Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:49])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:46])[CH2:30][C:31]2([OH:45])[CH2:36][CH2:35][CH:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:37][CH:34]1[CH2:33][CH2:32][C:31]([CH2:30][C:29]([NH:28][CH:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:49])[C:8]=3[O:23][B:15]2[OH:16])=[O:46])([OH:45])[CH2:36][CH2:35]1
Reactant: COc1c(CC(NC(=O)CC2(O)CCC(NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NC1CCC(O)(CC(=O)NC2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-[2-[2-(4-tert-Butoxycarbonylamino-1-hydroxy-cyclohexyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 363 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: OCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)cc(C)c1OCCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.00 g, 33.3 mmol) in DMF (30 mL) were added 4-bromo-butan-1-ol (6.11 g, 39.9 mmol) and Cs2CO3 (16.2 g, 50.0 mmol). The reaction mixture was stirred at room temperature for 48 hours, then water (100 mL) was added, and the products were extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Solvent was removed and the crude product was purified by the Simpliflash system, using 40% ethyl acetate in hexane as eluent, to give 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 0.66 g (7%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C)C=O>[N:12]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[N+:13]=[N-:14]
Reactant: ClCCOCc1c[nH]cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1c[nH]cn1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A stirred suspension of 4-(2-chloroethoxymethyl)imidazole hydrochloride (14.7 g.) and sodium azide (9.8 g.) in dry dimethylformamide (103 ml.) was maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate was concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product was basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue was extracted with isopropyl alcohol (3×50 ml.). Concentration of the extracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave 4-(2-aminoethoxymethyl)imidazole (6.48 g.). A sample of the monopicrate monohydrochloride had m.p. 139°-140° (from nitromethane). (Found: C, 35.4; H, 3.8; N, 20.5; Cl, 8.8. C12H15ClN6O8 requires: C, 35.4; H, 3.7; N, 20.7; Cl, 8.7).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:24]=2[C:25]([OH:27])=O)=[CH:18][CH:17]=1.N>P(=O)(O)(O)O>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:22][C:23]3[C:24](=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[C:25](=[O:27])[C:20]=2[CH:21]=1
Reactant: Nc1ccc(Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Agent: N
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Nc1ccc2[nH]c3ccc([N+](=O)[O-])cc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
See Korolev et al., 1976. Polyphosphoric acid was freshly prepared by slowly adding, with stirring, 85% orthophosphoric acid (360 mL) to phosphorus pentoxide (600 g). The mixture was then heated on a steam bath with stirring until a clear viscous liquid was obtained. 2-(-4-amino-phenylamino)-5-nitrobenzoic acid 10 (107.76 g, 0.394 mol) was added with stirring over the course of 5 min. Heating on the steam bath was continued for 6 hr, the mixture being stirred occasionally. Whilst still hot, the mixture was poured into 4 L of ice-water, stirred for 30 min, and allowed to stand overnight. The mixture was adjusted to pH 8.0 by the addition of 0.88 s.g. aqueous ammonia, chilled for 2 hr, and the crude product collected on a glass sinter. It was washed with dilute ammonia (1% 0.88 s.g. aqueous ammonia in water, 250 mL) followed by water (3×250 mL), ice-cold ethanol (2×250 mL), dry ether (2×250 mL) and finally hexane (250 mL). The product, 11, was dried over P2O5 under vacuum to yield a red-brown solid (97.04 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The mixture of 2 g of 2-amino-3-cyano-4-hydroxy-6-(4-methylpiperazino)quinoline and 4 mL of phosphoryl chloride is stirred at 120° C. for 4 hours. The cooled reaction mixture is poured onto 40 g of ice, the pH of the mixture is adjusted to 8 with 10% NaOH solution, and the precipitated material is filtered off. After drying 1.5 g of the title compound is obtained, m.p.: 189° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:34]=[CH:33][C:20]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].O.NN.[OH-].[Na+]>CO>[NH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:10][CH:11]=2)=[CH:34][CH:33]=1
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
The compound (521.6 mg) obtained in Example 39-1 was dissolved in methanol (15 ml) and added with hydrazine monohydrate (0.11 ml), followed by stirring at 60° C. for 1.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent had been distilled off, the subject compound (372 mg) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([Si](C(C)C)(C(C)C)C(C)C)[CH:20]=2)O)=[C:11]([F:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[C:11]([F:38])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncccc23)c(F)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
(4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (655, 1.49 g, 2.79 mmol) was dissolved in acetonitrile (50 mL) and trifluoroacetic Acid (1.1 mL) was added. The reaction was stirred for 5 minutes. Triethylsilane (2.2 mL) was added to the reaction. The reaction was heated at 80° C. for 6 hours. The reaction was concentrated and the crude material was dissolved into ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate, and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. The solid obtained was used in the next reaction without further purification (656, 833 mg, 83%). MS (ESI) [M+H+]+=363.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH3:44][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:37][C:38](=[O:42])[N:39]([CH3:41])[CH3:40])[CH2:20][C@@H:21]3[O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)N(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 39.7 %

