Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:14])[CH:3]=1.[O:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.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>[F:14][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COCOc1cc(C=O)c(F)cc1Br
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)c(F)cc1-c1ccoc1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
4-Bromo-2-fluoro-5-methoxymethoxy-benzaldehyde (160 mg, 0.61 mmol) and 3-furanboronic acid (100 mg, 0.90 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) and Cs2CO3 (400 mg, 1.23 mmol) were mixed in N,N-dimethylformamide (10 mL) and degassed and then heated at 100° C. for 1 hour. The mixture is allowed to cool to room temperature and an aqueous work up is performed. The residue is purified to afford the desired product (60 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:1][CH2:2][CH2:3][CH3:4])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Solvent: ClCCl
Product: CCCCOC(=O)Cc1ccc(C)cc1
Reaction time: 36 h
Yield: 176.9 %

Procedure:
To a stirred solution of 4-methylphenylacetic acid (20.6 g, 137 mmol) in methylene chloride (100 mL) in a pressure flask cooled on a dry-acetone bath was added isobutene (190 mL) followed by concentrated sulfuric acid (2.5 mL). After 36 hours, the mixture was cooled (dry ice/acetone bath) and isobutene was removed in a slow stream of nitrogen. The residue was treated with 10% NaHCO3, and extracted with methylene chloride (3×100 mL). The combined methylene chloride extract was washed with 10% NaHCO3 and brine, and dried (Na2SO4). Evaporation of the solvent gave t butyl 4-methylphenylacetate as a colorless oil (25 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[O:4][C:5]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:6][N:7]=1.COC1C(OC)=NS(=O)(=O)N=1.CN(C)C1OC(CSC[CH2:35][NH:36][C:37]2[C:41](OC)=[N:40][S:39](=[O:45])(=[O:44])[N:38]=2)=NN=1.CN>>[CH3:1][N:2]([CH3:13])[C:3]1[O:4][C:5]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:41]2[C:37]([NH:36][CH3:35])=[N:38][S:39](=[O:45])(=[O:44])[N:40]=2)=[N:6][N:7]=1
Reactant: COC1=NS(=O)(=O)N=C1NCCSCc1nnc(N(C)C)o1
Reactant: CN(C)c1nnc(CSCCN)o1
Agent: CN
Agent: COC1=NS(=O)(=O)N=C1OC
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nnc(N(C)C)o1

Procedure:
When the above amine is reacted with an equimolar amount of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide, and the resultant 3-{2-[(2-dimethylamino-1,3,4-oxadiazol-5-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an excess of methylamine, the title compound is thereby produced.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](OCC(=O)OC(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 16.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7-diene (150 mg, 0.267 mmol) was treated in tetrahydrofuran (2.7 ml) with sodium hydride (60% in oil, 65 mg, 1.625 mmol), 15-crown-5 (16 mg, 0.268 mmol) and tert-butyl bromoacetate (316 mg, 1.62 mmol) in the same manner as shown in Example 17(1) (heated at reflux for 17 hours), followed by work up and separation using preparative thin layer chromatography (0.5 mm×5 plates, hexane:ethyl acetate=5:1, developed once and then 0.5 mm×2 plates, hexane:ethyl acetate=7:1, developed twice) to give the titled compound (30 mg, 17%) as a colorless foam.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:21][C:15]1[CH:14]=[C:13]([CH:10]([C:9](=[O:22])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:24][CH:23]=2)[O:11][CH3:12])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C(OC)C(=O)NCc2ccc(C#N)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (0.303 g) at rt in DMF (3 ml) were added K2CO3 (0.14 g) and ethyl bromoacetate (0.169 g). The reaction mixture was then stirred at rt under an argon atmosphere for 5 h 45. The mixture was diluted with EtOAc (25 ml), washed with water (25 ml) and brine (25 ml), dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude product as a light yellow gum. The product was purified by chromatography (Silicagel (20 g) using a gradient profile: cyclohexane to cyclohexane/EtOAc 35:65) to give (RS)-{5-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.342 g) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C@@:12]([CH2:19][O:20][C:21](=[O:36])[N:22]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:18])[CH2:13]2)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C@@:12]([CH2:19][O:20][C:21](=[O:36])[N:22]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:18])[CH2:13]2)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cccc2c1CC[C@](O)(COC(=O)N(c1ccccc1)c1ccc(F)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc2c1CC[C@](O)(COC(=O)N(c1ccccc1)c1ccc(F)cc1)C2
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To a solution of (2R)-5-[(ethoxycarbonyl)methoxy]-2-[(N-4-fluorophenyl-N-phenylcarbamoyloxy)methyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (80 mg) in ethanol (5 ml) was added 1N-NaOH solution (0.2 ml). After being stirred for 4 hours at the same temperature, the solvent was removed in vacuo. The residue was washed with 1N-HCl solution and brine. The dried solvent was removed in vacuo to give (2R)-5-(carboxymethoxy)-2-[(N-4-fluorophenyl-N-phenyl-carbamoyloxy)methyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (32 mg).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4O[CH:21]=[N:20][C:19]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH2:26])=O>O>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:26]=[CH:21][NH:20][C:19]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: Cc1ncoc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O

