Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][CH:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: CC1CCC(CC(=O)O)CC1
Product: COc1ccc(-c2nn(NC(=O)CC3CCC(C)CC3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 151A and 2-(4-methylcyclohexyl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.37-8.44 (m, 1H), 7.86-8.04 (m, 2H), 7.74-7.80 (m, 1H), 7.51-7.55 (m, 2H), 7.10-7.14 (m, 2H), 3.85 (s, 3H), 2.23-2.34 (m, 2H), 1.95-2.09 (m, 1H), 1.77-1.88 (m, 1H), 1.42-1.72 (m, 5H), 1.20-1.35 (m, 2H), 0.88-1.06 (m, 1H), 0.92 (d, J=6.7 Hz, 3H); MS (ESI+) M/Z 406 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:44]1[O:45][CH:46]=[CH:47][CH:48]=1)CCC>O1CCOCC1.C(OCC)(=O)C.C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:4]=[CH:3][C:2]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:7][N:6]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(OCCOc3ncc(-c4ccco4)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 86.7 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl)]4-(tert-butyl)benzenesulfonamide (Example 3) (277 mg) in 1,4-dioxane (7.5 ml) at room temperature was added 2-(tributylstannyl)furan (329 mg) and bis(triphenylphosphine)palladium (II) chloride (32 mg) the mixture was stirred and heated to reflux for 16 hrs. The reaction was diluted with ethyl acetate (100 ml) and washed with a 10% solution of potassium fluoride in water (100 ml), the aqueous portion was then extracted with ethyl acetate (100 ml). The organic fractions were separated and combined, washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (3:2) to yield an oil which was dissolved in acetonitrile (20 ml) and washed with hexane (6×10 ml). Evaporation of the acetonitrile under reduced pressure yielded the title compound as a white solid (235 mg).
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.[ClH:17].N([O-])=O.[Na+].[S:22](=[O:24])=[O:23]>C(O)(=O)C.O>[Cl:17][S:22]([C:6]1[CH:5]=[CH:4][C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:2][CH:1]=1)(=[O:24])=[O:23]
Reactant: O=S=O
Reactant: Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 0.08 h

Procedure:
5.2 g (20.4 mmol) of sulfathiazole was added to a mixed solution of 14 ml of water and 3.4 ml of concentrated hydrochloric acid and the mixture was stirred. To the mixture was added dropwise an aqueous saturated solution of 2.1 g (30.4 mmol) of sodium nitrite at 0° C. or less. Then, 5 ml of acetic acid was added thereto, followed by stirring at 5° C. for about 10 minutes. An acetic acid solution saturated with sulfur dioxide (solution prepared by saturating 18 ml of acetic acid with sulfur dioxide and then adding 830 mg of cupric chloride.dihydrate thereto) was added dropwise to the reaction solution at 0° C. under stirring. After 5 minutes, the reaction solution was poured into ice-water. The precipitates were collected by filtration, washed with water and dried, to give 2.9 g of 4-chlorosulfonyl-N-(2-thiazolyl)benzenesulfonamide. 570 mg (1.68 mmol) of the product was reacted with 200 mg (1.2 mmol) of the compound of Production Example 1a in the same manner as in Production Example 4a and treated, to give 456 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[C:8]1([CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:21][C:17]=2[C:18](O)=[O:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH:23]=[CH:24][C:16]=2[O:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[N:3]1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Reactant: Cn1cc(N)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cn1cc(NC(=O)c2cc(-c3ccncc3)ccc2OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1-methyl-1H-pyrazol-4-amine (38.2 mg, 0.39 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 100 mg, 0.33 mmol), EDC (188 mg, 0.98 mmol) and HOBT (150 mg, 0.983 mmol) in dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (20 ml) was added, and the mixture was extracted with ethyl acetate (20 ml×2). The organic phase was dried over Na2SO4, and concentrated in vacuo to give crude product, which was purified by prep-HPLC (Gilson GX-281; waters X-Bridge 5 μm 30*100 mm; A: 0.1M NH3.H2O/Water; B: CH3CN) twice to yield the title compound as a white solid. 58 mg.
Reaction SMILES: [CH3:1][C:2]1([NH:18]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C:2]([NH2:18])([CH3:1])[CH2:3][CH2:4]1)=[O:47]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(C)(NC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1N1CCCC(C)(N)CC1
Yield: 74 %