Procedure:
In 10 ml of benzene was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of one drop of concentrated sulfuric acid. The mixture was stirred in an atmosphere of argon gas under ice-cooling for 1 hour. The reaction mixture was then worked up in the same manner as Example 124 to give 135 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(tert-butyldimethylsilyl)oxy-3β-(N,N-dimethylcarbamoyl)oxypregna-5,7-diene showing the following properties.
Reaction SMILES: C(O)C(N)(CO)CO.[Na+].N[C@H](C([O-])=O)CCC([O-])=O.[Na+].[CH2:21]([N:32]([CH2:37][C:38]([O-:40])=[O:39])[CH2:33][C:34]([O-:36])=[O:35])[CH2:22][N:23]([CH2:28][C:29]([O-:31])=[O:30])[CH2:24][C:25]([O-:27])=[O:26]>O>[CH2:22]([N:23]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C:25]([OH:27])=[O:26])[CH2:21][N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=[O:35]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: NC(CO)(CO)CO
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
Dissolve 24.23 gm of Tris base, 8.47 gm of glutamic acid sodium salt, and 1.86 gm of ethylenediaminetetraacetate (EDTA) in 1 liter of deionized water. Adjust pH to 9.0.
Reaction SMILES: [OH-].[K+].O.[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[CH:13](=[O:16])[CH2:14][CH3:15]>C(O)CO>[CH3:15]/[C:14](=[CH:8]\[C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH3:4])[CH:6]=1)/[CH:13]=[O:16]
Reactant: Cc1cccc(C=O)c1
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C/C(C=O)=C\c1cccc(C)c1
Temperature: 40 °C
Yield: 69.7 %

Procedure:
A solution of potassium hydroxide (24 g, 0.36 mol, 0.6 eq, with a purity of 85%) in ethylene glycol (120 g) and water (12 g) was charged into a 500 mL three-necked round-bottom flask equipped with a reflux condenser and a mechanical stirrer. 3-methyl benzaldehyde (70 g, 0.59 mol) was added dropwise. The stirred reaction mixture was heated at 38-42° C. and propionaldehyde (41 g, 0.71 mol, 1.2 eq) was dosed in over 3.25 h. After a further hour at 40° C., the reaction mixture was cooled to ambient temperature and the two layers separated. The organic layer thus obtained was washed with water (2×100 mL), dried over magnesium sulphate and concentrated. The resulting crude product was distilled via a Vigreux column (1.0 mBar, 87-92° C.), to give (2E)-2-methyl-3-(3-methylphenyl)acrylaldehyde (65.9 g, gc purity>95%; yield 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][C:10]=1[F:32])[C:2]1[CH:7]=[CH:6]C=CC=1.[F:33]C1(CO)CC1>>[F:32][C:10]1[CH:11]=[C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1([F:33])[CH2:6][CH2:7]1
Reactant: OCC1(F)CC1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4(F)CC4)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[C:3]1SC>CO.[Ni].O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1
Reactant: CNc1cc(=O)n(C)c(SC)n1
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CNc1cc(=O)n(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Referring to scheme 1, 3-methyl-6-(methylamino)-2-(methylthio)pyrimidin-4(3H)-one (compound 1A; 650 mg, 0.35 mmol, 1 eq) was suspended in methanol (5 ml). A large excess of Raney Nickel slurried in water was added (approx 5 ml) and the mixture stirred at room temperature overnight to yield compound 1B. The product was confirmed by LC-MS. The mixture was filtered and the solid washed several times with methanol. The filtrate was then removed in vacuo and the residue was purified by flash chromatography with 1:10 MeOH:DCM to leave 3-methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B) as a yellow/green solid (380 mg, 86%). 1H NMR (400 MHz, MeOD) δ ppm 2.78 (s, 3H) 3.35 (s, 3H) 5.22 (br. s., 1H) 8.10 (br. s., 1H); [M+H] calc'd for C5H7N3O, 126. found, 126.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([N:13]=[C:14](Cl)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(C=CS(N)(=O)=O)=CC=1)([O-])=[O:25].C(Cl)(=O)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)N=C(Cl)c2ccccc2)cc1
Reactant: NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76 %

Procedure:
N-(4-Nitrostyrylsulfonyl)benzimidoyl chloride. A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 1.5 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192°-195° C., from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH:17]([OH:26])[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1>>[OH:26][CH:17]([CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CN1CCN(CC(O)CN)CC1
Product: Cc1[nH]c2c(c1C(=O)NCC(O)CN1CCN(C)CC1)CCCC2=O
Yield: 71.7 %