Procedure:
A mixture of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(4-methyloxazol-5-yl) methyl]-1H-pyrido[4,3-b]indol-1-one (180 mg) and formamide (20 ml) was heated at 180° for 18 h. The solution was then cooled (0°), diluted with water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were concentrated in vacuo and purified by FCC eluting with System A (100:8:1) to give the title compound (110 mg), m.p. 230°-233°.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=O)[CH2:15][CH2:14]1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:20][CH2:19][CH:16]2[CH2:17][CH2:18][S:13][CH2:14][CH2:15]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=CCC1CCSCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 541 mg (tetrahydro-thiopyran-4-yl)-acetaldehyde (3.75 mmol) were dissolved in 7.5 ml methanol and stirred for 30 min at rt and then refluxed for 2.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was refluxed for 2¾ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:2 then EtOAc) to give 632 mg light yellow viscous oil (87%). MS (ISP) 292.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[Na+].Br[CH2:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[C:13]([CH3:18])=[CH:12][CH:11]=1.O>C1COCC1>[C:16]([C:14]1[N:15]=[C:10]([CH2:9][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH:11]=[CH:12][C:13]=1[CH3:18])#[N:17]
Reactant: Cc1ccc(CBr)nc1C#N
Reactant: CNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(C)c(C#N)n1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of N-methylacetamide (416 mg, 5.69 mmol) in THF (15 mL) at room temperature was treated with NaH (228 mg, 5.69 mmol), stirred for 15 min, treated with 6-bromomethyl-3-methylpyridine-2-carbonitrile (1.0 g, 4.74 mmol), stirred for 16 h, poured into water (50 mL), extracted with EtOAc (3×15 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (665 mg, 69%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.15 (3H, s), 2.53 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.43 (1H, d, J 8.0 Hz) and 7.61 (1H, d, J 8.0 Hz); M/Z 204 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:2]=1.S(Cl)(Cl)=O.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccncc1)c1cccnc1Oc1cccnc1
Temperature: 25 °C