Procedure:
Following the procedure for Example 101 starting from tert-butyl 4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonyl-amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave 412 as a pale brown solid (87 mg, 74% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.13 (t, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.39-7.30 (m, 1H), 7.26-7.11 (m, 2H), 6.11 (s, 2H), 3.75 (s, 3H), 3.40-3.18 (m, 3H), 3.17-3.09 (m, 1H), 1.98-1.89 (m, 1H), 1.90-1.71 (m, 5H), 1.23 (s, 3H). Exchangeable NH2 not observed. LCMS (ES+) m/z 444 (M+1)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[CH3:12][O:13][CH:14]([O:20]C)[CH2:15][C:16](OC)=O>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][CH:16]=[C:15]2[C:14]([O:13][CH3:12])=[O:20]
Reactant: COC(=O)CC(OC)OC
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1c[nH]c2ccc(OC)cc12
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 110.2 %

Procedure:
4-Methoxyphenylhydrazine hydrochloride (200 mg) and methyl 3,3-dimethoxypropionate (194 mg) were added to acetic acid (8.0 ml) and stirred for 4.5 hours at 70° C. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; ethyl acetate:n-hexane 1:5→1:3) to give methyl 5-methoxy-1H-indole-3-carboxylate (259 mg, Y.:97%).
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[CH2:11]([N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[S:25]C=[CH:27][CH:28]=2)=[C:18]([O:29][CH3:30])[CH:17]=1)[CH2:12][CH2:13][CH3:14]>CN(C)C=O>[C:5]([C:4](=[C:3]([C:1]1[S:25][C:24]([CH:23]=[CH:22][C:19]2[CH:20]=[CH:21][C:16]([N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][C:18]=2[O:29][CH3:30])=[CH:28][CH:27]=1)[C:9]#[N:10])[C:7]#[N:8])#[N:6]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C(C#N)=C(C#N)C#N)s2)c(OC)c1
Temperature: 50 °C
Yield: 41.8 %

Procedure:
In 7 ml of N,N-dimethylformamide, 235 mg (1.83 mmol) of tetracyanoethylene was dissolved. With stirring under ice cooling, 600 mg (1.75 mmol) of dibutyl[3-methoxy-4-[2-(thiophene-2-yl)vinyl]phenyl]amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 1.5 hours. After the ice bath was removed, the mixture was stirred at room temperature for 1 hour and further stirred with heating at 50° C. overnight. After the reaction mixture was poured into 80 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with methanol to give 324 mg of a dark reddish crystal having a mp of 189-192° C. (yield: 41.8%).
Reaction SMILES: NC1CC2[C:5](=CC=CC=2)[N:4](CC2CO2)[C:3]1=O.[Cl:17][C:18]1[S:44][C:21]2[NH:22][C:23]([C:25]([NH:27][CH:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:38][CH:39]([OH:42])[CH2:40]O)[C:29]3=[O:43])=[O:26])=[CH:24][C:20]=2[CH:19]=1>>[Cl:17][C:18]1[S:44][C:21]2[NH:22][C:23]([C:25]([NH:27][CH:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([CH2:38][CH:39]([OH:42])[CH2:40][N:4]([CH3:5])[CH3:3])[C:29]3=[O:43])=[O:26])=[CH:24][C:20]=2[CH:19]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: NC1Cc2ccccc2N(CC2CO2)C1=O
Product: CN(C)CC(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21

