Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)CCC>>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:4]1[C:5]2[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=2[C:2]([C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[CH:3]1)#[N:21]
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccc3C#N)c2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: CC1(C)CC(=O)c2c(-c3nccs3)cn(-c3ccccc3C#N)c2C1
Yield: 44 %

Procedure:
In the same way as described in Example 15, Step 4 using 3-bromo-1-(2-cyanophenyl)-6,6-dimethyl-4,5,6,7-tetrahydroindol-4-one and 2-tributylstannylthiazole, the title compound (200 mg, 44%) was isolated as a colourless solid. 1H NMR (400 MHz, d6-DMSO) δ 1.05 (6H,s), 2.43 (2H,s), 2.53 (2H,s), 7.63 (1H,d, J=3.3 Hz), 7.75-7.80 (4H,m), 7.92 (1H,dd, J=7.8 and 1.4 Hz), 8.13 (1H,dd, J=7.7 and 1.3 Hz). MS (ES+) 348 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:15].Cl>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: OB1OCc2ccc(O)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 120 mg, 3.0 mmol) and iodomethane (0.1 mL, 2.0 mmol). The reaction mixture was stirred for 2 h then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (81.9 mg, 50% yield). 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.07 (dd, J=8.1 & 2.4 Hz, 1H), 5.06 (s, 2H) and 3.84 (s, 3H) ppm; Mp: 107-109° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].S(OC)(O[CH3:24])(=O)=O>S(=O)(=O)(O)O.CN(C=O)C.O.C(O)(=O)C>[Br:1][C:2]1[C:3]2[C:11](=[O:13])[C:10]3[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([CH3:24])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1ccccc1Nc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2ccccc2c(=O)c2c(Br)cccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
(Method E-1) 2-(3-Bromo-phenylamino)benzoic acid, 13 (9.5 g, 32.5 mmol) was dissolved in conc. sulphuric acid (50 ml) and heated to 100° C. for 40 mins. After cooling, water was added slowly giving a green solid. The solid was filtered off and washed with water, and dried over phosphorous pentoxide. The crude material was partially dissolved in DMF (100 ml) and slowly added under nitrogen to sodium hydride (3.75 g, 156 mmol) in DMF (50 ml), and the mixture stirred for 30 mins. Dimethyl sulphate (12 ml, 72 mmol) was added and stirring continued for a further 30 mins before adding acetic acid (1 ml), then water (400 ml). The precipitate was filtered off, and the crude mix of 1 and 3-bromo acridones separated by column chromatography to give the title compound (2.43 g, 8.86 mmol, 26% over 2 steps). See, for example, Hodgeman et al., 1972.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH:11]([NH:12]C=O)[C:5]=2[CH:4]=1)#[N:2].[ClH:15]>>[ClH:15].[C:1]([C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH:11]([NH2:12])[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc2c(s1)CCCC2NC=O
Agent: Cl
Product: N#Cc1cc2c(s1)CCCC2N

Procedure:
A mixture of 4.8 grams of 2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 70 ml. of 1N hydrochloric acid is refluxed for an hour and evaporated to dryness to afford 4.7 grams of 2-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride, melting point 241° C. to 246° C. (dec.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH3:20])[C:13]=3[C:12]([CH:21]([OH:44])[C:22]3[CH:23]=[CH:24][C:25]([N:29]([C:37]4[CH:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=4)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:26][C:27]=3[F:28])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH3:20])[C:13]=3[C:12]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([N:29]([C:37]4[CH:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=4)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:26][C:27]=3[F:28])=[O:44])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNc1ncnc2c1c(C(O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: CNc1ncnc2c1c(C(=O)c1ccc(N(C(=O)OC(C)(C)C)c3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl N-[5-[[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate (86, 0.07 g, 0.11 mmol) in DCM (10 mL) was added DMP (0.06 g, 0.14 mmol). The reaction was stirred at room temperature for 20 minutes. The reaction was concentrated, and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give product (87, 0.065 g, 93.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH3:11])=[CH:4][N:3]=2)=[N:14]1
Reactant: Cn1ccc(N)n1
Reactant: CCCOc1ccc(Br)nc1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: CCCOc1ccc(Nc2ccn(C)n2)nc1
Temperature: 80 °C
Yield: 43 %

