Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH:18][C:19](=[O:29])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)#[N:2].[OH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CN1C(=O)CCC1>[C:16]([CH2:15][CH2:14][S:13][C:9]1[CH:8]=[C:7]([NH:18][C:19](=[O:29])[C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:6]([S:5][CH2:4][CH2:3][C:1]#[N:2])=[CH:11][C:10]=1[NH:12][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][C:31]([OH:30])=[CH:32][CH:33]=1)#[N:17]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: N#CCCSc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(SCCC#N)cc1N
Solvent: CN1CCCC1=O
Product: N#CCCSc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(SCCC#N)cc1NC(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
2,5-Bis[(2-cyanoethyl)sulfanyl]-N-(4-nitrobenzoyl)-1,4-phenylenediamine (1.0 g, 2.34 mmol) as prepared from the above Example 1 was admixed with 4-hydroxybenzoic acid (0.328 g, 2.38 mmol) in 11.7 mL NMP under nitrogen purge, followed by addition of lithium chloride (LiCl, 0.58 g), triphenylphosphite (TPP, 2.92 mL) and pyridine (2.92 mL). The resultant mixture was heated to a temperature of 80˜95° C. for about 4 h, followed by cooling to room temperature. 400 mL of water was subsequently added with stirring for a few minutes, and the resultant precipitate was collected by filtration, washed with water (400 mL, twice) and methanol (400 mL, once), followed by drying at room temperature under vacuum overnight, giving the title compound in a yield of 76.3%.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]1[SH:16])[CH2:2][CH2:3][CH3:4].Cl[Sn:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]1[S:16][Sn:18]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(S)nc2ccccc2c1=O
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1c(S[Sn](c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccccc2c1=O
Reaction time: 1 h

Procedure:
A mixture of 0.85 g (0.004 mole) 3-n-butyl-2-mercapto-4(3H)-quinazolinone (the product of Example 6), 1.54 g (0.004 mole) chlorotriphenyl tin and 0.4 g (0.004 mole) triethylamine in methylene chloride (about 100 ml) was stirred for one hour, refluxed 5.5 hours, stirred overnight and refluxed 8 hours. The reaction mixture was washed with water. The organic phase was dried over magnesium sulfate, and stripped to obtain the above-identified product as a solid, melting point 112° to 114° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7](Cl)[CH:6]=1.[Cl:14]C1C=CC=CC=1CCl.II.ClCC(Cl)=O>[Zn].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>[Cl:1][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:14]
Reactant: O=C(CCl)Cc1ccc(Cl)c(Cl)c1
Reactant: ClCc1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: II
Agent: O=C(Cl)CCl
Product: O=C(CCl)Cc1ccccc1Cl
Yield: 22 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-(3,4-dichlorophenyl)propan-2-one was followed, reacting 2-chlorobenzyl chloride (1.6 mL, 2.0 g, 12 mmol) with zinc dust (1.22 g, 18.6 mmol) in the presence of iodine (0.157 g, 0.620 mmol), then with chloroacetyl chloride (1.5 mL, 2.1 g, 19 mmol) in the presence of Pd(PPh3)4 (0.287 g, 0.248 mmol). Flash chromatography over silica gel (10% ethyl acetate in hexanes) gave product of sufficient purity to be used in the next step (0.556 g, 22% yield): 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 2H) 4.19 (s, 2H) 7.19-7.29 (m, 3H) 7.38-7.42 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)=[CH:5][CH:4]=1>CC1C=CC(C(C)C)=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([OH:19])=[CH:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3c(c2)CCCC3=O)cc1
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: COc1ccc(-c2ccc3c(O)cccc3c2)cc1
Yield: 14 %

