Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][S:22]([N:19]2[CH2:20][CH2:21][CH:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=3[CH3:15])[CH2:17][CH2:18]2)(=[O:23])=[O:24])=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccc(Cl)cc3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution {4-[1-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (28.5 mg, 0.057 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (27.3 mg, 1.14 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (1.1 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum. This crude product was further purified using preparative reverse-phase HPLC to give {4-[1-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (11.2 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 7.90 (dd, J=9.00, 6.50 Hz, 1H), 7.78-8.11 (m, 1H), 7.69 (s, 1H), 7.50 (s, 4H), 7.36 (td, J=9.00, 2.50 Hz, 1H), 4.53 (br. s, 2H), 3.64-3.86 (m, 5H), 2.91-3.19 (m, 3H), 2.41 (br. s., 3H), 2.15-2.35 (br. s, 1H), 1.61-1.73 (m, 2H). MS cald. for C25H25ClFNO4S [(M+H)+]: 490, obsd. 490.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:33][C:34]([F:41])([F:40])[CH2:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:33][C:34]([F:41])([F:40])[CH2:35][S:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of Example 3 (0.05 g, 0.151 mmol) and triethylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0 mL) was added dropwise 2,2,2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol). The reaction mixture was stirred for 1 hour at room temperature and then purified by flash chromatography (silica gel, 0-5% methanol in dichloromethane) to afford 0.050 g (68%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H) 4.55 (q, J=9.91 Hz, 2H) 6.28 (t, J=2.38 Hz, 1H) 6.86 (d, J=7.54 Hz, 2H) 6.95-7.07 (m, 2H) 7.20-7.31 (m, 5H) 7.40 (d, J=2.78 Hz, 1H) 10.43 (s, 1H) 12.02 (s, 1H). MS (APCI+) m/z 478 [M+H]+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CC#CC(CC(=O)O)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Yield: 20.59 %

Procedure:
Compound 85 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.2 g, 0.74 mmol) and methyl 3-(4-hydroxyphenyl)hex-4-ynoate (0.16 g, 0.74 mmol) by following the procedure described in scheme 28 (0.03 g, yield: 20.59%); Purity: 98.37%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[C:20]([O:36][CH3:37])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2/[CH:11]=[C:12]1\[O:13][C:14]2[C:21]([CH2:22][N:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[C:20]([O:36][CH3:37])[CH:19]=[CH:18][C:15]=2[C:16]\1=[O:17]
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccc(Br)cc13)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccc(Br)cc13)C2=O
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-bromo-1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.160 g, 0.281 mmol) in methylene chloride (4 mL) was added with trifluoroacetic acid (4 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated, and then added with water (10 mL) and saturated aqueous sodium hydrogencarbonate (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-[(5-bromo-1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0860 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:40])=[O:39]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2-chlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 552.7 ([M+H]+)
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:6])[CH2:4]Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>CO.O.O>[Cl:1][CH2:2][C:3](=[O:6])[CH2:4][S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(SCC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,3-dichloro-2-propanone (12.70 g, 0.1 mol) in methanol/water (100 ml, 1:3) at 0° C. is added a suspension of 3-methoxybenzenethiol (14.02 g, 0.1 mol) and sodium hydroxide (4.00 g, 0.10 g) in water (100 ml). The mixture is stirred at 0° C. for 7 h and at mom temperature for 10 h. The precipitated product is extracted with dichloromethane (100 ml), washed with water (80 ml), and dried with sodium sulfate. After removal of the solvent, we obtained the good product (oil, 18.70 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[C:21]([NH2:24])=[N:22][O:23][C:19]=2[CH:18]=1>>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[C:21]([NH:24][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[C@H:3]3[OH:14])=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Nc1noc2cc(Cl)ccc12
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Nc2noc3cc(Cl)ccc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 6-chloro-benzo[d]isoxazol-3-ylamine (prepared by literature known method) as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](O)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:21][NH:22][CH3:23].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([N:22]([CH3:23])[CH3:21])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccccc1Oc1ccc2[nH]ncc2c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
