Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CCN=C=NCCCN(C)C>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 5 °C
Yield: 84.4 %

Procedure:
N-Hydroxysuccinimide (25.3 g) was added to a solution of 1-(t-butoxycarbonyl)piperidine-4-carboxylic acid (45.8 g) in DMF (250 ml) and the mixture stirred at 5° C. EDAC (42 g) was added and the mixture stirred for 4 hours at 5° C. A further portion of EDAC (5.73 g) was added and the mixture allowed to warm to ambient temperature and stirred overnight. The mixture was evaporated to half its original volume and the residue partitioned between ethyl acetate (1000 ml) and water (250 ml). The ethyl acetate phase was separated, washed with water (2×250 ml), brine (50 ml), dried (MgSO4) and evaporated to give a solid which was recrystallised from a mixture of ethyl acetate/hexane (250 ml/500 ml) to give 1-(1-(t-butoxycarbonyl)piperidin-4-ylcarbonyloxy)2,5-dioxopyrrolidine (55 g);
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc(Cl)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 4-chloro-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=O)[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][N:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1ccc2cc(Cl)ncc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1cc2ccc(Cl)nc2cn1

Procedure:
A mixture of 1.08 g (6 mmoles) of 6-chloro-1,7-naphthyridin-2-one and 10 ml of POCl3 were warmed at reflux for one hour to give a clear solution. Upon cooling, a precipitate formed and the mixture was poured cautiously over ice. CH2Cl2 was added and the mixture was neutralized with solid K2CO3. The CH2Cl2 layer was separated and the aqueous layer washed twice with CHCl3. The combined organic layers were washed with water, dried over K2CO3 and evaporated to give a white solid. The solid was recrystallized from hexane/acetone to give 1.14 g (95% of theoretical) of the desired product as short, white needles having a melting point of 213°-216° C. Analysis calculated for C8H4Cl2N2 : C, 48.27; H, 2.03; N, 14.08. Found: C, 48.80; H, 2.09; N, 14.55.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].Cl.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:14])=[N:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CN)nc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccc(C#N)cn1
Yield: 93 %

Procedure:
As described for example 1a, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.266 g, 1.2 mmol) was converted, by using 6-aminomethyl-nicotinonitrile hydrochloride salt (0.17 g, 1 mmol) instead of 2-picolylamine, to the title compound (296 mg, 93%) which was obtained as a white solid. MS: m/e: 319.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][OH:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48, and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 2.26 (s, 3H), 3.18 (m, 2H), 3.53 (m, 2H), 3.70 (br s, 1H), 6.21 (br s, 1H), 6.40 (d, 1H, J=9.7 Hz), 7.09 (m, 4H), 7.21-7.65 (m, 3H). LC MS (m/e)=427 (MH+). Rt=1.96 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH:32]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH3:33])=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH:32]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[CH3:33])=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: CC(OC(=O)Cl)c1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OC(C)c1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 1-(4-chlorophenyl)ethyl chloroformate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:18]([O:27]C(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC.CCCCCC.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:19][B:18]([OH:27])[OH:23])=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(OB(O)O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2-(Benzyloxy)-5-bromobenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene, and at −78° C., an n-butyllithium/hexane solution was dropwise added. This was heated up to room temperature, and 1 M hydrochloric acid was added to the reaction mixture, followed by stirring to obtain [4-(benzyloxy)-3-cyanophenyl]boric acid. ES: 254.
Reaction SMILES: O[CH:2]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([SH:21])[CH:18]([SH:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:3]([C:2]1[S:21][CH2:17][CH:18]([CH3:19])[S:20][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(S)CS
Reactant: CCCCCCC(=O)C(O)CCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCC1=C(CCCCCC)SC(C)CS1
Yield: 63 %

