Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([N:16]4[CH2:20][CH2:19][NH:18][C:17]4=[O:21])=[N:14][N:13]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[H-].[Na+].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43]Br)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[O:21]=[C:17]1[N:16]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:14]=2)[CH2:20][CH2:19][N:18]1[CH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=C1NCCN1c1nn(C2CCCCO2)c2cnc(-c3cccnc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)C2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-one (0.120 g, 0.329 mmol) dissolved in N,N-Dimethylformamide (3.43 mL) and cooled to 0° C. was added NaH in Oil (6:4, Sodium hydride:Mineral Oil, 26.3 mg). The reaction mixture was stirred at RT for 30 mins then cooled to 0° C. 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.183 g, 0.659 mmol) was added. The reaction was stirred at RT for 18 hr. The mixture was quenched with H2O then extracted with EtOAc. The organic layers was dried, filtered, and concentrated to give tert-butyl 4-((2-oxo-3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate which was dissolved in 4.0 M of Hydrogen chloride in 1,4-Dioxane (6.00 mL) and 1,4-Dioxane (3.00 mL, 38.4 mmol;) was stirred at RT 18 h. The reaction was concentrated and submitted for rHPLC purification to give 296 (11.6 mg, 9.3% yield). ESI MS m/z=378.2 (M+1). 1H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 9.03 (s, 1H), 8.78 (s, 1H), 8.55 (d, J=4.7 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.50 (dd, J=8.0, 4.7 Hz, 1H), 4.03-3.93 (m, 2H), 3.65-3.56 (m, 2H), 3.11 (d, J=7.2 Hz, 2H), 2.92 (d, J=12.0 Hz, 2H), 2.42 (d, J=10.9 Hz, 1H), 1.79-1.67 (m, 1H), 1.59 (d, J=11.8 Hz, 2H), 1.05 (dd, J=21.5, 9.9 Hz, 2H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:32]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:46]=[CH:45][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:37][C@@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:37][C@@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])=[O:32])=[CH:45][CH:46]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)C)cc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)C)cc2)cc1
Yield: 93.1 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-valine (0.015 g, 0.023 mmol) was dissolved in methanol (3 ml). NABH4 (0.006 g, 0.158 mmol) was added and when the reaction was complete a few drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 25% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.014 g (93%) of the title product was obtained. NMR (500 MHz, CD3COOD) 0.93 (d, 3H), 0.95 (d, 3H), 2.12-2.22 (m, 1H), 2.91-3.07 (m, 2H), 3.75 (s, 1.5H), 3.76 (s, 1.5H), 3.94-4.06 (m, 3H), 4.33 (d, 1H), 4.60 (s, 2H), 4.72-4.78 (m, 1H), 4.81-4.88 (m, 1H), 6.79-6.83 (m, 2H), 6.97-7.08 (m, 4H), 7.20-7.36 (m, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+:26]>CO.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:23][CH:24]=1)([CH3:3])[CH3:2].[Na+:26]
Reactant: CC(C)c1ccc(C(=O)NCCOc2ccc(C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(C(=O)NCCOc2ccc(C(=O)[O-])cc2)cc1
Yield: 70.5 %

Procedure:
4-[2-(4-Isopropylbenzamido)ethoxy]benzoic acid (3.27 g) was dissolved in 50 ml of methanol, a solution of 0.40 g of sodium hydroxide in 5 ml of water was added thereto, the mixture was concentrated in vacuo, and crystallized residue was recrystallised from methanol to give 2.46 g of crystalline product, m.p. not lower than 300° C. IR γmaxKBr (cm-1): 1640, 1605.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O>[O:11]=[C:9]([CH3:10])[C:3](=[N:2][O:1][CH2:18][CH2:19][CH3:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCON=C(C(C)=O)C(=O)OCC
Yield: 81.2 %

Procedure:
To a suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15 g.) and potassium carbonate (19.8 g.) in acetone (75 ml.) was added dropwise propyliodide (16.2 g.) with stirring, and the mixture was stirred at ambient temperature for 1,5 hours. The insoluble substance was collected by filtration and washed with acetone. The washings and the filtrate were combined and evaporated to dryness under reduced pressure. To the resultant residue was added water and the aqueous solution was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2=[N:6][C:7]([S:10][CH3:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:13].[CH2:14](Cl)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>CC#N>[CH3:1][C:2]1[N:12]=[C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[C:7]([S:10][CH3:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:13]
Reactant: O=C(CCl)c1ccccc1
Reactant: CSc1ccc2c(C)c(C)[nH]c2n1
Solvent: CC#N
Product: CSc1ccc2c(C)c(C)nc-2n1CC(=O)c1ccccc1
Yield: 41.2 %