Procedure:
2-Bromo-5-propoxy-pyridine (0.96 mmol), sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.3 eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C. Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (5.9 mg) in degassed dioxane (1 ml) is added and the reaction mixture is heated for 60 min to 150° C. in the microwave. The reaction is quenched with ethylacetate/methanol (30 ml, 9:1) and filtrated over celite. The solvent of the filtrate is removed in vacuo. (1-Methyl-1H-pyrazole-3-yl)-(5-propoxy-pyridine-2-yl)-amine (“A23”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as a colorless powder in a yield of 43%; HPLC (method C): 1.41 min; LC-MS (method A): 0.81 min, 233.0 (M+H+); 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 10.651 (s, 1H), 7.869 (d, 1H, J=2.9 Hz), 7.747-7.710 (m, 2H), 7.299 (d, 1H, J=9.6 Hz), 6.099 (d, 1H, J=2.3 Hz), 3.949 (t, 2H, J=6.4 Hz), 3.841 (s, 3H), 1.785-1.697 (m, 2H), 3.323 (t, 3H, J=7.4 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2.[H-].[Na+].[CH3:16]I>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:16])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2
Reactant: CI
Reactant: OCCCc1nc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CCCO)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.40 g of 2-(3-hydroxy-propyl)-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 33), 0.81 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.2 ml of methyl iodide and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatograpy through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 3.10 g of the title compound, melting at >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH3:22])[CH2:7][CH2:6]2
Reactant: CI
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C)CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A solution of 1C (30 g, 114 mmol) in DMF (100 mL) was added over a period of 30 min to an ice cold solution of NaH (11.44 g, 286 mmol) in DMF (100 mL), and the mixture was stirred for 10 min. Methyl iodide (21.36 mL, 343 mmol) was then added, and the mixture was stirred for 6 h at room temperature. The reaction was then brought to 0° C., excess NaH was quenched with ice water, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound (30 g, 81%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J=8.4 Hz, 2H), 6.72 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.62 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.08-2.80 (m, 3H), 2.46 (d, J=15.6 Hz, 1H), 2.39 (dd, J1=4.4 Hz, J2=12.0 Hz, 1H), 1.90 (dt, J1=14 Hz, J2=4.4 Hz, 1H), 1.26 (s, 3H), 1.21 (t, J=7.2 Hz, 1H). ESI-MS m/z: 277 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=[O:24])[CH2:15][OH:16])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(OC(=O)CO)cc1
Reaction time: 48 h

Procedure:
2-[4-(2-Benzyloxy-acetoxy)-phenoxy]-propionic acid methyl ester 15 (13 grains, 37.79 mmol) is dissolved in methanol (100 ml) in a pressure vessel, palladium on carbon (50% wet, 5%, 10 grams) added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 48 hours. The catalyst is removed by filtration and distilled off the methanol. The crude 16 can be purified by column chromatography on silica gel using chloroform: Ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(C)([O-])C.[Na+].[Cl:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)(=[O:36])=[O:35])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
Alternatively, to a stirred solution of 2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno-[2,3-b]pyridin-4-amine (460 mg, 1.317 mmol) (Description 17) in DMF (10 mL) was added sodium tert-butoxide (316 mg, 3.29 mmol) and 3-chlorobenzenesulfonyl chloride (0.371 mL, 2.63 mmol). The reaction mixture was stirred at RT under nitrogen for 1 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and NaHCO3 (50 mL). The organic layer was then separated and the aqueous layer re-extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over Na2SO4 and the solvent concentrated in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, afforded the title compound (447 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][CH2:13][CH2:12][N:11]([C:15]3[C:16]([F:36])=[CH:17][C:18]4[N:27]=[CH:26][C:25]5[N:24]([CH3:28])[CH:23]=[C:22]([C:29]([O:31]CC)=[O:30])[C:21](=[O:34])[C:20]=5[C:19]=4[CH:35]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)C.[OH-].[K+].O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][CH2:13][CH2:12][N:11]([C:15]3[C:16]([F:36])=[CH:17][C:18]4[N:27]=[CH:26][C:25]5[N:24]([CH3:28])[CH:23]=[C:22]([C:29]([OH:31])=[O:30])[C:21](=[O:34])[C:20]=5[C:19]=4[CH:35]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CCNC(c5ccc(C)c(C)c5)C4)cc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C2CN(c3cc4c(cc3F)ncc3c4c(=O)c(C(=O)O)cn3C)CCN2)cc1C
Temperature: 100 °C
Yield: 70.7 %