Procedure:
The method of Example 4 was used, using 7-hydroxytetradecan-8-one (22.8 g), propane-1,2-dithiol (10.8 g) and p-toluenesulphonic acid (0.5 g) to give 2,3-dihexyl-5,6-dihydro-5-methyl-1,4-dithiin as a greenish oil, bp 148°-155°/0.2 mm, yield 63%. NMR, 0.7-1.8 δ (multiplets), 2.05-2.35 δ (broad triplet), 2.45-3.6 δ (multiplets), 2.95 δ (doublet).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:17][C:18]1[N:22]([CH2:23][CH3:24])[N:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2].O.C(O)(=O)C>[CH2:23]([N:22]1[C:18]([NH:17][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=[N:21]1)[CH3:24]
Reactant: CCn1nccc1N
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nccc1Nc1ccccc1C(=O)O
Temperature: 0 °C
Yield: 42.4 %

Procedure:
To a solution of 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) is added potassium carbonate (33.4 g, 0.242 mol), followed by 5-amino-1-ethylpyrazole (24.2 g, 0.218 mol) and finally Cu(OAc)2.H2O (0.9 g, 0.0045 mol). The reaction mixture is refluxed overnight, cooled and then poured into ice water. Acetic acid and HCl are added until a pH of about 4 is obtained. A precipitate forms which is collected by filtration, washed with water and dried to afford 21.4 g of N-(1-ethylpyrazol-5-yl) anthranilic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[N:9]=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:26])=[CH:22][CH:21]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(-n3nc(-c4ccccc4O)nc3-c3ccccc3O)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid (Example 5) and 1.25 ml of 1-chloro-N,N-2-trimethyl-1-propen-1-amine are stirred for 2 h in 50 ml of tetrahydrofuran. 2.2 ml of triethylamine and 1 ml of N-methylpiperazine are added and the mixture is stirred at room temperature for 48 h. It is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, {4-[3,5-bis(2-hydroxy-phenyl)-[2,4]triazol-1-yl]-phenyl}-(4-methylpiperazin-1-yl)methanone remains as colorless crystals of m.p. 226-229° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([S:16](Cl)(=[O:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:7].[CH3:20][NH:21][CH3:22]>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([S:16]([N:21]([CH3:22])[CH3:20])(=[O:18])=[O:17])[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[Cl:7]
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1c(S(=O)(=O)Cl)nc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)c1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonyl chloride (0.826 mmol) in acetone (2.5 mL) and THF (1.5 mL) was added to dimethylamine (2.0 mL of a 2M solution in THF, 4.0 mmol). The reaction mixture was stirred at RT for 1 h and then evaporated to dryness. The residue was taken up in EtOAc and washed with brine. The organic layer was dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-30% EtOAc/hexanes) to provide the title compound (0.18 g, 57%) as a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.62 (s, 2H), 3.61-3.75 (m, 2H), 3.06 (s, 6H), 0.84-1.00 (m, 3H), 0.00 (s, 9H).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][S:7]([CH2:10][C:11](Cl)=[O:12])(=[O:9])=[O:8]>C1COCC1>[C:1]([O:5][C:11](=[O:12])[CH2:10][S:7]([Cl:6])(=[O:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CS(=O)(=O)Cl