Procedure:
A mixture of 2,3-dimethyl-6-methylthiopyrrolo[2,3-b]pyridine (100 mg, 0.5 mmol) and phenacyl chloride (804 mg, 5 mmol) in 3 ml CH3CN was refluxed for 72 h. The solvent was evaporated and the residue chromatographed (silica, CH2Cl2 /MeOH;59/5). Pure fractions were pooled, evaporated, and taken up in 100 ml CH2Cl2. The organic layer was washed with 25 ml 2M HCl, dried over MgSO4, and evaporated leaving 64 mg (35%) pure product as the hydrochloride.
Reaction SMILES: [N:1]#[N:2].C(O[C:11]([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:12])C1C=CC=CC=1.[CH2:42]([O:49][C:50]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55](=[O:57])[NH2:56])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.[Pd]>[N:1]#[N:2].[CH2:42]([O:49][C:50]([NH:52][C@H:53]([C:11]([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:33][CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:23])[CH3:24])=[O:12])[CH2:54][C:55](=[O:57])[NH2:56])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)[C@H](O)C[C@@]2(C(N)=O)CCCN2C(C)(C)C)cc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)[C@H](O)C[C@@]2(C(N)=O)CCCN2C(C)(C)C)cc1
Yield: 31.1 %

Procedure:
A solution of 1.58 g of N2 -[3(S)-(benzyloxyformamido)-4-(4-tert.butoxyphenyl)-2(R)-hydroxybutyl]-N1 -tert.butyl-L-prolinamide in 200 ml of ethanol was hydrogenated over 100 mg of 10% palladium-on-carbon for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to give an oil which was coupled with 0.74 g of N-(benzyloxycarbonyl)-L-asparagine in a manner analogous to that described in Example 1. The crude product was chromatographed on a column of silica gel using 10% methanol in dichloromethane for the elution. There was obtained 0.59 g of N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-4-(4-tert.butoxyphenyl)-2(R)-hydroxybutyl]-N1 -tert.butyl-L-prolinamide as a white solid; MS: m/e 654 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=O.[Cl-].[C:31]([CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:32].O>ClCCl>[C:31]([CH:33]=[CH:3][C:5]1[C:14]2[O:15][C:16]3([C:26]([CH3:28])([CH3:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[CH3:29])[CH:17]=[N:18][C:13]=2[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)#[N:32]
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=CC#N)cc3ccccc13)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of a 50% strength sodium hydroxide solution is added to a solution of 0.36 g (1 mmol) of the compound of Example 1 and of 0.34 g (1 mmol) of cyanomethyltriphenylphosphonium chloride in 3 ml of dichloromethane. The mixture is stirred at ambient temperature for 1 hour. 10 ml of water are then added and the aqueous phase is extracted with twice 10 ml of dichloromethane. The organic phase is washed, dried and evaporated. A purification is performed on a silica column (CH2Cl2 eluent).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:13][NH2:14])=[O:8]
Reactant: NN
Reactant: COC(=O)c1cncc(Br)c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cncc(Br)c1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
To a solution methyl 5-bromonicotinate (5 g, 23 mmol) in ethanol (40 mL) was added hydrazine hydrate (6 mL, 115 mmol). The reaction mixture was refluxed at 90° C. for 4 h. After this time, the reaction mixture was evaporated to dryness and then redissolved in ethyl acetate. The organic layer was washed with water, dried and evaporated to yield 5-bromonicotinohydrazide (3.4 g, 72%). LCMS Method T: retention time 0.573 min; [M+1]=216.0, 218.0.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1)(C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C=C.C(=O)([O-])[O-:25].[Na+].[Na+]>O1CCCC1>[CH2:15]([N:14]([CH2:19][CH3:18])[C:1](=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of allyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature under nitrogen for 2 days. The reaction solution was poured into ice water/ethyl acetate and separated. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica gel. The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane, and the second isomer was obtained with 1.6% ethanol in dichloromethane. Fractions containing the second isomer were combined and the solvent removed in vacuo to give 1.44 g of 4-(αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[C:14]([O:20][CH2:21][C:22](N)=[S:23])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C(OCC)(=O)C>S1(CCCC1)(=O)=O>[CH3:16][C:15]([CH3:18])([CH3:17])[C:14]([O:20][CH2:21][C:22]1[S:23][C:4]2[C:5]([N:11]=1)=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][N:3]=2)=[O:19]
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)C(=O)OCc1nc2cc([N+](=O)[O-])cnc2s1
Temperature: 105 °C
Yield: 16.7 %

Procedure:
A mixture of 6 g (29.48 mmol) of 2-chloro-3,5-dinitropyridine and 7.74 g (44.22 mmol) of 2-amino-2-thioxoethyl pivalate in 50 mL of sulfolane is heated for 2 hours at 105° C. After this time, 150 mL of ethyl acetate are added to the mixture, and the organic phase is washed three times with 200 mL of water and then once with 100 mL of saturated sodium chloride solution. The organic phase is then separated out, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 1.45 g of a yellow solid are obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[F-:11].[Cs+]>CS(C)=O.O>[F:11][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cccc(Cl)c1C#N
Reactant: [F-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(F)c1C#N
Temperature: 140 °C
Yield: 65.7 %