Procedure:
The title compound was prepared by a two-step coupling-epoxide opening sequence. Standard amide bond formation analogous to Method 3 except using 3-amino-1-(oxiran-2-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (Method 19) as amine and 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9) as the acid component formed the title compound as a white solid which was used without further purification. The crude amide product (150 mg) was dissolved in EtOH (5 mL) followed by addition of dimethylamine in EtOH (5.0–6.0 M in EtOH, 0.5 mL) and the reaction was stirred overnight under argon. The reaction was diluted with EtOAc (40 mL) and sat. aqueous NaHCO3 (20 mL) and the separated organic layer was dried (MgSO4), filtered and evaporated to dryness. Purification by column chromatography (MeOH:DCM 2:9) afforded the title compound (41 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(=O)OC.O.[NH2:38][NH2:39]>>[C:33]([N:25]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:39][N:38]=2)[CH:23]=[N:24]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1-c1ccccc1)OC
Solvent: O
Product: CC(C)(C)n1ncc(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)c1-c1ccccc1

Procedure:
light yellow solid. MS (EI): 386.3 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-phenyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCCC1.O>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@H]1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
D-hPro-OH (5.0 g, 38.7 mmol) was dissolved in tetrahydrofuran (100 mL) and water (30 mL). The pH of the solution was adjusted to 9.5 with 2N NaOH and benzyl chloroformate (5.5 mL, 38.7 mmol) was added dropwise and the pH maintained at 9.5 with 2N NaOH. The reaction was stirred for an additional 1 hour at room temperature. The organic solvent was evaporated in vacuo, and diethyl ether (100 mL) and water (50 mL) were added to the residue. The aqueous layer was separated, the pH of the aqueous solution was adjusted to 2.8 with 3N HCl, and ethyl acetate (150 mL) was added. The organic layer was separated and dried (MgSO4) and the filtrate was concentrated in vacuo to give 9.6 g (95%) of a clear oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC=CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hexen-l-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:3].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.CN1[C:35](=[O:36])CCC1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]1[O:3][C:35](=[O:36])[N:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:28])([F:29])[F:17])=[CH:25][CH:24]=2)[N:27]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CN1CCCC1=O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1nn(-c2ccc(OC(F)(F)F)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.43 mL of dodecyl chloroformate was cautiously added dropwise to a mixture consisting of 0.84 g of 4-trifluoromethoxyphenylhydrazine, 15 mL of NMP and 2 mL of pyridine while cooling in ice, and the mixture was then stirred for 2 hours while slowly warming to room temperature. After dilution with 50 mL of water, extraction by shaking was carried out with 30 mL of methylene chloride, the organic phase was dried with sodium sulfate and, while stirring and cooling in ice, 5 mL of pyridine and 3 mL of a 20% strength solution of phosgene in toluene were added dropwise. This mixture was allowed to stand overnight at room temperature and was diluted with a further 10 mL of methylene chloride and then washed 3 times with water. After drying over sodium sulfate, the mixture was concentrated in vacuo and the product was purified by column chromatography (silica gel, solvents:methanol:methylene chloride=2:98).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[C:15]([CH3:21])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:36][CH2:37][C:38](=[O:41])[CH2:39][CH3:40]>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:11][CH3:12])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:38]([CH2:39][CH3:40])([OH:41])[CH2:37][CH3:36])=[C:15]([CH3:21])[CH:14]=2)[CH2:22][CH3:23])=[CH:6][C:5]=1[CH3:24]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C
Reactant: CCC(=O)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C)CC
Yield: 70.7 %