Procedure:
A solution of 2-(Pyridin-3-yloxy)-nicotinic acid (0.0664 grams, 0.31 mmole) in thionyl chloride (1.12 ml, 15.4 mmole) was heated to 50° C. After 1.5 hours the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Pyridine (2.5 ml) was added followed by C-Pyridin-4-yl-methylamine (47 μl, 0.47 mmole) at room temperature. After 2 hours the mixture was concentrated to remove pyridine. The crude product was purified by chromatography on silica gel eluting with 9/1 ethyl acetate/methanol to give a solid. (0.0331 g). M.P. 142-144° C.; Anal. calcd. for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29. Found: C, 66.40; H, 4.56; N, 17.94.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[F:19])[C:3]=1[CH3:20].[CH:21]([C:24]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)[O:26][N:25]=1)([CH3:23])[CH3:22].CC(C)([O-])C.[K+].Cl.CCOCC>C1COCC1.C(Cl)Cl>[F:19][C:10]1[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:4]1[C:3]([CH3:20])=[C:2]([O:35][CH:32]2[CH2:33][CH2:34][N:29]([C:27]3[O:26][N:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[N:28]=3)[CH2:30][CH2:31]2)[N:7]=[CH:6][N:5]=1
Reactant: Cc1c(Cl)ncnc1Nc1ccc(S(C)(=O)=O)cc1F
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(Nc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Yield: 30 %

Procedure:
A mixture of (6-chloro-5-methyl-pyrimidin-4-yl)-(2-fluoro-4-methanesulfonyl-phenyl)-amine (HCl salt, 1.76 g, 5.0 mmol) and 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.05 g, 5.0 mmol) in anhydrous THF (10 mL) was treated with potassium t-butoxide (20 mL, 20 mmol), placed under inert atmosphere, and refluxed for 4 hours, at which point the reaction had stalled at 60% conversion. The reaction mixture was cooled, quenched with water (30 mL), and extracted with ether (2×50 mL). The combined organic extract was rinsed with water (20 mL), followed by brine (20 mL), and was dried over MgSO4. After solvent removal, the residue was rinsed with boiling ether (2×20 mL), and the combined rinses were set aside to cool. Crystallization yielded a white solid (91% pure by LCMS) which was triturated in hot ether and filtered hot to furnish Compound A93 as a white solid in >95% purity (731 mg, 30% yield). This material was taken up in CH2Cl2 (10 mL), to which was added 1 N HCl/ether (1.5 mL). Upon solvent removal, a light gray foam was obtained (800 mg): 1H NMR (DMSO-d6) δ 10.26 (brs, 1 H), 8.77 (s, 1 H), 8.22 (s, 1 H), 7.83-7.71 (m, 3 H), 5.33 (m, 1 H), 3.75 (m, 2 H), 3.57 (m, 2 H), 3.37 (s, 3 H), 2.83 (m 1 H), 2.13 (s, 3 H), 2.04 (m, 2 H), 1.78 (m, 2 H), 1.20 (d, 6 H, J=6.9 Hz), MS m/z 491.2 (M+).
Reaction SMILES: C(=[N:4][N:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)C(OC(C)(C)C)=O)(C)C.[ClH:21]>C1COCC1>[ClH:21].[ClH:21].[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:5][NH2:4])=[CH:15][CH:16]=1
Reactant: CC(C)=NN(Cc1ccc(C)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(CNN)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mechanically stirred solution of tert-butyl 2-isopropylidene-1-(4-methylbenzyl)hydrazinecarboxylate (crude product from Step 2) in THF (950 mL) and HCl (3N aq., 360 mL) was warmed to reflux. After being stirred for 3 h, the yellow solution was cooled to rt and concentrated to a white solid. The crude material was dried under high vacuum overnight, was suspended in Et2O, and was filtered to provide the title compound as a crystalline white solid (87.8 g, 87% for 2 steps): 1H NMR (300 MHz, d6-DMSO) δ 2.27 (s, 3H), 4.00 (s, 2H), 7.17 (d, 2H), 7.29 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1ccc(CN2C(=O)CCCC2c2c(OC)cccc2OC)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(chloromethyl)-4-methoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.72 min.; [M+H]+: 356.26 g/mol.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16]1>ClCCl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22]
Reactant: CC(C)(S)CN
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
To a suspension of 1-Amino-2-methylpropane-2-thiol hydrochloride (1.41 g, 10 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.5 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and glutaric anhydride (1.14 g, 10 mmol) in anhydrous dichloromethane (20 mL) was added at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The solvent was evaporated at reduced pressure and the residue was extracted with ethyl acetate and water. The combined ethyl acetate extracts were washed with 1 N HCl, dried over sodium sulfate and solvent was evaporated at reduced pressure to give colorless oil, which upon trituration with ethyl ether/hexane gave 1.57 g of the title compound as a colorless powder in 72% yield, mp 101-104° C.; 1H NMR (CDCl3): δ1.31 (s, 6H), 1.94 (m, 2H), 2.22-2.38 (m, 4H), 3.33 (d, J=6.1 Hz, 2H), 6.28 (s, 1H), 9.2 (br s, 1H; LRMS (APIMS) (m/z) 220 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N+:14]([O-])=[C:13]([Cl:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([O:23][CH:16]1[C:15]2[N:14]=[C:13]([Cl:19])[CH:12]=[CH:11][C:10]=2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ccc(Cl)[n+]2[O-])C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC1CN(C(=O)OC(C)(C)C)Cc2ccc(Cl)nc21
Temperature: 70 °C
Yield: 66.4 %

