Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=O)[CH2:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].CC[O-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]1[C:8]([C:9]#[N:10])=[CH:7][NH:6][CH:5]=1
Reactant: N#CC=CNCC(=O)c1cccc(Cl)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
To 4.2 g of the 3-(2,3-dichlorophenacylamino)acrylonitrile obtained in (a) is added 0.5 g of sodium ethylate in 50 ml of ethanol. The reaction mixture is heated to reflux temperature, cooled to room temperature, poured into a mixture of dilute hydrochloric acid and ice, and stirred for c. 1 hour. The precipitate is isolated by filtration, washed with water and dried, affording the title compound in quantitative yield. Melting point: 149°-150° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(Cl)cc1/C=C/c1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2/C=C/c2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.81 (1H, d, J=2.0 Hz), 6.96-7.04 (3H, m), 7.18-7.28 (3H, m), 7.35-7.39 (3H, m), 7.59 (1H, d, J=1.6 Hz), 7.63 (1H, d, J=2.4 Hz), 7.90 (1H, s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd for C24H16ClFN4O, 431. Found, 431.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:18]([O:25][C:26](=[O:34])[CH2:27][C@@H:28]([NH2:33])[CH2:29][N:30]([CH3:32])[CH3:31])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:34])[CH2:27][C@@H:28]([NH:33][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:29][N:30]([CH3:31])[CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCc1ccccc1

Procedure:
The title compound, m/e=335.4 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 7-phenylheptanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(7-phenyl-heptanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[C:19](=[O:26])[C:18]([C:27](O)=[O:28])=[CH:17]2)=[CH:13][CH:12]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:59][C@H:60]1[O:65][C@@H:64]([CH3:66])[CH2:63][NH:62][CH2:61]1.Cl>CN(C=O)C>[CH3:66][C@H:64]1[O:65][C@@H:60]([CH3:59])[CH2:61][N:62]([C:27]([C:18]2[C:19](=[O:26])[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][N:16]([CH2:15][C:14]3[CH:30]=[CH:31][C:11]([F:10])=[CH:12][CH:13]=3)[CH:17]=2)=[O:28])[CH2:63]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)O)c1=O
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)N2C[C@@H](C)O[C@@H](C)C2)c1=O
Reaction time: 0.25 h

Procedure:
DIPEA (228 μl) was added to a solution of the compound obtained in Step 2 of Example 26 (200 mg) and COMU (365 mg) in DMF (2.5 ml) at room temperature, and the mixture was stirred for 15 minutes. cis-2,6-Dimethylmorpholine (162 μl) was added and the mixture was stirred for four hours. A 1 N hydrochloric acid solution was added at room temperature, and the organic layer was extracted with ethyl acetate, washed with brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 30 mg of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:13]=[CH2:14]
Reactant: COC(=O)c1cccnc1Cl
Reactant: C=CCN
Product: C=CCNc1ncccc1C(=O)OC
Temperature: 140 °C
Yield: 73.6 %

Procedure:
Methyl 2-chloropyridine-3-carboxylate (5 g) was reacted neat with allylamine (3.1 g) with heating at 140° C. for 4 hours. The volatiles were removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate in hexane to afford 4.12 g of the title compound. MS (DCl/NH3) m/e 207 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([NH:49][CH:50]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:51](Cl)=[O:52])(=[O:48])=[O:47])=[CH:42][CH:41]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:51](=[O:52])[CH:50]([NH:49][S:46]([C:43]3[CH:42]=[CH:41][C:40]([CH3:39])=[CH:45][CH:44]=3)(=[O:48])=[O:47])[CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(=O)N2Cc3c(nc(C(C)C)c(C(OC(C)(C)C)C(=O)O)c3-c3ccc(F)cc3)C(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 2-(4-methylphenylsulfonamido)-3-phenylpropanoyl chloride (23.65 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air and taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column) The product-containing fractions were concentrated to remove the organic solvent and the resulting precipitate was collected by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-(4-methylphenylsulfonamido)-3-phenylpropanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (3.7 mg, 21% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.56-7.80 (1H, m), 6.91-7.57 (12H, m), 6.71-6.92 (1H, m), 4.85 (1H, s), 3.99-4.26 (1H, m), 3.78-4.00 (0.5H, m), 3.46-3.77 (1.5H, m), 3.36-3.46 (2H, m), 3.13-3.28 (1H, m), 2.60-2.87 (2H, m), 2.11-2.50 (3H, m), 0.85-1.46 (21H, m). 19F NMR (400 MHz, CD3OD) δ ppm −114.16, −115.11, −117.98, −118.41. LCMS (M+H) calcd for C41H49FN3O6: 730.33. found: 730.03.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(OCC)(=O)C.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]([CH3:32])[CH2:24][C:25]2([CH3:31])[CH3:30]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]([CH3:32])[CH2:24][C:25]2([CH3:31])[CH3:30])=[O:9]
Reactant: CC1CC(C)(C)c2cccc(N)c21
Reactant: Cc1ncsc1C(=O)O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ncsc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Yield: 51.7 %

