Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[C:21]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1nc(C(C)(C)C)cs1)C(=O)OCC

Procedure:
2-Amino-4-(2-methyl-2-propyl)thiazole (15.6 g., 0.1 mole) and diethyl ethoxymethylenemalonate (23.8 g., 0.11 mole) were combined and heated on a steam bath for 2 hours. 2-(2,2-Dicarbethoxyethenylamino)-4-(2-methyl-2-propyl) thiazole was obtained as a wet solid on cooling and used directly in the next step.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>>[OH:38][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccccc2Cl)cc1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3Cl)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-chloro[1,1′-biphenyl]-4-carboxylic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=492.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[C:27]([NH2:28])=[C:26]([CH3:29])[CH:25]=[C:24]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:23]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:21][C:22]1[C:27]([NH:28][C:8](=[O:10])[CH2:7][C:3]2[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=2)=[C:26]([CH3:29])[CH:25]=[C:24]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:23]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: Cc1cc(N2CCOCC2)nc(C)c1N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)Nc2c(C)cc(N3CCOCC3)nc2C)c1
Reaction time: 0.03 h
Yield: 14 %

Procedure:
m-Tolylacetic acid (0.33 g), N,N-diisopropyl-ethylamine (0.90 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (1.00 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-ylamine (0.30 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, heptane/ethylacetate 3:1) to furnish 0.069 g (14% yield) of the title compound as a white solid. LC-MS (m/z) 340 (MH+); tR=1.42, (UV, ELSD) 96%, 100%. 1H NMR (500 MHz, DMSO-d6): 2.00 (s, 3H), 2.11 (s, 3H), 2.29 (s, 3H), 3.37 (m, 4H), 3.56 (s, 2H), 3.67 (m, 4H), 6.52 (s, 1H), 7.06 (d, 1H), 7.15 (m, 2H), 7.21 (t, 1H), 9.30 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][N:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 40.5 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-4-ylcarbamate (100 mg, 0.370 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (88.9 mg, 0.370 mmol), diisopropylethylamine (0.0645 ml, 0.370 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (55.0 mg, 40.4%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[CH:13][N:12]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:11]=3[CH:21]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[CH:13][N:12]([CH:15]4[CH2:20][CH2:19][N:18]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:17][CH2:16]4)[C:11]=3[CH:21]=2)=[N:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnc(-c2ccc3ncn(C4CCNCC4)c3c2)o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc3ncn(C4CCN(S(C)(=O)=O)CC4)c3c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of 6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(4-piperidinyl)-1H-benzimidazole (0.25 g, 0.88 mmol) and triethylamine (0.24 mL, 1.76 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (0.10 mL, 1.32 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=1/0-19/1) and recrystallized from diethyl ether/methanol to give the title compound (0.19 g, yield 60%) as colorless crystals.
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:11][C:5]1[C:10]([S:1]([Cl:4])=[O:2])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1
Product: Cc1ccccc1S(=O)Cl

Procedure:
24.6 g (0.1 mol) of freshly recrystallized p-tolyldisulfide was slurried in 18.8 ml (0.2 mol) of distilled acetic anhydride in an oven-dried 250 ml sidearm round bottom flask with magnetic stirring bar and a stopcock connector. The resulting reaction composition was cooled to -10° to -20° C. in a water-ethylene glycol-dry ice bath. All transfers and reactions in this example occurred under nitrogen blanket. About 7 ml of chlorine was condensed at -78° C. and transferred by cannula over 15 minutes to the reaction composition. The reaction composition became a clear bright orange solution and then the orange color began to fade. Additional chlorine was added in 1 ml portions until the solution turned to a greenish-yellow color. The solution was stirred at -10° C. for 1 hour and acetyl chloride was distilled off under reduced pressure employing a water aspirator while allowing the solution to return to room temperature. Bubbling of the solution ceased after about 45 minutes and the solution was connected to a vacuum pump for 1/2 hour at room temperature and then hearted to about 40° C. under vacuum for 20 minutes to yield 34.5 g of a green liquid, p-toluene sulfinyl chloride. Thereafter, 34.43 g of p-toulene sulfinyl chloride were diluted into a 50 ml solution in toluene and stored under a nitrogen blanket for further use.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: O=C(O)c1ccoc1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Furoic acid (2.4 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for l5 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3.52 min, MH+ 328. NMR: δH [2H6]-DMSO 9.92,(1H, b), 8.36,(1H, d), 8.23,(1H, d), 7.80,(1H, t), 7.66,(1H, dd), 7.29,(1H, d), 6.98,(1H, d), 2.33,(3H, s).
Reaction SMILES: C([CH:4]1[C:10]2[C:11](Br)=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=2[CH2:8][CH2:7][N:6]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:5]1)(=O)C.[CH:23]([O-:25])=O.[Na+].[CH3:27]N(C=O)C>CCOC(C)=O.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>[C:23]([C:13]1[CH:12]=[CH:11][C:10]2[CH2:4][CH2:5][N:6]([C:17](=[O:22])[C:18]([F:20])([F:19])[F:21])[CH2:7][CH2:8][C:9]=2[C:14]=1[OH:15])(=[O:25])[CH3:27]
Reactant: CN(C)C=O
Reactant: CC(=O)C1CN(C(=O)C(F)(F)F)CCc2c(O)ccc(Br)c21
Reactant: O=C[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Yield: 68 %

