5 mL), satd aq NaHCO3 solution (5 mL) and brine (4 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel column, eluted with a 0˜20% EtOAc in hexanes gradient, to afford 3-(1-(4-bromophenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (33.4 mg, 61%).
Reaction SMILES: OC(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:25][C@@H:21]4[CH2:22][NH:23][CH2:24][C@@H:20]4[C@H:19]3[CH3:26])=[C:15]([C:27]([NH2:29])=[O:28])[CH:14]=[N:13][N:12]2[CH:30]=1.[OH:31][C:32]([CH3:37])([CH3:36])[C:33](O)=[O:34].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:25][C@@H:21]4[CH2:22][N:23]([C:33](=[O:34])[C:32]([OH:31])([CH3:37])[CH3:36])[CH2:24][C@@H:20]4[C@H:19]3[CH3:26])=[C:15]([C:27]([NH2:29])=[O:28])[CH:14]=[N:13][N:12]2[CH:30]=1
Reactant: C[C@@H]1[C@H]2CNC[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CC(C)(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2CN(C(=O)C(C)(C)O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt from Step 2 of Example 59 (151 mg, 0.307 mmol), 2-hydroxy-2-methylpropanoic acid (38.3 mg, 0.368 mmol), triethylamine (0.128 mL, 0.920 mmol) and (benzotriazol-1-yloxy)tris(dimethylamine)phosphonium hexafluorophosphate (163 mg, 0.368 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (80 mL), washed with saturated sodium bicarbonate, water, brine, dried (MgSO4) and concentrated to give the expected product (120 mg). 1H NMR (400 MHz, methanol-d4) d 8.13 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 4.35-4.03 (m, 2H), 3.99-3.51 (m, 3H), 2.88-2.79 (m, 1H), 2.72-2.66 (m, 2H), 1.82-1.61 (m, 2H), 1.47-1.39 (m, 6H), 1.16 (d, J=6.6 Hz, 3H); MS (ES+) m/z: 436.1, 438.2 (M+H); LCMS (M+1): 464.1, 466.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3C=NC=C[N:25]=3)[CH:21]=[CH:20][N:19]=2)=[CH:12][CH:11]=1.[N:31]1C=CN=[CH:33][C:32]=1C(=O)C.N1NC(C(=O)C)=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[NH:25][N:31]=[CH:32][CH:33]=3)[CH:21]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: CC(=O)c1cnccn1
Agent: CC(=O)c1ccn[nH]1
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccn[nH]3)n2)cc1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material 1-(2H-pyrazol-3-yl)-ethanone (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Rh]>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]([CH:9]([OH:18])[CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(Br)cc1)C(O)CCc1cccnc1

Procedure:
(2S,3RS)-2-(4-Bromophenoxy)-5-pyridin-3-ylpent-4-yn-3-ol (5.93 g, Example 15c)) was dissolved in ethyl acetate (100 ml) and hydrogenated at 5 atmospheres using 5% rhodium on charcoal (2.0 g) as catalyst. The mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to give the sub-title compound as an oil and as a 4:1 mixture of diastereomers (5.6 g). The diastereomers were separated using normal-phase HPLC eluting with 3% isopropyl alcohol in dichloromethane to give (2S,3R)-2-(4-bromophenoxy)-5-(pyridin-3-yl)-3-pentanol as the major diastereomer (3.21 g) and (2S,3S)-2-(4-bromophenoxy)-5-(pyridin-3-yl)-3-pentanol as the minor diastereomer (0.71 g).
Reaction SMILES: [Na].N[C:3]1[C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:7][C:6](N)=[CH:5][CH:4]=1.Cl.[OH2:15]>>[OH:15][C:5]1[C:6]2[C:7](=[CH:8][CH:3]=[CH:4][CH:5]=2)[C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:3][CH:4]=1
Reactant: Nc1ccc(N)c(S(=O)(=O)O)c1
Reactant: O
Agent: Cl
Agent: [Na]
Product: O=S(=O)(O)c1ccc(O)c2ccccc12

Procedure:
A solution of 21 parts of the sodium salt of 1,4-diaminobenzene-6-sulphonic acid in 100 parts of water is stirred with a neutral solution of 24.5 parts of (4,6-dichloro-s-triazin-2-yl)-phosphoramide-acid in 200 parts by volume of H2O at 20° to 40° C, whilst constantly neutralising the hydrochloric acid liberated to keep the pH at 6 to 7, until a sample, on diazotisation and coupling with 1-hydroxynaphthalene-4-sulphonic acid, gives a clear, yellowish-tinged red dyeing. After addition of ice, the resulting dyestuff intermediate product is directly diazotised with 7 parts of sodium nitrite and 28 parts of concentrated hydrochloric acid and subsequently combined with a previously prepared solution of 47 parts of the sodium salt of 1-benzoylamino-8-hydroxynaphthalene-3,6-disulphonic acid and 12 parts of sodium carbonate in 200 parts of water, whereupon coupling to give 4-chloro-6-(3'-sulpho-4'-[1"-benzoylamino-2"-hydroxy-3",6"-disulphonaphthyl-7"-azo]-phenylamino)-s-triazine-2-phosphoramide-acid takes place; the latter is salted-out, filtered off, washed and dried in vacuo at 40° to 50° C. The dyestuff readily dissolves in water to give a red colour and gives, by one of the processes described, clear bluish-tinged red dyeings and prints on cellulose materials.
Reaction SMILES: [CH3:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[C:5]([CH2:6][S:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[C:5]([CH2:6][S:7]([C:8]2[NH:12][CH:11]=[CH:10][N:9]=2)=[O:31])=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCNc1cc(C)c(OC)c(C)c1CSc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCNc1cc(C)c(OC)c(C)c1CS(=O)c1ncc[nH]1
Yield: 37.3 %