Procedure:
6-(4-Methoxyphenyl)-3,4-dihydronaphthalene-1(2H)-one (510 mg, 2.02 mmol, 1 eq) and Pd/C (528 mg) are suspended in p-cymene (7 ml). The reaction mixture is refluxed for 24 h, cooled, filtered over Celite and extracted with 1 M NaOH. The aqueous phase is acidified with 1 M HCl and extracted with ether. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with dichloromethane/hexane 5/5 as the eluent yields the desired product in a yield of 14%, 69 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].Cl.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1.C(N=C=NC(C)C)(C)C>>[OH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([NH:28][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:26])[CH2:30][CH2:31]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)N[C@H]1CC[C@H](O)CC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and trans-4-aminocyclohexanol hydrochloride in a manner similar to that described in Example 11 but using 1,3-diisopropylcarbodiimide instead of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].C([Li])(CC)C.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[C:8]1=[O:12]
Reactant: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [Li]C(C)CC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(Cc3ccc(C(F)(F)F)cc3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (1.76 g, 6.63 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add dropwise a solution of sec-butyllithium (5.10 mL, 1.3 M in hexane, 6.63 mmol). After 45 minutes, slowly add a solution of 4-(trifluoromethyl)benzyl bromide (1.58 g, 6.63 mmol) in tetrahydrofuran (5 mL). After 5 hours, add water (10 mL) and warm to ambient temperature. Separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound: Rf=0.35 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].[CH:24](OCC)=[O:25]>C1COCC1>[CH:24]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:15])([F:16])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6]2=[O:23])=[O:25]
Reactant: CCOC=O
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CNC=O)cc2c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A suspension of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (400 mg, 1.14 mmol) in ethyl formate (27.4 mL, 340.7 mmol) and THF (25 mL) was stirred at 60° C. for 16 h. Subsequently the solvent was evaporated and the residue dried in vacuo for 2 h. The crude product was purified by flash-master chromatography (DCM 100-90/MeOH 0-10, %-gradients) to yield N-(6-formylaminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (316 mg, 0.831 mmol, 73%) as a light-yellow solid. 1H-NMR (DMSO-d6, 400 MHz) 3.17 ppm (s, 3H, SO2—CH3); LC-MS rt=2.32 min; MS: m/z 380.9 [M+H]+ Column: SunFireC18, 4.6*50 nm, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: CC(C1C=CC(OCC2OC2)=CC=1)(C1C=CC(OCC2OC2)=CC=1)C.C[C:27]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)(C1C=CC(O)=CC=1)C.[CH2:43]1[O:45][CH:44]1[CH2:46]Cl>>[CH2:41]1[CH:40]2[CH:39]3[O:42][CH:27]3[CH:36]1[CH:37]1[CH:46]2[CH:44]2[O:45][CH:43]2[CH2:38]1
Reactant: ClCC1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Product: C1C2OC2C2C1C1CC2C2OC12

Procedure:
Diglycidyl ether of bisphenol A available commercially under the trade designation of Epon 828,
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1.Cl>CS(C)=O.O>[Br:19][C:20]1[C:21](=[O:26])[N:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=2[CH3:12])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Reactant: O=c1[nH]cccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
223 g (38% strength, 0.5 mol) of 2-fluoro-1,3-dimethyl-5-nitrobenzene and 138 g (1.0 mol) of potassium carbonate were introduced as initial charge in 1.95 l of DMSO and heated to 120° C. At this temperature, a solution of 100 g (87% purity, 0.5 mol) of 3-bromopyridone in DMSO was added dropwise. The reaction mixture was stirred for 3.5 h at 120° C., cooled to RT, stirred into water, rendered slightly acidic with hydrochloric acid and extracted with ethyl acetate. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with water, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The crude product was purified over silica gel with dichloromethane then ethyl acetate/dichloromethane=1:20. The isolated product was stirred into diethyl ether/petroleum ether=1:1.5, filtered off with suction and washed with petroleum ether. This gave 75.2 g (47%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[NH2:23][C:24]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:35])=[N:29]2.C([BH3-])#N.[Na+]>>[F:34][C:33]1[C:24]([NH:23][CH2:14][C:13]([OH:20])([C:16]([F:17])([F:19])[F:18])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)([CH3:21])[CH3:22])=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([CH3:35])[CH:27]=[CH:26]2
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Reactant: Cc1ccc2c(N)c(F)ccc2n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)c(F)ccc2n1