Procedure:
A mixture of 2-chloro-6-methylbenzonitrile (5 g, 33.0 mmol) and CsF (14 g, 92.2 mmol) in DMSO (30 ml) was heated at 140° C. for 15 hr and then allowed to cool to room temperature. It was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and concentrated to give 2-fluoro-6-methylbenzonitrile (2.93 g, 66%). A mixture of the above nitrile (250 mg), 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (200 mg, 0.76 mmol) and Raney Ni (50% in water, 100 mg) in glacial acetic acid (15 ml) was shaken in a Parr apparatus under H2 (40 psi) for 7 hr. The catalyst was removed by filtration and the solvent was evaporated. Chromatography on silica gel (hexane/ethyl acetate=2:1) afforded the title compound (146 mg). 1H-NMR (CDCl3): 1.30 (t, J=7.5 Hz, 3H), 2.46 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 3.92 (bs, 1H), 4.38 (s, 2H), 6.58 (s, 1H), 6.78 (d, J=8.6 Hz, 2H), 6.99 (t, J=6.8Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.19-7.38 (m, 4 H), 8.20 (d, J=7.8 Hz, 1H), 8.56 (d, J=3.7Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH:20]([CH3:22])[CH3:21])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([N:8]([CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C@H:7]([CH:20]([CH3:21])[CH3:22])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine t-butyl ester (4.38 g, 13.0 mmol) in dimethylformamide (200 mL) is added 3-picolyl chloride hydrochloride (2.3 g, 14.0 mmol) followed by potassium carbonate (17.94 g, 130.0 mmol). The reaction mixture is stirred at room temperature for 2 days. The mixture is then diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate) to give t-butyl 2(R)-[N-[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanoate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[S:8][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
2.5 g of methanesulfonyl chloride was dropped into a solution of 5.0 g of 2-amino-4,5-diphenylthiazole and 3.3 ml of pyridine in dichloromethane under stirring at room temperature, and the resulting mixture was stirred as such overnight. Then the reaction mixture was successively washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using isopropyl ether and ethyl acetate as a developer. The crystals thus obtained were recovered by filtration from isopropyl ether and washed with diethyl ether to give 1.6 g of 2-methanesulfonylamino-4,5-diphenylthiazole. The melting point of this product was from 225° to 227° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: NC(=O)N1CCNCC1
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C(N)=O)CC3)nn12

Procedure:
The title compound was prepared in analogy to Example 3 using 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B) and piperazine-1-carboxamide instead of piperazin-2-one (tR 3.17 min (conditions 1), MH+=438, 1H-NMR in DMSO-d6: 8.95 (d, 1H); 8.46 (d, 1H); 7.80 (d, 1H); 7.65 (d, 1H); 7.61 (s, 1H); 7.60 (m, 1H); 7.08 (d, 1H); 6.07 (s, 2H); 4.98 (m, 1H); 3.15-3.40 (m, 8H); 1.88 (d, 3H)).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH3:26])(=O)=O.O>CS(C)=O>[CH2:26]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:25][CH2:24][CH:23]=[CH:22][CH3:21]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC=CCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of theobromine (2.16 g, 12 mmol) and sodium hydride (288 mg, 12 mequivalents) in dimethylsufoxide (10 mL) was stirred for 30 minutes and then a solution of 1-methansulfonyloxy-4-hexene in dimethylsulfoxide (10 mL) was added. After 84 hours of stirring, water (70 mL) is added and the mixture extracted with ether (3×50 mL). The combined extracts were washed with water (50 mL) and dried over magnesium sulfate. The solvent was then evaporated under vacuum. The residue was purified by flash chromatography (22 g silica gel using an ethyl acetate eluant, 500 mL), yielding 2.1 g (67%) 1-(4-hexenyl)-3,7-dimethylxanthine. To a solution of 1-(4-hexenyl)-3,7-dimethylxanthine (270 mg, 1.03 mmol) in dichloromethane (10 mL) was added saturated aqueous sodium bicarbonate solution (10 mL), followed by a solution of 50-60% 3-chloroperoxybenzoic acid (889 mg, 2.58 mmol) in dichloromethane (5 mL) over 1 minute. After 20 hours of stirring, 20% aqueous sodium metabisulfite solution (15 mL) was added over 1 minute. The mixture was then extracted with dichloromethane (3×15 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (3×20 mL) and dried over magnesium sulfate. The sovent was evaporated under vacuum. The residue was purified by flash chromatography using 14 g of silica gel and eluting with ethyl acetate (100 ml) followed by 8% methanol-dichloromethane (60 mL), yielding 80 mg (28% yield) of 1-(4,5-oxohexyl)-3,7-dimethylxanthine as a white powder.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCCCC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCCCCC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.054 g, 0.15 mmol) was reacted with cycloheptanone (0.84 g, 7.5 mmol) in N,N-dimethylacetamide (1mL) in a sealed tube at 135° C. for 45 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether (3 mL) and filtered to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][C:33]=1[CH3:42]>>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:34][C:33]=1[CH3:42]
Reactant: Cc1cc(S(=O)(=O)Cl)cnc1Cl
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cnc1Cl

Procedure:
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 6-chloro-5-methylpyridine-3-sulfonyl chloride (270 mg), the title compound was obtained as a solid (yield 244 mg, 68%).