Procedure:
Mix-acetyl-9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (833 mg, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol) and sodium formate (224 mg, 3.3 mmol) in anhydrous DMF (15 mL). Degas twice then flush with argon. Keep the flask under argon and heat the reaction at 95° C. for 16 h. Dilute with EtOAc then wash with 1N aqueous HCl. Separate the organic layer, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1, 1:9 and 1:4) to give the desired intermediate (448 mg, 68%). MS (ES+) m/z: 302 (+H)+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>CO.ClCCl>[CH2:40]([S:42]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:24][CH2:25][OH:26])[C:16]=2[CH2:22]1)(=[O:44])=[O:43])[CH3:41]
Reactant: CCS(=O)(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCS(=O)(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in MeOH (0.5 mL) and dichloromethane (5 mL). Triethylamine (0.033 mL, 0.23 mmol) was added followed by ethanesulphonyl chloride (0.022 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h before the solvent was evaporated under reduced pressure. The crude was dissolved in dimethylformamide and acetonitrile and purified by preparative HPLC yielding 2-((6-(ethylsulfonyl)-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (22.0 mg, 18.11%). MS (ESI) (M+1) m/z 521;
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCOCC1

Procedure:
To a clear solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.1 g, 178 mmol) in a mixture of n-propanol/ethyl acetate (600/200 mL) at 30-35° C. was added 3-trifluoromethyl benzoyl chloride slowly with stirring. The reaction mixture became turbid initially and solids were separated after the mixture was stirred at ambient temperature for 3 to 5 hours. The solids were filtered, washed with n-propanol, and dried in vacuo at 40° C. overnight to produce N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide as a white solid in 72% yield (as the HCl salt). LCMS m/z (%)=509 (M+H35Cl, 100), 511 (M+H37Cl, 33) 1H NMR (400 MHz, DMSO-d6) δ: 10.7 (bs, 1H), 8.39-8.44 (m, 2H), 8.01 (d, J=2.61 Hz, 1H), 7.98 (s, 1H), 7.75-7.83 (m, 2H), 7.69 (s, 1H), 7.35 (d, J=9.01, 1H), 4.45-4.65 (m, 2H), 3.79-3.89 (m, 4H), 3.69 (s, 3H), 3.36-3.53 (m, 4H with water), 3.05-3.25 (m, 2H), 2.99-3.05 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:24]
Reactant: CCN
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Product: CCNC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and ethylamine were reacted in the same manner as in Example 8 to obtain the desired product as an oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][O:6][CH2:5][C@H:4]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:8][C@@H:4]1[CH2:5][O:6][CH2:7][C@H:3]1[NH:2][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@@H]1COC[C@H]1O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2COC[C@H]2O)CS1
Yield: 40.8 %

Procedure:
To a solution of trans-4-aminotetrahydrofuran-3-ol hydrochloride (1.00 g) in ethanol (30 mL) were added 4-thioxo-1,3-thiazolidin-2-one (954 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (3.87 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (591 mg).
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=C[C:9]=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([OH:49])=O)=[N:45][CH:46]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(NCC)C>CN(C)C=O>[CH2:10]([NH:6][C:47]([C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:46][N:45]=1)=[O:49])[CH3:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: F[B-](F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) was added to a solution of 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid (0.10 g) and diisopropylethylamine (50 μL) in dimethylformamide (1 mL) at room temperature. The resulting solution was stirred for 25 min, before diethylamine (70% in water, 50 μL) was added. The solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound as a foam-like solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C-:21]#[N:22].[K+].O>CCO.O>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([C:21]#[N:22])([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Reactant: C1COCCN1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC1(N2CCOCC2)CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.5 ml of morpholine and then 5.1 g of Na2S2O5 are added to a mixture of 5 g of 1-benzylpiperid-4-one and 1.9 g of potassium cyanide in 50 ml of an EtOH/water mixture (50/50; v/v) and the resulting mixture is heated at 60° C. for 2 hours. A further 2.5 ml of morpholine are added and the reaction mixture is stirred overnight at RT. Water is added and the crystalline product formed is filtered off to give 5.5 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[CH:6]=[CH:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[Cl:14][C:15]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=1[C:17](=[O:20])[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH:7]=[CH:6]3)=[CH:11][C:2]=2[O:1][C:18]=1[C:17]([C:16]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:15]=1[Cl:14])=[O:20]
Reactant: N#Cc1cc2c(cc1O)CCC=C2
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)C=CCC3
Temperature: 90 °C
Reaction time: 17 h
Yield: 19 %