Procedure:
A solution of 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine 1-oxide (150 mg, 0.53 mmol) in acetic anhydride (2.5 mL, 26.3 mmol), was stirred and heated at 70° C. overnight under nitrogen atmosphere. DCM (20 mL) was added to the reaction mixture, and the resulting solution was washed sequentially with water, saturated aqueous NaHCO3 solution and brine, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 0% to 30% EtOAc in hexane to give the title compound (115 mg, 66.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (9H, s), 2.13 (3H, s), 3.30-3.49 (1H, d, J=12.0 Hz), 4.25-4.40 (1H, m), 4.45-4.55 (1H, d, J=12.0 Hz), 5.20-5.00 (1H, m), 5.73 (1H, br. s), 7.34 (1H, d, J=8.22 Hz), 7.51 (1H, d, J=8.41 Hz) ppm; LC/MS m/z: 327 (M+1).
Reaction SMILES: [NH3:1].[C:2]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=S)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O=O>CC([O-])=O.CC([O-])=O.[Cu+2].CO>[C:2]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:1])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CO
Solvent: O
Product: N=C(Nc1ccccc1)Nc1ccccc1

Procedure:
The amount of ammonia is varied in the following examples. 0.2 mol of diphenylthiourea and ammonia together with 75 g of water, 75 g of methanol, and 0.1 mmol of Cu(OAc)2 are reacted with oxygen (1.5 bar). The other experimental conditions and diphenylguanidine yields are shown in Table 3.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:33]1(S(N2CCNCC2)(=O)=O)[CH:38]=[CH:37]C=[CH:35][CH:34]=1>>[C:32]1([S:29]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:11])=[CH:20][CH:19]=4)=[O:22])[CH2:28][CH2:27]2)(=[O:30])=[O:31])[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)c5ccccc5)CC4)cc3c2)CC1
Yield: 92 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-benzenesulfonyl-piperazine to afford the desired product as a light-brown foam (92%). MS (ISP): 524.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[CH2:3]([S:10][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)OCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCSCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (0.45 g, 60% in mineral oil, 11.1 mmol) in DMF (5 mL) is added benzylmercaptan (1.43 mL, 11.03 mmol) and the resulting yellow solution is stirred at RT for 30 min. The mixture is cooled to 0° C. then acetic acid 4-bromobutyl ester (2.2 g, 11.2 mmol) is added dropwise (exothermic). The mixture is allowed to warm to RT and is quenched with 1N HCl (35 mL). The mixture is extracted with MTBE and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using EtOAc/hexane (4:1) as eluent to give the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.005 g, 14.7%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.41 (m, 4H), 2.55-2.62 (m, 4H), 3.52-3.55 (2 s, 4H, 2NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.67 (m, 4H), 3.68 (m, 3H, imidazole Me), 6.80 (s, 1H, imidazole 4-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): R=1.79 min—551/553 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 551.1882, calculated for C26H32N8OBr (M+H)+: 551.1882.