Procedure:
4-[1-Ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-benzoic acid methyl ester (2.50 g, 7.47 mmol), lithium hexamethyldisilazide (8.22 ml, 8.22 mmol, 1.0 M in THF) and 3-pentanone (870 μL, 8.22 mmol) are reacted and purified analogous to Example 1H to give the title compound (2.22 g, 71%).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)c1ccccc1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N[C@H](C(=O)N(C)C)c2ccccc2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.45 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.92 g of the compound obtained in Step 87-2 (5.16 mmol, crude form) as starting materials, 1.09 g (Isomer A, colorless amorphous) and 1.31 g (Isomer B, colorless amorphous) of the respective diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[N:11]=[CH:10][NH:9][C:8]=3[C:7](=[O:13])[NH:6][C:5]2=[O:14])[CH2:3][CH2:2]1.[H-].[Na+].[H][H].Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH:1]1([N:4]2[C:12]3[N:11]=[CH:10][N:9]([CH2:20][CH2:21][CH3:22])[C:8]=3[C:7](=[O:13])[NH:6][C:5]2=[O:14])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc[nH]c12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(=O)[nH]c(=O)n2C1CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
9.6 g (0.05 mol) of 3-cyclopropylxanthine were suspended in 150 ml of dimethylformamide and slowly deprotonated using 1.45 g (0.06 mol) of sodium hydride. When evolution of hydrogen was at an end, the solution was heated to 60° C. and treated dropwise with 6.77 g (0.055 mol) of bromopropane. After stirring at 70° C. for 3 hours, the solution was filtered, the dimethylformamide was evaporated under reduced pressure and the residue was crystallized from diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:4].[CH3:33]I>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])[N:11]([CH3:33])[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(NC(=O)C(F)(F)F)C(=O)C1CCC(C)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)N(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (1.6 g, 3.4 mmol) in THF (17 mL) was added K-OtBu (4.1 mmol, 1.0 M in THF), followed by MeI (1.0 g, 6.8 mmol). After stirring at rt for 16 h the reaction was diluted with EtOAc washed once with 20 mL of brine and purified by silica gel chromatography 0-20% EtOAc/hexanes to give 5-(3,3-dimethyl-but-1-ynyl)-3-[N′-methyl-N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester. This was then diluted with EtOAc (20 mL) and treated with NaOH (6.8 mL of 2M aq solution) to give 5-(3,3-Dimethyl-but-1-ynyl)-3-[N′-methyl-N-(4-methyl-cyclohexanecarbonyl)-hydrazino]-thiophene-2-carboxylic acid.
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.[CH3:47][N:48]([CH3:57])[CH2:49]CC1CCCCN1>>[CH3:47][N:48]([CH3:57])[CH2:49][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1
Reactant: CN(C)CCC1CCCCN1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CN(C)CCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B8 was prepared following the procedure reported for B4 using A1 and rac-2-(2-(dimethylamino)ethyl)piperidine and obtained as a white crystalline solid; yield: 230 mg (61%). MS (ES) C19H29N7O2S requires: 419. found: 420 (M+H)+.
Reaction SMILES: C(Cl)Cl.[CH:4]1([N:10]2[C:18]3[C:17](=O)[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:34][CH3:35])=[N:14][C:13]=3[C:12]([CH3:36])=[N:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1.[OH2:50]>>[CH:4]1([N:10]2[C:18]3[C:17](=[O:50])[NH:16][C:15]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][CH:29]([N:32]([CH3:33])[C:37](=[O:39])[CH3:38])[CH2:28][CH2:27]5)=[CH:22][C:21]=4[O:34][CH3:35])=[N:14][C:13]=3[C:12]([CH3:36])=[N:11]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CNC1CCN(c2ccc(-c3nc4c(C)nn(C5CCCCC5)c4c(=O)[nH]3)c(OC)c2)CC1
Reactant: O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(N2CCC(N(C)C(C)=O)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a 4 ml methylene chloride solution of 105 mg (0.23 mmol) of the compound obtained in Example 92, 33 μl (0.35 mmoml) of acetic anhydride and 33.7 μl (0.47 mmoml) of pyridine were added, and the mixture was stirred at room temperature for 1 hour. Then, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=60/1) to obtain 92 mg (80%) of the captioned compound.