Procedure:
Analogously to Example 1, the corresponding imine is produced starting from 250 mg of 4-(2,3-dihydro-5-fluoro-7-benzofuranyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 138 mg of 5-amino-6-fluoro-2-methylquinoline. After reaction with sodium cyanoborohydride, the title compound is obtained.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH2:15][O:14]1>C(O)C>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]3=[O:11])=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc2c(c1)COC2
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc3c(c2)COC3)C1=O
Yield: 83.7 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 1,3-dihydroisobenzofuran-5-amine (0.608 g; 4.36 mmol) in ethanol (3 mL). 1-(1,3-dihydroisobenzofuran-5-yl)-2-oxopyrrolidine-3-carboxylic acid 0.300 g (84%) was obtained as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:47])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH:43][CH2:44][CH2:45][OH:46])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[OH:46][CH2:45][CH2:44][NH:43][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:47])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(NCCO)n1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(NCCO)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-{3-[2-(2-hydroxy-ethylamino)-6-methyl-pyrimidin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K50) (250 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (100 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1ccccc1F
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3ccccc3F)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 437 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]3)[C:8]=2[CH:30]=1)([O-:3])=[O:2].NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][N:9]2[C:8]3[CH:30]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[O:12][CH2:11][C:10]2=[O:13])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc([N+](=O)[O-])cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc([N+](=O)[O-])cc32)CC1

Procedure:
tert-Butyl {1-[2-(6-nitro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 82) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1SCC(O)=O.[CH:26]1[CH:31]=[C:30]([C:32]([OH:34])=[O:33])[C:29]([SH:35])=[CH:28][CH:27]=1.Cl[C:37]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)/[C:39](=[N:48]/[S:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)(=[O:51])=[O:50])/[CH:38]=1>>[C:55]1([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:56]=[CH:57][C:52]([S:49]([NH:48][C:39]2[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]([OH:47])=[C:37]([S:35][C:29]3[CH:28]=[CH:27][CH:26]=[CH:31][C:30]=3[C:32]([OH:34])=[O:33])[CH:38]=2)(=[O:51])=[O:50])=[CH:53][CH:54]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21
Reactant: O=C(O)c1ccccc1S
Agent: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(O)c1ccccc1Sc1cc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2c1O

Procedure:
5.2.62 2-(4-(biphenyl-4-ylsulfonamido)-1-hydroxynaphthalen-2-ylthio)benzoic acid (14t) was prepared according to the procedure of procedure B for 10a except using 2-thiosalicylic acid and (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)biphenyl-4-sulfonamide (12b), which afforded the title compound 17.4 mg (65.9%) as an off-white solid, m.p.: 205° C. (dec.).
Reaction SMILES: BrC(C)[C:3](=[O:11])[CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[K+]>O>[OH:11][C:3]1[CH:8]([CH3:9])[O:7][C:5](=[O:6])[C:4]=1[CH3:10]
Reactant: CCOC(=O)C(C)C(=O)C(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1=C(O)C(C)OC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To ethyl 4-bromo-2-methyl-3-oxopentanoate (7.49 g, 31.6 mmol) was added cold potassium hydroxide (4.7 g, 84 mmol) in water (36 mL) at 0° C., the resulting mixture was vigorously stirred at 0° C. for 4 h. The reaction mixture was extracted with methylene chloride (2×100 mL), the alkaline phase was acidified to ph 1 by 6N hydrogen chloride followed by extraction with methylene chloride (3 times 100 mL). The combined latter organic phase was dried over sodium sulfate, and concentrated to give 4-hydroxy-3,5-dimethylfuran-2(5H)-one. LC/MS: (M+23)+: 151.10, 1HNMR (500 MHz, CDCl3), δ4.882-4.842 (dd, J=6.8 Hz, 1H), 3.744 (s, 1H), 1.759 (s, 3H). 1.526-1.513 (d, J=6.8 Hz, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[CH:7][C@@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9].C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][C:23]([CH3:25])=O>>[CH3:22][C:23]1([CH3:25])[O:9][C@@H:8]2[C@@H:10]([C@@H:12]([CH2:14][OH:15])[O:13][CH:7]2[OH:6])[O:11]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a suspension of D-ribose (12.5 g, 83 mmol) in acetone (125 mL). The reaction mixture was stirred at room temperature for 90 min to obtain a clear solution which was then neutralized with saturated aqueous sodium carbonate. The mixture was filtered over Celite® and concentrated in vacuo.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([N+:15]([O-])=O)[C:10]=1[O:11][CH2:12][O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[C].[Pd]>[NH2:15][C:9]1[CH:8]=[C:7]([C:18](=[O:20])[CH3:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1c([N+](=O)[O-])cc(C(C)=O)cc1C(C)(C)C
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COCOc1c(N)cc(C(C)=O)cc1C(C)(C)C
Reaction time: 7 h
Yield: 87 %