Procedure:
To a solution of t-butanol (0.3 mL) in THF (3 mL) was added 2-chlorosulfonylacetyl chloride (0.1 mL, 1.0 mmol) at room temperature for 1 h. The volatiles were removed to provide the chlorosulfonyl-acetic acid tert-butyl ester (230 mg). The crude product was used without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][C:19]2[CH:42]=[CH:41][C:22]([CH2:23][NH:24][C:25]([C:27]3([NH:30][C:31]([C:33]4[CH:34]=[N:35][C:36]([S:39][CH3:40])=[N:37][CH:38]=4)=[O:32])[CH2:29][CH2:28]3)=[O:26])=[CH:21][CH:20]=2)=[C:16]([C:45]([F:48])([F:47])[F:46])[CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]([C:27]3([NH:30][C:31]([C:33]4[CH:34]=[N:35][C:36]([S:39]([CH3:40])=[O:9])=[N:37][CH:38]=4)=[O:32])[CH2:28][CH2:29]3)=[O:26])=[CH:41][CH:42]=2)=[C:16]([C:45]([F:47])([F:48])[F:46])[CH:15]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(SC)nc4)CC3)cc2)c(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
186 mg (1.08 mmol) of 3-chloroperbenzoic acid were added at approx. 5° C. to a solution of 575 mg (1.08 mmol) of 2-methylthio-pyrimidine-5-carboxylic acid{1-[4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylcarbamoyl]-cyclopropyl}-amide (product from Example 144) in 10 mL dichloromethane. Then the cooling was removed and the reaction mixture stirred for a further three hours at ambient temperature. Half the solution was evaporated down and the crude product thus obtained was purified by chromatography (reversed phase HPLC).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])[N:6]=1.[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>>[NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:15]([NH:14][C:12]#[N:13])=[N:18][CH3:19])[N:6]=1
Reactant: CN=C(NC#N)SC
Reactant: NCCSCc1c[nH]c(N)n1
Product: CN=C(NC#N)NCCSCc1c[nH]c(N)n1

Procedure:
By the procedure of Example 75, 2-amino-4-[(2-aminoethyl)-thiomethyl]imidazole is reacted with N-cyano-N',S-dimethylisothiourea to give the title compound.
Reaction SMILES: C1[C@H](N)[C@@H]([O:8][C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[C@@H](O)[C@@H]1N.FC(F)(F)C(O)=O.C(OCC)C.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(O)(=O)C>[CH:53]1([N:52]=[C:51]=[N:50][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1.[C:51]([NH:50][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)([NH:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:8]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 8 h

Procedure:
30 g. of ribostamycin (the free base form) was added to 127 ml. of trifluoroacetic acid under ice-cooling and stirring, and the mixture was allowed to stand at ambient temperature overnight. The resulting solution of amber color was admixed with 400 ml of ethyl ether, and the admixture was cooled to precipitate 69 g of a salt of ribostamycin with trifluoroacetic acid which was then removed by filtration. A 20 g. portion of this ribostamycin trifluoroacetate was taken and then dissolved in 250 ml of tetrahydrofuran together with 16.4 g. of (S)-α-hydroxy-γ-N-phthalimido-n-butyric acid of the formula ##STR25## The solution was cooled with ice. A solution of 36.4 g of dicylcohexylcarbodiimide in 146 ml of tetrahydrofuran was prepared and cooled with ice. Both the solutions was combined together under ice-cooling and stirring. The combined solutions were agitated at ambient temperature for 2-3 hours and admixed with 8 ml of glacial acetic acid to decompose the excess of dicyclohexylcarbodiimide. 3286 mg of dicyclohexylurea produced was deposited and filtered off. The filtrate was concentrated to dryness, giving 43 g of a pale yellow colored solid comprising mixed trifluoroacetic acid salts of O-((S)-α-hydroxy-γ-N-phthalimido-n-butyryl)-ribostamycins.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:24][C:25](=[O:39])[C@@H:26]([NH:28][C:29]1[N:34]=[C:33](Cl)[N:32]=[C:31]([C:36]([NH2:38])=[O:37])[CH:30]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.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>[NH2:24][C:25](=[O:39])[C@@H:26]([NH:28][C:29]1[N:34]=[C:33]([C:10]2[CH:9]=[N:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)=[CH:12][CH:11]=2)[N:32]=[C:31]([C:36]([NH2:38])=[O:37])[CH:30]=1)[CH3:27]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)nc2)n1)C(N)=O
Temperature: 100 °C
Reaction time: 14 h
Yield: 50.5 %