Procedure:
A mixture of 1.7 g (10.3 mmols) of 4-methyl-5-thiazole carboxylic acid and 10 ml of thionyl chloride was refluxed for 1 hour. The reaction solution was distilled under reduced pressure to remove excess thionyl chloride. The residue was dissolved in 10 ml ethyl acetate. The solution was added to 10 ml of an ethyl acetate solution of 1.8 g (10.3 mmols) of 4-amino-1,1,3-trimethylindane and 4 ml of triethylamine, and the resultant solution was stirred at room temperature for 3 hours. The solution was washed sequentially with water, aqueous sodium hydrogen carbonate solution, water, and saturated brine. The solution was dried with magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane =1/2), to obtain 1.6 g of amorphous solid substance (Compound No. 6 shown in Table 4). The yield was 50.2%.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(N4CCOCC4)cc3F)c2C#N)CC1
Temperature: 80 °C
Yield: 45.4 %

Procedure:
A mixture of 4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (60 mg, 0.114 mmol), morpholine (50 μL, 0.571 mmol), CuI (21 mg, 0.114 mmol), proline (23 mg, 0.205 mmol) and potassium carbonate (36 mg, 0.262 mmol) in DMSO (1 mL) was heated in microwave for 30 minutes at 80° C. The mixture was purified by HPLC to give Compound A71 as a solid (25.1 mg, 45%). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.31 (s, 1H), 7.61 (t, 1H), 7.08 (s, 1H), 6.69 (m, 2H), 5.35 (m, 1H), 4.86 (m, 1H), 3.82 (m, 4H), 3.68 (m, 2H), 3.38 (m, 2H), 3.19 (m, 4H), 1.90 (m, 2H), 1.75 (m, 2H), 1.18 (d, 6H). Exact mass calculated for C24H29FN6O4 484.22, found 485.2 (MH+).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2nsnc2c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4nsnc4c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,1,3-benzothiadiazole-5-carbaldehyde and 2-methyl- N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: Clc1cccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)c1
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (5.0 g, 17.10 mmol) and 9-borabicyclo[3.3.1]nonane (136.8 ml, 68.39 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-3-chloro-benzene (6.12 g, 25.65 mmol), triphenylphosphine (717.5 mg, 2.74 mmol), tetrakis(triphenylphosphine)palladium(0)(395.1 mg, 0.34 mmol), and 3N NaOH (14.0 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H2SO4 then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 5.01 g (72%) of the title compound: mp 56°–60°; mass spectrum (ion spray): m/z=405.4 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(#N)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2)cc1
Yield: 52.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3′-{[({4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)-amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.130 g, 0.16 mmol) in acetonitrile (7.2 mL) and H2O (4800 μL) was added TFA (100 μL, 0.160 mmol). The resultant mixture was applied to a GeneVac EZ-2 evaporator at 45° C. for 8 h. The mixture was further purified using a Gilson HPLC (with 0.1% TFA) and the product-containing fraction concentrated on a GeneVav EZ-2 evaporator at 45° C. for 8 h. The extra TFA was removed by re-dissolving the resultant mixture in DCM and passing it though an amino cartridge. The mixture was concentrated down again by Glas-Col evaporator to afford the title compound 0.0600 g (52%). LC-MS m/z 716 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.40 (t, J=7.53 Hz, 3 H) 1.48 (t, J=7.15 Hz, 3 H) 1.81-1.97 (m, 2 H) 2.09 (d, J=12.05 Hz, 2 H) 3.16 (q, J=7.45 Hz, 2 H) 3.56 (s, 8 H) 3.68 (t, J=11.42 Hz, 2 H) 3.99-4.11 (m, J=8.41, 3.14 Hz, 2 H) 4.29-4.41 (m, J=4.27 Hz, 1 H) 4.43-4.53 (m, 4 H) 4.64 (s, 2 H) 4.71 (s, 2 H) 7.35-7.46 (m, 2 H) 7.47-7.61 (m, 3 H) 7.65 (s, 1 H) 7.74 (d, J=7.53 Hz, 1 H) 7.81 (s, 1 H) 7.92-8.03 (m, 4 H) 8.28 (s, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C>C1C=CC=CC=1.CCCCCC>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:5][C:4]([OH:21])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: O=C(O)CC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
Saponification of Intermediate 80A as described in the preparation of Intermediate 1B gave the title acid as white needles: mp 106-107° C. (benzene-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.05 (2H, d, J=8.1 Hz, CH2), 4.51 (1H, t, J=8.1 Hz, CH), 7.0 (4H, m, aromatics), 7.18 (4H, m, aromatics). Anal. Calcd for C15H12F2O2: C, 68.69; H, 4.61. Found: C, 68.71; H, 4.63.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[CH:11]12[O:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][NH:13][CH2:12]2>CC(C)=O.O.C([O-])(O)=O.[Na+]>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:13]2[CH2:12][CH:11]3[O:18][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Clc1nc(Cl)nc(N2CC3CCC(C2)O3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of cyanuric chloride (2.00 g, 10.85 mmoles) in acetone (20 mL) and water (10 mL) at 0° C. was added a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.46 g, 9.76 mmoles) in saturated aqueous NaHCO3 (25 mL) and acetone (25 mL) via addition funnel over 15 minutes. The reaction was stirred at 0° C. for 2 hours, then filtered to collect a white precipitate. The precipitate was washed with water (25 mL) and dried. The crude product was purified by column chromatography (30:70 ethyl acetate in hexanes) to provide 3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.55 g) as a white solid.
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32]O)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2].[CH3:36][S:37](Cl)(=O)=O.CCN(C(C)C)C(C)C.C([S-])C.[Na+]>CN(C=O)C>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][S:37][CH3:36])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Agent: CC[S-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CSC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of compound 164 (203 mg, 0.413 mmol), methansulfonyl chloride (38.6 μl, 0.496 mmol) and DIPEA (108 μl, 0.620 mmol) in dry DMF (3 ml) is stirred at RT under nitrogen for 1 hour. Further methansulfonyl chloride (16.09 μl, 0.207 mmol) and DIPEA (54.1 μl, 0.310 mmol) are added and the mixture is stirred at RT for 2 hours. Sodiumethanethiolate (87 mg, 1.239 mmol) is added and the mixture is stirred at RT for 16 hours. The reaction the mixture is partitioned between AcOEt and brine, then the aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (eluent: AcOEt/petroleum ether 2/3) to afford the title compound (118 mg, 0.226 mmol, 54.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[H-].[Na+].Br[CH2:17]COC1CCCCO1>CN(C=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:4]2[CH2:17][CH2:1][O:2][C:3]2=[O:13])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.4 %