Procedure:
Similar procedure as Example 13, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 0.36 g (2.1 mmol) was reacted to give 0.25 g (72%) of the titled compound as a white solid.
Reaction SMILES: OCCC[N:5]1[C:9]2[CH:10]=[C:11]([CH3:15])[C:12]([CH3:14])=[CH:13][C:8]=2[N:7]=[CH:6]1.[NH+]1C=CC=CC=1.[C:22]([CH2:24][CH2:25][O:26][P:27](=[O:30])([O-:29])[O-:28])#N.[NH+]1C=CC=CC=1>>[CH3:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:6]([CH2:22][CH2:24][CH2:25][O:26][P:27](=[O:28])([OH:30])[OH:29])[NH:5][C:9]=2[CH:10]=1
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: Cc1cc2ncn(CCCO)c2cc1C
Agent: c1cc[nH+]cc1
Product: Cc1cc2nc(CCCOP(=O)(O)O)[nH]c2cc1C

Procedure:
Using 0.2 g of the crude 1-(3-hydroxypropyl)-5,6-dimethylbenzimidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml) as the starting substances, according to the same processes as in Example 1, 0.3 g of crude 3-(5,6-dimethylbenzimidazolyl)propylphosphoric acid was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][N:60]1[C:64]([CH3:65])=[CH:63][C:62]([CH2:66]O)=[N:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:62]2[CH:63]=[C:64]([CH3:65])[N:60]([CH3:59])[N:61]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1cc(CO)nn1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc(C)n(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (1,5-dimethyl-1H-pyrazol-3-yl)methanol (0.53 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.80 g, 61%).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[F:47][C:48]1[CH:49]=[C:50]([NH:54][NH2:55])[CH:51]=[N:52][CH:53]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:50]3[CH:51]=[N:52][CH:53]=[C:48]([F:47])[CH:49]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1cncc(F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(F)c2)n1

Procedure:
500 mg (1.16 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 265 mg (1.62 mmol) of 5-fluoropyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 340 mg (66% of theory) of the title compound is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(F)cc4)cc3c2C1
Yield: 36 %

Procedure:
The product of Example 29, step B and sodium 4-fluorobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) provided tert-butyl 8-(4-fluorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (217 mg, 36%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.07 (s, 1H), 8.01-7.91 (m, 2H), 7.81 (dd, J=8.7, 1.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.22-7.11 (m, 2H), 4.57 (s, 2H), 3.89-3.76 (m, 2H), 2.92-2.80 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:56]1[CH:60]=[C:59]([CH2:61][C:62]([OH:64])=O)[N:58]=[CH:57]1>C1COCC1>[NH:56]1[CH:60]=[C:59]([CH2:61][C:62]([N:2]([CH3:1])[C@@H:3]2[CH2:7][CH2:6][N:5]([C:8]3[C:9]4[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:4]2)=[O:64])[N:58]=[CH:57]1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)Cc1c[nH]cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.29 mmol), TBTU (0.35 mmol) and DIPEA (0.58 mmol) in THF was slowly added 2-(1H-imidazol-4-yl)acetic acid (0.29 mmol). The mixture was stirred at room temperature overnight, then concentrated, diluted with water, and extracted with EtOAc. The combined extracts were dried, filtered and concentrated. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:3][CH:2]=1.[OH:26]O>>[N:1]1[CH:2]=[CH:3][C:4]([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])=[CH:5][CH:6]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccncc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccncc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-pyridylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][N:8]([CH3:31])[C:9]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([OH:29])[C:12]=1[OH:30])=[O:10].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:31][N:8]([CH3:7])[C:9]([C:11]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([OH:29])[C:12]=1[O:30][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[O:10]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(O)c(OC(=O)N(C)C)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5.9 %

Procedure:
Dimethylcarbamic chloride (163 μL, 1.77 mmol) was added dropwise to a stirred suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (494 mg, 1.42 mmol) and K2CO3 (255 mg, 1.85 mmol) in MeCN (8 mL). The resulting mixture was stirred at RT for 24 h then partitioned between water (30 mL) and DCM (20 mL) the aqueous layer was extracted with DCM (2×20 mL), the combined organics were dried (MgSO4), filtered and solvents removed in vacuo to give an orange oil. The residue was purified by silica gel chromatography (12 g, 0-10% MeOH (+1% NH3) in DCM) to afford ethyl 5-(dimethylcarbamoyl)-4-((dimethylcarbamoyl)oxy)-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-066) (35 mg, 6%) as a white solid: m/z 420 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 7.16-7.06 (m, 2H), 6.95-6.86 (m, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.98 (s, 3H), 2.88 (s, 3H), 2.78 (s, 3H), 2.69 (s, 3H), 1.00 (t, J=7.1 Hz, 3H).