Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:38])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][CH2:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[C:21]=1[F:35])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:40]([C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([OH:46])=[O:45])[NH2:41]>>[CH3:32][N:31]([CH3:33])[C:30]([CH2:29][O:28][C:22]1[C:21]([F:35])=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:38])[N:40]([C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44]([OH:46])=[O:45])[N:41]=2)[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=1)=[O:34]
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c1
Yield: 60.2 %

Procedure:
The same procedure was carried out as in Example (2f), except that 0.409 g of {2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methyl -[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester was used instead of the [2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (2f), and 0.160 g of 2-hydrazinobenzoic acid hydrochloride was used instead of (1-oxypyridin-2-yl)hydrazine, to give the title compound (0.280 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([O-:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1cc(F)cc(F)c1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cc(F)cc(F)c4)ccc31)C1CCC(C2)N1
Yield: 13 %

Procedure:
Intermediate 21 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3,5-difluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (40 mg, 13%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.17 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 6.91-6.96 (m, 1H), 5.26 (br s, 1H), 4.71 (br s, 1H), 3.62 (s, 3H), 3.39 (br s, 1H), 2.48 (d, J=16.0 Hz, 1H), 2.18-2.35 (m, 2H), 1.91-1.99 (m, 1H), 1.50-1.68 (m, 1H), 1.37 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.Cl.Cl.[CH:49]([N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1)([CH3:51])[CH3:50]>CN(C=O)C>[CH:49]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[O:23])[CH2:54][CH2:53]1)([CH3:51])[CH3:50]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1cc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2cc3cccnc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.135 g (0.4 mmol) of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, 0.432 g (3.8 mmol) of NEM and 135 mg (0.4 mmol) of TOTU were dissolved in 3 mL of DMF and stirred at RT for 20 min. 89 mg (0.4 mmol) of 1-Isopropyl-piperidin-4-ylamine dihydrochloride salt was added to the reaction solution and stirred at RT for 4 h. The product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1.[OH-:17].[Na+].C[OH:20]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:20])=[O:17])=[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1
Reactant: COc1ccc(C#N)c(-c2ncccn2)c1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(-c2ncccn2)c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-(pyrimidin-2-yl)benzonitrile (85 mg, 0.4 mmol) was dissolved in MeOH (20 mL) was treated with 2M aq NaOH (15 mL). The reaction was heated at reflux overnight, the reaction was cooled to room temperature and filtered to remove the solids and washed with cold MeOH. The filtrate was concentrated to minimum volume and then acidified to pH=3 with 6 N aq. HCl and cooled to 0° C. then filtered and washed with cold water. This material was used crude in subsequent reactions.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3]1>CO.C(Cl)(Cl)Cl.C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH:4]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCc2ccccc2O1
Reaction time: 24 h
Yield: 83.3 %

Procedure:
A solution of ethyl 4-oxo-4H-1-benzopyran-2-carboxylate (2.0 g, 9.17 mmol) in methanol (60 ml), chloroform (25 ml) and glacial acetic acid (20 ml) was added with 10% palladium-on-charcoal and the mixture was left under stirring at room pressure and temperature for 24 h. under hydrogen atmosphere. After that, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was redissolved in ethyl ether and washed successively with a 5% sodium bicarbonate solution and a sodium chloride saturated solution. The mixture was dried and the solvent was evaporated off under reduced pressure, to obtain 1.575 g of the title product (84% yield).
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:32])[N:12]([CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=3)[O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl>[C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:32])[N:12]([CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=3)[O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:44])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)Oc1cccc(SCCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1cccc(S(=O)CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Yield: 94.3 %

Procedure:
To a solution of ethyl 2-[3-({3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl}sulfanyl)phenoxy]propanoate (175 mg) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (82 mg) at 0° C. for 20 minutes. The resulting mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane: EtOAc=1:1-1:10) to afford ethyl 2-[3-({3-[5-(diphenylmethyl)-2-oxopyridin-1(2H)-yl]propyl}sulfinyl)phenoxy]propanoate (170 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)C=O.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:15]([O:16][CH3:17])[O:14][CH3:13])[CH:9]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
A mixture of 5-chloro-2-nitro-benzaldehyde (0.0792 mol), trimethoxy-methane (0.126 mol) and PTSA (0.00079 mol) in methanol (80 mL) was refluxed until the 5-chloro-2-nitro-benzaldehyde had completely reacted. The mixture was cooled, Na2CO3 was added, and the reaction mixture was stirred for 5 min. The mixture was filtered and the filtrate was evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH2:9]([C:16]1N=[N:18][C:19](Cl)=[C:20]([CH3:23])[C:21]=1[CH3:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:25]N1C(=O)CCC1>C(Cl)Cl>[CH2:9]([C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[N:18][CH:25]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC1CCNCC1
Reactant: CN1CCCC1=O
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)cnc(N2CCC(CO)CC2)c1C
Temperature: 210 °C
Reaction time: 2 h