Procedure:
After adding 10% palladium-carbon (50% wet) (14 g) to a solution of the 1-[3-(tert-butyl)-4-(methoxymethoxy)-5-nitrophenyl]-1-ethanone (69.4 g, 247 mmol) in toluene (280 ml) at room temperature, the mixture was hydrogenated for 7 hours under normal pressure. The 10% palladium-carbon was removed by celite filtration and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to yield the title compound (54.0 g, 87.1% yield) as light green granular crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:20])C.[NH4+]>C(O)=O>[F:16][C:15]1[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:20])[CH:7]=2)=[N:11][CH:12]=[C:13]([F:17])[CH:14]=1
Reactant: Fc1cnc(COc2ccnc(Cl)c2)c(F)c1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Product: O=c1cc(OCc2ncc(F)cc2F)cc[nH]1
Yield: 63.8 %

Procedure:
2-((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine (3.42 g, 13.3 mmol) and ammonium acetate (20.5 g, 267 mmol) were heated to 110° C. in formic acid (45 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with saturated NaHCO3 solution. The solid was filtered off to provide the title compound (2.02 g, 63%) as a white solid: ESI MS m/z 239 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[N:24]=[C:23]([S:25][CH3:26])[N:22]=[C:21]([N:27]([CH3:29])[CH3:28])[CH:20]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:12][C:19]2[CH:20]=[C:21]([N:27]([CH3:28])[CH3:29])[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(Cl)cc(N(C)C)n1
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2cccc(OCc3ccccc3)c2)cc(N(C)C)n1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 93.7 %

Procedure:
A mixture of 3-(benzyloxy)aniline (5.13 g) and NaH (1.37 g) in tetrahydrofuran (15 mL) was refluxed for 30 minutes and then cooled to room temperature. A solution of N-[6-chloro-2-(methylsulfanyl)-4-pyrimidinyl]-N,N-dimethylamine (3.5 g) in tetrahydrofuran (35 mL) was added to this mixture and the resulting solution was stirred for 22.5 hours. The reaction mixture was quenched with saturated NH4Cl. Then the crude product was concentrated under reduced pressure and redissolved in EtOAc. The organic layer was separated and washed with aqueous citric acid (2×300 mL), water (2×300 mL) and brine (2×300 mL). The crude product was purified by column chromatography [eluent: EtOAc/hexane (1:4)], giving the desired product (5.9 g, 94%).
Reaction SMILES: C[Al](C)C.[CH3:5][C@H:6]1[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:8]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=O)=[CH:16][CH:15]=2)[CH2:7]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH2:42])[NH:40][N:41]=2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1(C)C=CC=CC=1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([CH2:35][CH2:36][C:37]2[CH:38]=[C:39]([NH:42][C:18](=[O:20])[C:17]3[CH:16]=[CH:15][C:14]([N:8]4[CH2:9][C@H:10]([CH3:13])[N:11]([CH3:12])[C@H:6]([CH3:5])[CH2:7]4)=[CH:24][CH:23]=3)[NH:40][N:41]=2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4C[C@@H](C)N(C)[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Yield: 33.7 %

Procedure:
A 2M solution of trimethylaluminium (2.500 mL, 5.00 mmol) in toluene, was added dropwise to a stirred suspension of ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (0.643 g, 2 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol) in toluene (10 mL) at room temperature. The solution was then heated at 60° C. for 18 h. The reaction mixture was cooled and quenched with methanol (15 ml) and 2N hydrochloric acid (5 ml). The crude reaction mixture was purified by ion exchange chromatography on a SCX column, eluting with 7N ammonia in methanol. The appropriate fractions were evaporated to give an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2.5N ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford, on crystallisation from DCM/diethyl ether, the title compound (0.322 g, 33.7%) as a cream solid.