The 2-(1H-indazol-5-yloxy)benzoic acid (80.8 mg, 0.318 mmol) synthesized in Example 479 and dimethylamine hydrochloride (33.7 mg, 0.413 mmol) were dissolved in N,N-dimethylformamide (2 ml), and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (72.5 mg, 0.380 mmol), hydroxybenzotriazole (47.1 mg, 0.349 mmol) and triethylamine (0.13 ml, 0.954 mmol) were added thereto at room temperature and then stirred for 2.5 hours. After the reaction, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 2-(1H-indazol-5-yloxy)-N,N-dimethylbenzamide (51 mg, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([Cl:27])[C:21]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:28][C:21]2[C:20]([Cl:19])=[CH:25][C:24]([F:26])=[CH:23][C:22]=2[Cl:27])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1c(Cl)cc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2c(Cl)cc(F)cc2Cl)ncn1
Temperature: 80 °C
Reaction time: 7 h
Yield: 61.4 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.20 g of 2,6-dichloro-4-fluorophenol, followed by stirring at 80° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(2,6-dichloro-4-fluorophenoxy)pyrimidine (the present compound (160)).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CN(C)C=O>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[N:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[S:6][N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(-c2cccs2)ns1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccs3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 5-chloro-3-(2-thienyl)-1,2,4-thiadiazole (4.80 g, 23.7 mmol) and tert-butyl piperazine-1-carboxylate (4.41 g, 23.7 mmol) in dimethylformamide (50 ml) was added triethylamine (13.2 ml, 94.7 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 4.33 g (51.9%) of the desired product as a solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:9]2[C:8]=1[Br:17].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:17][C:8]1[C:9]2[N:10]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:11]=[CH:12][C:7]=1[NH:6][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1cn2ccc(N)c(Br)c2n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccn2cc(C)nc2c1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A mixture of sodium bicarbonate (0.74 g, 8.81 mmol) and amine 18 (1.00 g, 4.42 mmol) in 50 mL of dry CH2Cl2 was treated over a period of fifteen minutes with ethyl chloroformate (2.40 g, 22.1 mmol). 4-Dimethylaminopyridine (0.08 g, 0.65 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Then, water (25 mL) was added and the solution was extracted with CH2Cl2 (3×25 mL). The extracts were dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford in order of elution: compound 19 (461 mg, yield: 35%); mp 137-138° C.; 1H NMR (200 MHz, CDCl3) δ 1.34 (t, 3H, J=7 Hz), 2.45 (s, 3H), 4.26 (q, 2H, J=7 Hz), 7.24 (brs, 1H), 7.31 (s, 1H), 7.81 (d, 1H, J=7.4 Hz), 7.92 (d, 1H, J=7.4 Hz); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 14.4, 60.8, 102.5, 109.7, 111.3, 125.1, 133.3, 142.4, 143.0, 153.8. Starting material 18 (0.31 g, 31%).
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[CH:54]=[CH:53][C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([C:38](=O)[C:39]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[N:48]=[CH:47][CH:46]=[CH:45]4)=[O:40])=[CH:30]2)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:54]=[CH:53][C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([C:38](=[S:10])[C:39]([NH:41][C:42]3[CH:43]=[C:44]4[C:49](=[CH:50][CH:51]=3)[N:48]=[CH:47][CH:46]=[CH:45]4)=[O:40])=[CH:30]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc2ncccc2c1)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2ncccc2c1)C(=S)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 75 °C

Procedure:
3.68 g (9.1 mMol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide are added, under nitrogen, to a suspension of 4.00 g (9.1 mMol) of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-quinolin-6-ylacetamide in 200 ml of toluene, after which the mixture is heated at 75° C. for 3 h. The residue which has formed is filtered off in the hot from the reaction solution and subsequently washed with 100 ml of methylene chloride. The filtrate is concentrated in vacuo and the residue is chromatographed on flash silica gel (eluent: methylene chloride/methanol 99:1). The product fractions are filtered on flash silica gel (eluent: n-heptane/ethyl acetate 1:1) after the solvent has been removed once more.
