Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:46]3[CH:45]=[N:44][CH:43]=[C:42]([O:41][CH3:40])[CH:47]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cncc(-c2ccc([C@H](Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 40.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-pyridine (69 mg, 0.27 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified by preparative HPLC to give 60 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert butoxycarbonylamino-propionic acid.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)/C=C/c2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-(E)-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 135; 116 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, quinoline-3-carboxaldehyde (40 mg, 0.255 mmol) was added and the solution was stirred at room temperature for 16 h. After the solvent was removed in vacuo, the residue was taken up in ethyl acetate (10 mL) and the solution was washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL). Each aqueous layer was back-extracted with ethyl acetate (10 mL). The combined organic extracts were dried, filtered, evaporated and chromatographed (50% ethyl acetate/hexanes) to give rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (110 mg, 89% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].C(P(=O)(OCC)OCC)#N>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:20]([C:16]1[CH:15]=[C:14]([C:13]2[N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[N:11]=[C:10]3[C:9]=2[C:8](=[O:34])[N:7]([CH3:35])[C:6](=[O:36])[N:5]3[CH2:1][CH:2]([CH3:3])[CH3:4])[N:18]([CH3:19])[CH:17]=1)=[O:22]
Reactant: CN(C)CCN
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Agent: CCOP(=O)(C#N)OCC
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)NCCN(C)C)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d}pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent Mass: 559.35 (M+H).
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CCOCC.CO>[CH3:14][C:13]1([CH3:15])[C:16]([CH3:18])([CH3:17])[O:1][B:2]([C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[O:11]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=C(O)c1ccc(B(O)O)s1
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CC1(C)OB(c2ccc(C(=O)O)s2)OC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(Dihydroxyboryl)-2-thiophenecarboxylic acid (1 g; 5.82 mmol; 1 eq.) is dissolved in a mixture of Et2O (100 ml) and MeOH (5 ml). Pinacol (687.2 mg; 5.82 mmol; 1 eq.) is added. The reaction mixture is stirred at rt for 24 hours. To complete the reaction, some pinacol is added (200 mg; 1.7 mmol; 0.3 eq.) and the mixture is stirred for 12 additional hours. Water (50 ml) is added and the two phases are separated. Aqueous phase is extracted with ether (50 ml). Combined organic phases is dried over MgSO4, filtrated and evaporated, affording 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid as white-off solid (1.33 g; 90%). 1H NMR (DMSO-d6, 300 MHz) δ 1.13 (s, 12H), 7.37 (d, J=3.8 Hz, 1H), 7.58 (d, J=3.8 Hz, 1H), 13.12 (s, 1H). M−(ESI): 253. HPLC, Rt: 0.98 min (purity: 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:11](OC(=O)C)(=O)[CH3:12]>S(=O)(=O)(O)O>[CH3:11][C:12]1[O:9][C:8](=[O:10])[C:7]2[C:2](=[CH:3][N:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1cnccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: Cc1nc2cnccc2c(=O)o1
Yield: 49 %

Procedure:
A mixture of 3-aminopyridine-4-carboxylic acid (3.38 g, 24.5 mmol), acetic anhydride (15 mL), and sulfuric acid (3 drops) was refluxed 4 hours. The reaction was cooled and carefully quenched with solid sodium bicarbonate. The mixture was filtered through Celite® (trademark). The filtrate was extracted with ethyl acetate. This organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 2-methyl-3-oxa-1,7-diaza-naphthalen-4-one (1.95 g, 49%) as a brown crystalline material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[C:36]2[C:37]([N+:47]([O-])=O)=[N:38][N:39](C3CCCCO3)[CH:40]=2)=[CH:4][C:5]([F:24])=[C:6]([S:8]([N:11]([C:19]2[N:20]=[CH:21][S:22][CH:23]=2)C(=O)OC(C)(C)C)(=[O:10])=[O:9])[CH:7]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:47][C:37]1[C:36]([C:27]2[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:26]=2[O:25][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([NH:11][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)(=[O:10])=[O:9])=[C:5]([F:24])[CH:4]=2)=[CH:40][NH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1n[nH]cc1-c1cc(C(F)(F)F)ccc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl

Procedure:
To a solution of tert-butyl [(5-chloro-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}phenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 872, 55 g, 74 mmol) in ethanol (800 mL) was added saturated aqueous ammonium chloride solution (200 mL, 3000 mmol) and iron (65 g, 1200 mmol). The reaction solution was heated at 80° C. for two hours at which point iron (10 g, 185 mmol) was added and the mixture heated for an additional hour. The solution was cooled, filtered and adjusted to pH=9 with saturated aqueous sodium bicarbonate solution. The mixture was filtered and then concentrated to remove most of the ethanol. The resulting slurry was extracted with dichloromethane (4×). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the free amine as an orange oil. Purification by manual flash column chromatography using 40% then 75% ethyl acetate/hexanes and a 5×31 cm column provided a mix of Boc protected sulphonamide and non-Boc protected sulphonamide free amine as an orange oil. To this mixture was added an HCl (g) saturated methanol solution (400 mL) and the mixture heated at 60° C. for 7 hours. The reaction solution was cooled and concentrated to give a white solid. The solid was redissolved in methanol, heated to reflux and ethyl acetate added until just before a precipitate formed. It was then cooled, washed with ethyl acetate and dichloromethane to provide the title compound as a white solid. This was repeated until no more clean product was obtained. The impure filtrate was purified by prep HPLC, the product fractions concentrated and the TFA salt exchanged for an HCl salt. All product was combined, dissolved in methanol, filtered, concentrated and isolated as a white solid with 1.5 eq of HCl present (30.3 g, 70%) via trituration with dichloromethane.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1([B:24]([OH:26])[OH:25])C=CC=CC=1.C1(C)C=CC=CC=1.Cl>CCOCC>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([B:24]([OH:26])[OH:25])=[CH:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(-c2ccccc2)c2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OB(O)c1ccc(-c2ccccc2)c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 14 g of 1-bromo-4-phenylnaphthalene synthesized in accordance with a conventional process or by the reaction of 1-bromo-4-iodo-naphthanlene and phenylboronic acid, 130 ml of anhydrous ether and 50 ml of anhydrous toluene were added, and the reaction system was purged with argon and cooled at −40° C. To the cooled mixture, 37 ml of a 1.6 M hexane solution of normal-butyllithium was added dropwise, and the resultant mixture was stirred for 1 hour. After the obtained mixture was heated to −5° C. and then cooled to −40° C., a solution obtained by diluting 34 ml of boronic acid triisopropyl ester with ether was added dropwise, and the resultant mixture was stirred for 3.5 hours and then left standing for one night. After the resultant mixture was acidified with a 10% dilute hydrochloric acid, the reaction mixture was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate, and the solvent was removed using an evaporator. The obtained white solid substance was washed with methylene chloride and dried, and 10 g of 1-phenylnaphthalene-4-boronic acid was obtained as white crystals (the yield: 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][C:7]1[C:12]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[CH:11][CH:10]=[C:9]([CH3:33])[N:8]=1)[CH3:2]>CCO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]([N:17]2[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][C@H:18]2[CH3:32])=[O:16])=[CH:11][CH:10]=[C:9]([CH3:33])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1nc(C)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CCc1nc(C)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
To a solution of 3-(3-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-6-methyl-pyridin-2-yl)-acrylic acid ethyl ester (0.54 g, 1.15 mmol) in EtOH (5.0 mL) was added platinum oxide (0.050 g) and the mixture was hydrogenated at 45 psi for 90 minutes. The mixture was filtered through celite and concentrated in vacuo to give the title compound (0.50 g).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]([F:27])([F:26])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([I:24])[C:15]=1[OH:25])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3](=[O:5])(=[O:4])[O:25][C:15]1[C:16]([I:24])=[CH:17][C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:19][C:14]=1[CH2:13][NH:12][C:10](=[O:11])[C:9]([F:8])([F:26])[F:27]
Reactant: CC(C)(C)c1cc(I)c(O)c(CNC(=O)C(F)(F)F)c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Oc1c(I)cc(C(C)(C)C)cc1CNC(=O)C(F)(F)F
Reaction time: 72 h