Procedure:
2.00 g (6.2 mmol) of 2-[4,6-dimethyl-5-methoxy-2-(2-methoxyethylamino)benzylthio]imidazole was dissolved in a mixture of 20 ml of chloroform and 2 ml of methanol. To the resulting solution was added 1.27 g of 85 % m-chloroperbenzoic acid under chilling with NaCl-ice for a period of 20 min. After the reaction was completed, chloroform and 5 % aqueous sodium carbonate were added. The organic portion was collected and washed twice with 20 ml of 0.05 N aqueous sodium hydroxide. The resulting mixture was then subject to extraction with 30 ml of 1 N aqueous sodium hydroxide. The aqueous portion was collected and washed with chloroform. To the washed solution was added 45 ml of 1 N aqueous ammonium chloride. The deposited oily product was extracted with dichloromethane. The dichloromethane portion was collected and dried over anhydrous sodium sulfate. Dichloromethane was distilled off and then the residue was crystallized from ether/hexane to give 0.78 g of the desired compound as a pale brown crystalline powder. (Yield: 37 %)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reaction time: 2 h

Procedure:
Alternative preparation: To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (495.4 mg, 1.610 mmol, 1 eq), 1-piperidinepropanoic acid (335.4 mg, 2.133 mmol, 1.3 eq), and TBTU (624.4 mg, 1.945 mmol, 1.2 eq) in anhydrous DMF (15 mL), DiPEA (1.4 mL, 8 mmol, 5 eq) was added at rt, under N2, and stirred for 2 h. The solvent was evaporated under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with MeOH:DCM 2%→5%→10%→7N NH3/MeOH:DCM 2%→5%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[S:13][CH:12]=[C:11]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=1.CS(O[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][N:42]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:43][C@H:44]([OH:56])[C:45]2[C:53]3[S:52][C:51](=[O:54])[NH:50][C:49]=3[C:48]([OH:55])=[CH:47][CH:46]=2)=[CH:37][CH:36]=1)(=O)=O>C(#N)C>[OH:56][C@H:44]([C:45]1[C:53]2[S:52][C:51](=[O:54])[NH:50][C:49]=2[C:48]([OH:55])=[CH:47][CH:46]=1)[CH2:43][N:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[C:9]([CH3:8])[S:13][CH:12]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:40][CH:39]=1)[C:57](=[O:58])[O:59][C:60]([CH3:63])([CH3:61])[CH3:62]
Reactant: Cc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 80 °C

Procedure:
Triethylamine (0.25 mL) was added to a solution of (5-methylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 104, step b) (0.195 g) in acetonitrile (2.5 mL). This solution was added to a solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.5 g) in acetonitrile (2.5 mL). The resulting mixture was heated at 80° C. for 48 hours. The reaction mixture was evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a cream solid. Yield 0.33 g.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[H-].[Na+].[C:13]([O:21][CH2:22][C:23]1([CH2:38][O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:25][CH:24]1[CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:40]([O:39][CH2:38][C:23]1([CH2:22][O:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][CH:24]1[CH2:26][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])(=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CC2(COC(=O)c2ccccc2)COC(=O)c2ccccc2)cc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CC1CC1(COC(=O)c1ccccc1)COC(=O)c1ccccc1
Reaction time: 3 h
Yield: 22.5 %

Procedure:
A suspension of 965 mg (7.14 mmoles) of adenine in 25 ml of dry DMF was stirred and 171 mg (7.14 mmoles; 286 mg of 60%) NaH emulsion was added. All of the NaH had reacted after 30 minutes and a solution of 3 g (6.5 mmoles) of 1,1-bis(benzoyloxymethyl)-2-(p-toluenesulfonyloxymethyl)cyclopropane (Example 2, product of Step D) in 10 ml of DMF was added and the mixture was heated at 40°. TLC in CMW (90:10:1), Rf 0.2, 0.95 (starting materials) 0.45, 0.55 (products) showed that the reaction was complete in 3 hours. The mixture was concentrated to dryness and the residue was triturated with three 20 ml portions of ether, filtered and dried. The resultant solid was washed with twenty 3 ml portions of water and dried (1.2 g, largely a mixture of the two isomeric products). One gram of the crude product was chromatographed on five 2000 micron silica gel plates in CMW (95:3:0.3) and the zones (UV absorbing) at Rf 0.29 and 0.18 (the 9 and 7 isomers, respectively) were eluted with CMW (70:30:3). After concentration of the solvents, there was obtained 670 mg (25%) of the title compound and 78 mg (2.5%) of the 7-isomer.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[C:4]([C:12]2[N:13]=[C:14]3[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]3=[N:16][CH:17]=2)[N:3]=1.Cl.[CH3:33][O:34][CH2:35][C@@H:36]([NH2:38])[CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[CH3:33][O:34][CH2:35][C@@H:36]([NH:38][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:4]3[N:3]=[C:2]([Cl:1])[N:6]4[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=34)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=1)=[O:23])[CH3:37]
Reactant: COC[C@H](C)N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3nc(Cl)n4cc(F)ccc34)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(Cl)n4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A round-bottomed flask was charged with 2-(3-chloro-6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (90 mg, 0.16 mmol) and (S)-1-methoxypropan-2-amine hydrochloride (40 mg, 0.32 mmol). DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.1 ml, 0.57 mmol) and HATU (71 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight then water was added. The resulting suspension was filtered, washing with water and petroleum ether. The brown powder was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2% MeOH) to afford 37 mg (44%) of 2-(3-chloro-6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow solid.