Procedure:
To the solution of piperidin-4-yl-methanol (125 mg, 1.03 mmol) in NMP (3 mL) is added 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (60 mg, 0.258 mmol) and TEA. The reaction mixture is stirred at 210° C. in a microwave reactor for 2 h. Then the reaction mixture is diluted with DCM (15 mL) and washed with NaHCO3 and water. The organic solvent is separated and removed under reduced pressure. Purification by HPLC of the crude product with acetonitrile in water (from 20% to 100% with 3% 1-propanol) at 220 nm wavelength detection provides the desired product as off white powder (200 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:40])[C@@H:29]([NH2:39])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][CH2:23]1)=[O:21])[CH3:18].C(Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:40])[C@@H:29]([NH:39][C:14]([C:10]2[CH:11]=[C:12]([OH:13])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:9]=2)=[O:16])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(O)n(-c2cccc(F)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.500 g 1-(3-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid (prepared by standard procedure using 3-fluorophenylhydrazine hydrochloride and sodium diethyl-2-oxosuccinate followed by ester hydrolysis) and 3.864 g 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml DMF 1.723 g HOBt, 1.9 ml DIPEA and 2.157 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:40][CH3:41])[CH2:25][CH2:26][N:27]([CH2:29][C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=O)[C:33]2=[CH:32][CH:31]=1)[CH3:28])[CH3:23].Cl>C1COCC1>[CH2:40]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][N:27]([CH2:29][C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:33]2=[CH:32][CH:31]=1)[CH3:28])[CH3:41]
Reactant: CCN(CC)CCN(C)Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCN(C)Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (125 mg, 0.83 mmol.) in THF (4 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.66 mL of a 1M solution in THF, 1.66 mmol) dropwise. The resulting solution is stirred for 20 min at room temperature. A solution of 2-{[(2-diethylamino-ethyl)-methyl-amino]-methyl}-7H-furo[3,4-b]pyridin-5-one (115 mg, 0.41 mmol) in THF (1.5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred at room temperature for 4 h and then poured into 10% aqueous HCl solution (30 mL) previously cooled to 0° C. The ice bath is removed and the solution is stirred at room temperature for 16 h. The yellow solution is then cooled and solid NaHCO3 is carefully added to adjust the solution to pH=8. The aqueous layer is extracted with EtOAc. The combined organic extracts are dried with anhydrous Na2SO4 and concentrated. The solid residue is broken up in isopropyl alcohol to give a yellow solid. The yellow solid is collected by filtration to give the title compound (102 mg, 61%).
Reaction SMILES: N[CH2:2][C:3]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:14]=[C:8]2[CH:7]=1)([CH3:5])[CH3:4].[CH3:29]O.C=O.[BH3-][C:34]#[N:35].[Na+]>C1COCC1.C(O)(=O)C>[CH3:29][N:35]([CH3:34])[CH2:2][C:3]([C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:14]=[C:8]2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(CN)c1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Reactant: CO
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)CC(C)(C)c1ccn2c(-c3ccnc(N)n3)c(-c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 28 mL Pyrex-Plus tube containing amine 28 (Example 3, 170 mg, 0.452 mmol) was charged with methanol (2.0 mL), then acetic acid (170 □L), then formaldehyde (110 mg of a 37% aqueous solution, 1.35 mmol), then NaBH3CN (2.26 mL of a 1.0M solution in THF, 2.26 mmol). After stirring at room temperature for 1 hour, the reaction mixture was injected directly onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated arnmonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure, yielding 140 mg of dimethylamine 29. This sample was dissolved in 5 mL methanol and purified on an HPLC column, from 5×1.0 mL injections, using a gradient that started at 40% methanol and 60% water and ended at 100% methanol. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 29: 104 mg (57%). 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 6H), 2.15 (s, 6H), 2.54 (s, 2H), 5.11 (bs, 2H), 6.54 (d, J=5.5 Hz, 1H), 7.06 (dd, J=7.3, 2.0 Hz, 1H), 7.13 (m, 2H), 7.67 (m, 3H), 8.12 (d, J=5.5 Hz, 1H), 9.44 (dd, J=7.3, 0.5 Hz, 1H). MS (ESI+) 405.3.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17]OS(C)(=O)=O)(=O)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:30]1[CH2:17][CH2:16][C:8]2[C:7](=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=2)[CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCc1ccc([N+](=O)[O-])cc1COS(C)(=O)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
A solution of [2-[2-[(methylsulfonyl)oxy]ethyl]-5-nitrophenyl]methyl methanesulfonate (Step 1, 1.75 g, 4.95 mmol) in CH2Cl2 (25 mL) under N2 is treated with benzylamine (2.70 mL, 24.75 mmol), and the resulting mixture is stirred at ambient temperature for 24 hrs and then washed with water (20 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is then chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with EtOAc/heptane (10/90), and those fractions with an Rf=0.32 by TLC (EtOAc/hexane, 25/75) are pooled and concentrated to give 1.33 g (100%) of the title compound as an orange solid, mp 85-86° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([NH2:11])[CH:10]=1)[OH:6].CN(C)C1C=CC=CC=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:11][C:9]1[CH:8]=[CH:7][C:5]([OH:6])=[C:4]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:12])=[O:29].[NH2:11][C:9]1[CH:10]=[C:4]([C:3]([OH:12])=[O:2])[C:5]([OH:6])=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCCCCBr
Reactant: COC(=O)c1cc(N)ccc1O
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(NC(=O)CCCCCBr)ccc1O
Product: Nc1ccc(O)c(C(=O)O)c1