Procedure:
To a solution of N,N-dimethylsulfamoyl chloride (17.4 g., 0.12 mole) in dry methylene chloride (75 ml.) maintained under a nitrogen atmosphere is added slowly and with good stirring a solution of 2,2,2-trifluoro-N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethyl]acetamide (8 g., 0.02 mole) and triethylamine (12.12 g., 0.12 mole) in dry methylene chloride (200 ml.) at 20°-25° C. The resulting reaction mixture is stirred at 20°-25° C. under nitrogen for 72 hours. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and water. The phases are separated and the organic phase is washed successively with 2N hydrochloric acid, water and saturated brine, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves the intermediate 2-(2,2,2-trifluoroacetamidomethyl)-4-(1,1-dimethylethyl)-6-iodophenyl N,N-dimethylsulfamate as a tan oil (10.3 g., 100%).
Reaction SMILES: N[C:2]1[N:11]=[C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]([O:16][CH2:17][CH2:18][OH:19])=[C:14]([CH3:23])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[C:4]([O:26][CH3:27])=[CH:5][C:6]([O:24][CH3:25])=[N:7]2.N([O-])=[O:29].[Na+]>O.Cl>[OH:19][CH2:18][CH2:17][O:16][C:15]1[C:20]([CH3:22])=[CH:21][C:12]([C:10]2[NH:11][C:2](=[O:29])[C:3]3[C:4]([O:26][CH3:27])=[CH:5][C:6]([O:24][CH3:25])=[N:7][C:8]=3[CH:9]=2)=[CH:13][C:14]=1[CH3:23]
Reactant: COc1cc(OC)c2c(N)nc(-c3cc(C)c(OCCO)c(C)c3)cc2n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)cc2n1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
2-[4-(5-amino-2,4-dimethoxy-[1,6]naphthyridin-7-yl)-2,6-dimethylphenoxyl]-ethanol (0.302 g, 0.82 mmol) in water (5 mL) and conc. Hydrochloric acid (3 mL) were mixed with stirring. The reaction mixture was cooled to 0° C. and a solution of sodium nitrite (0.305 g, 4.42 mmol) in water (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 40 min. To the reaction mixture was added 1 N hydrochloric acid (10 mL) and heated at 55° C. for 50 min and then stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and the aqueous layer was basified with aqueous 5% NaOH and saturated NaHCO3 solution. Water was evaporated and the organic compound was washed with a dichloromethane/methanol solution and concentrated to leave a crude which was purified by silica gel (50 g) column chromatography, employing 50% ethyl acetate in hexane and hexane/ethyl acetate/methanol (3:2:1) as eluent, to obtain 7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one (0.080 g, 26%). Selected data: MS (ES) m/z: 371.1; MP 224.9-225.4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].C1N2CCN(CC2)C1>CN(C=O)C>[C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:8][C:14](=[S:15])[N:13]([CH3:17])[CH3:12])(=[O:11])[CH3:10]
Reactant: CN(C)C(=S)Cl
Reactant: CC(=O)c1c(O)cccc1F
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
1-(2-Fluoro-6-hydroxy-phenyl)-ethanone (2.5 g, 16.22 mmol) (available from Apollo Scientific) was dissolved in anhydrous DMF (20 mL.) Dimethylthiocarbamoyl chloride (2.2 g, 17.84 mmol) and DABCO (2.0 g, 17.84 mmol) were added sequentially in one portion. The reaction was permitted to stir overnight at ambient temperature. The reaction was quenched by pouring it into a mixture of 1N HCl-ice. The oily residue was extracted with dichloromethane and dried over sodium sulfate. The crude residue was purified by SGC (20% ethyl acetate in hexanes) to provide the title compound (2.93 g.) 1H NMR (200 MHz, CDCl3): δ (ppm)=7.407 (dd, 1H), 7.026 (t, 1H), 6.876 (d, 1H), 3.404 (s, 3H), 3.341 (sd, 3H), 2.58 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)=[C:20]([Cl:33])[CH:19]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:33][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[C:15]3[NH:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[CH2:36][O:35][CH3:34])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: Nc1ccc(-c2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3[nH]2)cc1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)Nc1ccc(-c2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3[nH]2)cc1
Reaction time: 24 h
Yield: 54.9 %