Procedure:
A stirred suspension of 1.47 g of ethyl 9-[3-(3,4-dimethylphenyl)piperazin-1-yl]-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 25 cm3 of ethanol, 3.60 cm3 of 1 N aqueous potassium hydroxide and 15 cm3 of water was heated in the region of 100° C. for 4 hours. The reaction mixture was filtered, evaporated to dryness, the residue was suspended in 100 cm3 of water, the medium was acidified with 3.5 cm3 of a 1 N aqueous hydrochloric acid solution, 10 cm3 of ethanol was added, the medium was heated to 100° C. and filtered at high temperature. The residue was washed 3 times with 25 cm3 of water and then with 10 cm3 of ethanol. 0.98 g of 9-[3-(3,4-dimethylphenyl)piperazin-1-yl]-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted at 325° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([NH:13][C:14](=[O:31])[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][C:16]=3[N+:28]([O-])=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33](O)C>[Pd]>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([N:13]3[C:14](=[O:31])[C:15]4[C:16](=[CH:17][C:18]([N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)=[CH:19][CH:20]=4)[N:28]=[CH:33]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2cc(N3CCN(C)CC3)ccc2c1=O
Reaction time: 16 h

Procedure:
A suspension of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-(4-methylpiperazin-1-yl)-2-nitrobenzamide (0.23 g) and 10% palladium on carbon (0.04 g) in ethanol (30 ml) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate evaporated to dryness to give the title compound as a glass (0.16 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.22 (s, 3H), 2.24 (s, 3H), 2.43 (m, 4H), 2.85 (m, 1H), 3.19 (m, 4H), 6.18 (s, 1H), 6.25 (m, 1H), 6.44 (s, 2H), 7.30 (d, 1H), 7.59 (m, 1H), 7.64 (d, 1H), 7.76 (s, 1H), 8.35 (d, 1H), 9.37 (s, 1H); Mass Spectrum: M+H+ 408.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1.[OH-].[Na+].C1(C)C=CC=CC=1.[Na:34].COC1C=CC2N=C(S(CC3C(C)=C(OC)C(C)=CN=3)=O)NC=2C=1>C(C(C)=O)C>[Na:34].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of 650 mg (1.89 mmol) of (+)5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole in 6.5 mL of methyl ethyl ketone (MEK) in a 50 mL flask was added, at ambient temperature 0.39 mL of a 5M aqueous sodium hydroxide solution. To that mixture was added 13 mL of toluene. The resulting mixture was turbid, so an additional 6.5 mL of MEK was added and the mixture became a clear, yellow solution. This mixture was allowed to stir at ambient temperature overnight. The following morning, several crystals of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt were added to act as seed crystals, but no product crystals formed. A stream of dry nitrogen gas was blown over the mixture to begin removing the solvent After approximately 10 minutes, the product precipitated. The solids were isolated by vacuum filtration and washed with a small amount of diethyl ether. The solids were then placed into a vacuum desiccator to remove the last traces of ether, to yield approximately 500 mg of the desired product as an off-white powder.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(C[N:41]([C:43]3[CH:51]=CC(C(O)=O)=C[CH:44]=3)C)N=2)N=1.O.O.C([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])#N.CCN(C(C)C)C(C)C.C(O)(=O)C(O)=O.C(OP(CCCN)(=O)OCC)C>CN(C=O)C>[CH2:58]([O:57][P:56]([CH2:51][CH:43]([NH:41][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)[CH3:44])(=[O:63])[O:60][CH2:61][CH3:62])[CH3:59]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(CCCN)OCC
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC(C)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 3 hours, when diethyl(aminopropyl)phosphonate oxalate (34.9 mg, 122.6 μmol) was added. The solution was stirred for 2 additional hours, whereupon complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product (65.5 mg) collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount (32.8 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 23.2 mg (75%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 31.9; MS (m/z) 503.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13](C)(C)[CH2:12]1.[CH2:20]([N:24]=[C:25]=[O:26])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)=[O:26])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1(C)C
Product: CCCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 95.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1methyl-dimethyl-piperidin-4-yl)-1H indole and 11.1 mg (0.131 mMol) n-butyl isocyanate, 20.6 mg (96%) of the title compound were recovered.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:36])[N:19]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]3)[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:34]([O:33][C:31]([CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][N:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:16][CH:15]=3)[C:18]2=[O:36])[CH2:30][CH2:29]1)=[O:32])[CH3:35]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCN(CCn2cccc(-c3ccc(C(=O)OCc4ccccc4)cc3)c2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(CCn2cccc(-c3ccc(C(=O)O)cc3)c2=O)CC1
Yield: 50 %