Procedure:
A mixture of 2-(4-fluorophenoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (158 mg, 0.5 mmol), (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (121 mg, 0.5 mmol), Na2CO3 (2 M, 1 mL, 2 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.025 mmol) in DME/EtOH/H2O (2 mL/1 mL/2 mL) was purged with Ar for one minute, then stirred at 100° C. for 14 hrs. The reaction mixture was then worked up with DCM. The DCM was isolated, dried over MgSO4, and removed under vacuum. The residue was subjected to silica gel flash chromatography using dichloromethane/methanol as the eluent to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidine-4-carboxamide as a gray solid (100 mg, yield 50%). NMR (DMSO-d6): 9.3 (1H, s), 8.9 (1H, m), 8.3 (1H, s), 8.05 (1H, m), 7.75 (1H, s), 7.5 (1H, s), 7.2-7.4 (4H, m), 6.95-7.15 (2H, m), 6.80 (1H, s), 4.5 (1H, m), 1.35 (3H, d, J=7.0 Hz). LC/MS: m/z=398 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:39]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(CCO)c([N+](=O)[O-])cc1C2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 100 °C

Procedure:
To a stirred solution of (2S)-5-(2-hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step E (174 mg, 0.54 mmol) in DMF (4 mL) were added diphenyl phosphoryl azide (177 mg, 0.64 mmol) and DBU (0.096 mL, 0.64 mmol). The mixture was heated at 100° C. for 6 h, then quenched with H2O (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound. MS: m/2=351 (M−1).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2C(O)=O.C(=O)(O)[O-].[Na+].[I-:22].[Na+].II>ClC(Cl)C.O.ClCCl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:22]
Reactant: O=C(O)c1n[nH]c2ccc(OC(F)F)cc12
Reactant: [I-]
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: FC(F)Oc1ccc2[nH]nc(I)c2c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 84.2 %

Procedure:
To a mixture of 5-(difluoromethoxy)-1H-indazole-3-carboxylic acid (1 g, 4.38 mmol), and sodium bicarbonate (1.22 g, 563 μL, 14.5 mmol) in dichloroethane (10.0 mL) and water (10.0 mL) were added in one portion sodium iodide (1.71 g, 11.4 mmol) and iodine (1.45 g, 5.7 mmol) and the mixture heated at to 100° C. (oil bath temperature) with vigorous stirring for 45 minutes. After cooling to 25° C. the mixture was diluted with dichloromethane then washed with 10% Na2S2O3 and saturated NaHCO3. The organic phases were combined, dried (MgSO4) and concentrated to an off-white solid which was dissolved in dichloromethane, hexane added to promote solid formation and allowed to stand. The solid formed was separated by decanting the mother liquor and dried to give 5-(difluoromethoxy)-3-iodo-1H-indazole (1145 mg, 3.69 mmol, 84.3%) as a white fluffy solid. MS (M−H)−=308.9; 1H NMR (CDCl3) δ: 7.52 (d, J=9.1 Hz, 1H), 7.28-7.36 (m, 1H), 6.57 (t, J=73.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:27][CH:26]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc(F)cc1C(=O)O
Product: O=C(Nc1ccc(F)cc1C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
In analogy to example 1,5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid was prepared form 2-amino-5-fluoro-benzoic acid and 4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.4 (M−H−, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[NH:41][C:42](=[O:53])[C:43]2[N:44]=[CH:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=2[N:48]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:45]=[N:44][C:43]2[C:42](=[O:53])[NH:41][C:40]([NH:39][C:37]([O:36][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:38])=[N:48][C:47]1=2)[CH3:2]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Yield: 70.1 %

Procedure:
The title compound (2.61 g, 70%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid (2.10 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 11.63 (bs, 0.1H), 11.23 (bs, 1H), 8.27 (d, 1H), 8.17 (t, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.50˜7.25 (m, 10H), 6.86 (s, 1H), 5.12 (s, 1.2H), 4.93 (s, 0.8H), 4.44 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.04 (q, 1.2H), 3.65 (t, 1.2H), 3.45 (t, 1.2H), 3.41 (t, 0.8H), 3.21 (t, 0.8H), 1.23 (t, 1.2H), 1.17 (t, 1.8H).