Procedure:
To a solution of 3-hydroxy-5,6-dihydro-naphthalene-2-carbonitrile from step 1 (100 mg, 0.58 mmol) and 2,4-dichlorophenacyl chloride (144 mg, 0.64 mmol, 1.1 eq) in anhydrous N,N-dimethylformamide (2 mL) was added potassium carbonate (161 mg, 1.2 mmol, 2 eq). The reaction mixture was shaken at 90° C. for 17 h. The mixture was cooled to room temperature and poured into ethyl acetate and water. Separated the organic phase and extracted the aqueous layer with ethyl acetate twice. Combined the ethyl acetate extracts and the original organic layer and evaporated in vacuo. The crude product was purified by HPLC and gave 39.4 mg (14% for two steps) of (3-Amino-7,8-dihydro-naphtho[2,3-b]furan-2-yl)-(2,4-dichloro-phenyl)methanone as a brown oil. 1H-NMR (acetone-d6) δ 7.63 to 7.61 (m, 2H), 7.59 (s, 1H), 7.52 to 7.54 (m, 1H), 7.13 (s, 1H), 7.04 (broad, s, 2H), 6.59 (ft, J=10 Hz, 1.2 Hz, 1H), 6.07 (m, 1H), 2.92 (t, J=8.0 Hz, 2H), 2.33 (m, 2H); MS LC-MS (MH+=358.1/360.1); Rf=0.51, 30% ethyl acetate-hexane.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[C:22](=[O:31])([O:27][CH:28]([CH3:30])[CH3:29])[O:23][CH:24](Cl)[CH3:25]>>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][C@@H:24]([O:23][C:22]([O:27][CH:28]([CH3:30])[CH3:29])=[O:31])[CH3:25])=[O:19])[CH2:15]1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CC(C)OC(=O)OC(C)Cl
Product: C=CCOC(=O)N1COC(=O)[C@]12C1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O[C@H](C)OC(=O)OC(C)C
Yield: 18.1 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 400 mg) and 1-chloroethyl isopropyl carbonate (204 mg) were treated in the same manner as in Example A-1 (3) to give (1S,2S,3S,5R,6S)-3′-allyl 6-(1-((isopropyloxycarbonyl)oxy)ethyl) 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (A-15-1, 95 mg) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]=1[O:21][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([F:12])[CH:20]=1)#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1ccc(Oc2ccc(C=O)cc2C#N)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-fluoro-4-hydroxybenzonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Reactant: C1CCNC1
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2nc(N3CCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 86.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), pyrrolidine (0.084 mL, 0.998 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The crude product was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-(pyrrolidin-1-yl)pyrimidin-4-amine (172 mg, 0.433 mmol, 87% yield). 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H); 7.89 (dd, J=8.33, 2.34 Hz, 1H); 6.74 (d, J=8.92 Hz, 1H); 6.67 (s, 1H); 3.94 (s, 3H); 3.50 (s, 4H); 1.95 (s, 4H). m/z (ESI, +ve ion) 398.0 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4](=[S:6])=[S:5].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].O>C1COCC1>[C:4]([S:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[S:5])[CH3:1]
Reactant: CCOC(=O)CBr
Reactant: C[Mg]Cl
Reactant: S=C=S
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CSC(C)=S
Temperature: 40 °C

Procedure:
Methyl magnesium chloride (10 mL, 3M solution in THF) was diluted with THF (10 mL) and the resulting solution warmed to 40° C. Carbon disulfide (2.28 g, 0.03 mol) was added over 10 minutes while maintaining the reaction temperature at 40° C. The reaction was cooled to room temperature before adding ethyl bromoacetate (5.01 g, 0.03 mol) over 15 minutes. The reaction temperature was increased to 50° C. and maintained for a further 4 hours. Water (100 mL) was added and the organic products were extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. After removal of solvent and column chromatography (Kieselgel-60, 70-230 mesh, 10% diethyl ether in n-hexane eluent), pure ethoxycarbonylmethyl dithioacetate was obtained as a golden oil (1.3 g, 24.3% yield). 1H-nmr (CDCl3) d(ppm): 1.25 (t, 3H); 2.90 (s, 3H); 4.07 (s, 2H) and 4.20 (q, 2H).