Procedure:
10% Pd—C (360 mg) was added to an ethanol (30 ml) solution of ethyl 1-{2-[3-{4-[(benzyloxy)carbonyl]phenyl}-2-oxopyridin-1(2H)-yl]ethyl}piperidin-4-carboxylate (1.647 g), followed by stirring in a hydrogen atmosphere under normal pressure at room temperature for 27 hours. The reaction mixture was filtered through Celite, washed with THF and ethanol, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 80:20) to obtain 4-(1-{2-[4-(ethoxycarbonyl)piperidin-1-yl]ethyl}-2-oxo-1,2-dihydropyridin-3-yl)benzoic acid (671 mg) as a pale yellow amorphous solid.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([S:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=3)[C:20]#[N:21])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:18]=[C:19]([C:20]4[N:31]=[N:32][NH:33][N:21]=4)[CH:22]=[CH:23][N:24]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(Sc3cc(C#N)ccn3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Sc3cc(-c4nn[nH]n4)ccn3)c2)ccc(C(C)=O)c1O

Procedure:
Employing the procedure essentially as described in Example 1 using 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylsulfanyl]-isonicotinonitrile (380 mg, 0.908 mmol), sodium azide (590 mg, 9.08 mmol), and triethylamine hydrochloride (1.25 g, 9.08 mmol), the title compound is obtained as a white solid (261 mg, 62%): 1H NMR (DMSO-d6) δ 0.760 (t, 3H), 1.39 (sextuplet, 2H), 2.52 (t, 2H), 2.56 (s, 3H), 5.32 (s, 2H), 6.71 (d, 1H), 7.59 (m, 4H), 7.73 (m, 2H), 7.79 (d, 1H), 8.64 (d, 1H), 12.82 (s, 1H); MS (esi negative) m/z 460 (m−1).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:31][CH2:32][CH2:33][CH3:34])=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][N:8]([CH3:27])[C:9](=[O:26])/[CH:10]=[CH:11]/[C:12]1[CH:25]=[N:24][C:15]2[NH:16][C:17](=[O:23])[C:18](C)(C)[NH:19][CH2:20][C:14]=2[CH:13]=1)([CH3:3])[CH3:2].[ClH:35]>C(Cl)Cl.C(OCC)C>[ClH:35].[CH:1]([C:4]1[C:5]([O:31][CH2:32][CH2:33][CH3:34])=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][N:8]([CH3:27])[C:9](=[O:26])/[CH:10]=[CH:11]/[C:12]1[CH:25]=[N:24][C:15]2[NH:16][C:17](=[O:23])[CH2:18][NH:19][CH2:20][C:14]=2[CH:13]=1)([CH3:3])[CH3:2]
Reactant: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)cccc1C(C)C
Reaction time: 18 h
Yield: 91 %

Procedure:
A stirring solution of (E)-N-(3-isopropyl-2-propoxybenzyl)-3-(3,3-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-N-methylacrylamide (0.158 g, 0.362 mmol) in CH2Cl2 (4 mL) under N2 was treated with anhydrous HCl (0.18 mL of a 2.0 M solution in diethyl ether, 0.36 mmol) After stirring for 18 h, the resulting solid was collected by filtration, washed with Et2O (100 mL) and dried to yield the title compound (0.15 g, 91%) as an off white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 11.10-11.07 (m, 1H), 10.07 (br s, 2H), 8.77-8.72 (m, 1H), 8.33-8.24 (m, 1H), 7.63-7.55 (m, 1H), 7.40-7.31 (m, 1H), 7.26-7.21 (m, 1H), 7.13-7.05 (m, 1H), 6.90-6.83 (m, 1H), 4.83-4.67 (m, 2H), 4.28-4.22 (m, 2H), 3.85-3.69 (m, 4H), 3.30-3.25 (m, 1H), 3.14-2.89 (m, 3H), 1.81-1.75 (m, 2H), 1.20-1.17 (m, 6H), 1.06-1.01 (m, 3H); MS (ESI) m/e 437 (M+H)+.