Procedure:
was prepared in quantitative yield from 40.0 g (0.24 mol) of methyl-5-aminosalicylate, 32.0 g (0.26 mol) of N,N-dimethylaniline and 46.5 g (0.22 mol) of 6-bromohexanoyl chloride according to the procedure of Example 9, part a. The methyl 5-aminosalicylate was obtained by Fischer esterification of 5-aminosalicylic acid. The product was not recrystallized, but was obtained directly from trituration in 1N HCl, mp 100°-102° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=O.[C:14]([O:17][CH2:18][C:19](Cl)=O)(=[O:16])[CH3:15].C(N(CC)CC)C.C(=O)([O-])O.[Na+].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C(OCC)(=O)C.O1CCCC1>[C:14]([O:17][CH2:18][C:19]1[S:43][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)=[CH:3][N:2]=1)(=[O:16])[CH3:15]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)OCC(=O)Cl
Reactant: NCC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1ncc(-c2ccc(Cl)c(Cl)c2)s1
Reaction time: 1 h
Yield: 19 %

Procedure:
To a suspension of 2-amino-1-(3,4-dichlorophenyl)ethanone hydrochloride (2.18 g, 9.06 mmol) in ethyl acetate (25 mL) was added 2-chloro-2-oxoethyl acetate (0.975 mL, 9.06 mmol), and triethylamine (3.8 mL, 27.2 mmol) was added dropwise under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 min, and at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added and the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (30 mL) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson reagent, 2.56 g, 6.34 mmol) was added to the residue, and the mixture was heated under reflux for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL) and the mixture was stirred for 1 hr, extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give [5-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]methyl acetate (364 mg, 13%) as a colorless oil. The present compound was reacted in the same manner as in Example 1 to give the title compound (260 mg, 83%) as colorless crystals.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9]1([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18](OC)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C>CO.O>[ClH:1].[C:9]1([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([N:4]=[C:3]([NH2:5])[NH2:2])=[O:19])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1cccc(-c2ccccc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: NC(N)=NC(=O)c1cccc(-c2ccccc2)c1
Reaction time: 0.25 h
Yield: 17.6 %

Procedure:
To a solution of guanidine hydrochloride (2.7 g) in methanol (12 ml) was added sodium methoxide (5.13 g, 28% in methanol) and the mixture was stirred for 15 minutes under nitrogen. To this mixture was added a solution of methyl 3-phenylbenzoate (1.20 g) in methanol (2 ml) and the mixture was stirred for 6 hours. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml). The organic layer was successively washed with 5N-sodium hydroxide aqueous solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on alumina (100 ml) and eluted with chloroform-methanol (10:1). The fractions containing the desired product were collected and evaporated in vacuo. The residue was crystallized from 4N-hydrogen chloride-ethyl acetate. The crystalline was recrystallized from ethanol to afford 2-[3-phenylbenzoyl]guanidine hydrochloride (274.0 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>CN(C)C1C=CN=CC=1.CO>[CH2:11]([O:10][C:9]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:13])[CH3:12]
Reactant: NCC1CCNCC1
Reactant: CCOC(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: CO
Product: CCOC(=O)NCC1CCNCC1

Procedure:
The solution of 1.70 g (9.0 mmol) of 4-(ethoxycarbonylamino-methyl)-piperidine (obtained from 4-aminomethyl-piperidine and diethyl carbonate in the presence of 4-dimethylaminopyridine) in 18 ml of methanol was treated with 9.0 ml (9.0 mmol) of 1N methanolic hydrochloric acid. After addition of 0.53 g (3.0 mmol) of 8-methoxy-2-tetralone, the mixture was stirred for a further 5 minutes. 0.20 g (3.3 mmol) of sodium cyanoborohydride was then added and the mixture was stirred for 15 hours at room temperature, followed by standing for 18 days at about +4° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][N:34]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 4 h
Yield: 133.1 %

Procedure:
Methane sulfonyl chloride (10 mg, 0.09 mmol) was added to cold (0-5° C.) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (35 mg, 0.08 mmol) and Et3N (10 mg, 0.1 mmol) in DCM (1 mL); stirring was continued at 25-35° C. for 4 h. Reaction mixture was diluted with DCM, washed with water, aqueous NaHCO3 solution followed by brine to afford the crude compound, which was purified by preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 10% MeOH in CHCl3 as eluent) to afford 53.63 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.90 (1); Lys 0.19 (1); Arg 0.99 (1)