Procedure:
A mixture of 30 g (137 mmol) (3,4-Dichloro-phenyl)-acetic acid methyl ester (commercially available), 6.47 g (151 mmol) NaH (55%) and 35.8 g (171 mmol) 2-(2-Bromo-ethoxy)-tetrahydro-pyran in 100 mL DMF was stirred at room temperature for 17 h. The mixture was evaporated to dryness and partitioned between water and ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4 and evaporated. The residue was treated with 400 mL 4N HCl in dioxane in 250 mL methanol and stirred for 16 h at room temperature. The mixture was evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The combined product fractions were evaporated to yield 18.5 g (58%) of the title compound as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13].O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: OCCCO
Reactant: Cc1ncc(C=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ncc(C2OCCCO2)cn1
Temperature: 65 °C
Yield: 52 %

Procedure:
To a solution of 2-methylpyrimidine-5-carbaldehyde (0.808 g, 6.62 mmol) and propane-1,3-diol (1.01 g, 0.868 ml, 13.2 mmol) in toluene (7.6 ml) and THF (1.9 ml) was added p-toluenesulfonic acid (11 mg, 0.066 mmol). The reaction was heated at 65° C. for 4.5 hours. The reaction mixture was then poured into H2O (50 mL) and extracted with AcOEt (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to yield 5-(1,3-dioxan-2-yl)-2-methylpyrimidine (620 mg, 3.44 mmol, 52%) used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[CH2:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:4]=2[N:5]=[CH:6][N:7]=1.CO[C:22](OC)([CH3:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:12]4[O:19][C:22]([CH3:24])([CH3:23])[O:18][C@@H:13]4[C@@H:14]([CH2:16][OH:17])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1C[C@@H](n2ccc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Reaction time: 1.25 h
Yield: 67.6 %

Procedure:
A mixture of crude (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (10 g, ˜20 mmol, 54% pure by NMR) and 2,2-dimethoxypropane (100 mL, 800 mmol) was treated with p-toluenesulfonic acid monohydrate (7.28 g, 38.3 mmol) and the yellow-brown reaction mixture was stirred vigorously for 1.25 h, at which time the only solids were a fine tan precipitate. HPLC indicated nearly complete consumption of the starting material. The reaction mixture was diluted with water (30 mL) and neutralized with solid NaHCO3 (4.80 g, 57.1 mmol). The volatiles were carefully removed in vacuo and the resulting brown aqueous solution was extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a tan paste. Purification by column chromatography (4×22 cm silica; 0-66% EtOAc/Hex) afforded the title compound (4.38 g, 70%, one step) as a colorless foam/glass: MS (ESI+) for C15H18ClN3O3 m/z 324.2 (M+H)+; MS (ESI−) for C15H18ClN3O3 m/z 368.2 (M+HCO2)−; HPLC purity >95% (ret. time, 3.034 min).