Procedure:
A solution of 6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (100 mg), methoxyacetic acid (29.4 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole monohydrate (75 mg) and triethylamine (0.23 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 20 hrs. Methoxyacetic acid (29.4 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg) and 1-hydroxybenzotriazole monohydrate (75 mg) were added to the reaction system, and the mixture was further stirred for 24 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=14:85) to give the title compound (63.5 mg) as pale-brown powder crystals.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cncs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cncs2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.9 %

Procedure:
A mixture of 5-(bromomethyl)-1,3-thiazole (4.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (427 mg, 3.0 mmol), and triethylamine (1.7 mL, 12.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The mixture was evaporated and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/CH2Cl2), affording the title compound (28 mg, 4% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 4.64 (s, 2H), 4.16 (s, 2H), 6.02 (s (br), 1H), 7.87 (d, 1H, J=0.8 Hz), 8.94 (s, 1H); M+240.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].Cl.CN.[CH:14]([N:17](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:14][NH:17][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)C1(C(=O)OC)CC1
Reaction time: 3 h

Procedure:
1-(Methoxycarbonyl)cyclopropanecarboxylic acid 5a (2.5 g, 13.9 mmol, prepared by a known method disclosed in “Tetrahedron Letters, 1987, 28 (36), 4225-4228”) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of methylamine hydrochloride (1.4 g, 20.8 mmol), N,N-diisopropylethylamine (5.4 g, 41.7 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.9 g, 20.8 mmol), and then the reaction solution was stirred for 3 h. 50 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title product methyl 1-(methylcarbamoyl)cyclopropanecarboxylate 5b (700 mg, a colorless oil) in 32% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6]>C(#N)C>[C:12]([O:11][C:9]([NH:8][C@@H:4]([CH2:3][NH:1][CH2:2][CH2:3][C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6])[C:5]([OH:7])=[O:6])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCNC[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)O

Procedure:
A solution of (S)-4-amino-2-tert-butyloxycarbonylaminobutyric acid (1.03 g, 4.70 mmol) in acetonitrile (50 ml) was added to a solution of (S)-Boc-serine-β-lactone (0.80 g, 4.27 mmol) in acetonitrile (50 ml) and degassed H2O (50 ml). The pH was maintained at 5.5 by dropwise addition of 1M NaHCO3 with stirring. The mixture was stirred for 5 days at ambient temperature. The pH was controlled by NaHCO3 addition and the reaction monitored by TLC. The solvents were distilled off, the residue triturated with chloroform (5 ml), to which acetic acid was added to give pH 5. The chloroform solution was evaporated and the product isolated after chromatography on silica gel (CHCl3:MeOH 2:1).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH3:39]>O1CCOCC1>[NH2:39][C:31]1[N:30]=[C:29]([C:26]2[C:4]3[CH:5]=[C:6]4[C:19](=[C:2]([F:1])[C:3]=3[O:28][N:27]=2)[N:18]2[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]2[C:8]2([C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]2=[O:14])[CH2:7]4)[CH:34]=[CH:33][N:32]=1
Reactant: N
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: C1COCCO1
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(N)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and ammonia in dioxane (0.5M)