Reaction SMILES: [CH2:1]([N:8]([C:30]1[CH:31]=[C:32]([CH:57]=[CH:58][CH:59]=1)[C:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:44][CH2:45][CH2:46][C:47]([O:49]CC2C=CC=CC=2)=[O:48])[CH:36]=1)=[O:34])[CH:9]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCOCC1.[Pd]>[CH2:1]([N:8]([C:30]1[CH:31]=[C:32]([CH:57]=[CH:58][CH:59]=1)[C:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH:36]=1)=[O:34])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cc1ccc(C(c2ccc(CC(C)C)cc2)N(Cc2ccccc2)c2cccc(C(=O)c3cn(CCCC(=O)OCc4ccccc4)c4ccccc34)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(C(c2ccc(CC(C)C)cc2)N(Cc2ccccc2)c2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzyl 4-[3-[3-[N-benzyl-N-[bis(4-isobutylphenyl)methyl]amino]benzoyl]indol-1-yl]butyrate (24 mg) was dissolved in a mixture of methanol 93 mi) and 1,4-dioxane (3 ml), and 10% palladium on carbon (12 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel (2 g) eluting with a mixture of chloroform and methanol (50:1) to give 4-[3-[3-[N-benzyl-N-[bis(4-isobutylphenyl)methyl]amino]benzoyl]indol-1-yl]butyric acid as (14 mg) powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:32])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=O)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:41]1.NN.CCOC(C)=O>CN(C=O)C>[C:21]([C:20]1[CH:19]=[N:18][N:17]2[CH:24]=[C:25]([C:27]([NH:40][NH2:41])=[O:29])[CH:26]=[C:16]2[C:15]=1[NH:14][C@@H:11]1[CH2:12][CH2:13][C@@:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:32])[C:10]1([CH3:31])[CH3:30])(=[O:23])[NH2:22]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C1(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C1(C)C
Yield: 106.4 %

Procedure:
A solution of 4-(((1R,3S)-3-((tert-butoxycarbonyl)amino)-2,2,3-trimethylcyclopentyl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (3.0 g, 6.73 mmol), BOP (3.57 g, 8.08 mmol) and hydrazine (1.057 mL, 33.7 mmol) in DMF (25 mL) was stirred for 30 minutes, and then the reaction mixture was added 350 mL of EtOAc which was washed with 10% LiCl solution (2×100 mL), 100 mL of brine and dried over Na2SO4. Filtration and concentration gave the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (3.29 g, 99% yield). HPLC retention time=2.457 min., LC/MS (M+H)+=460.4.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[S:14][C:13]4[N:15]=[CH:16][CH:17]=[N:18][C:12]=4[N:11](COC)[C:10]=3[CH:22]=2)=[N:4][N:3]=[N:2]1>C(O)(=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[S:14][C:13]4[N:15]=[CH:16][CH:17]=[N:18][C:12]=4[NH:11][C:10]=3[CH:22]=2)=[N:4][N:3]=[N:2]1
Reactant: COCN1c2cc(-c3nnn[nH]3)ccc2Sc2nccnc21
Solvent: CC(=O)O
Product: c1cnc2c(n1)Nc1cc(-c3nnn[nH]3)ccc1S2
Yield: 52.4 %

Procedure:
40 mg of 8-(tetrazol-5-yl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was heated 5 ml of glacial acetic acid to 60° C. for 30 minutes. After the completion of the reaction, silica gel was added thereto. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/acetic acid) to thereby give 18 mg of the title compound as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC=CC=1.[C:34]1(=O)[O:39][C:37](=[O:38])[CH2:36][CH2:35]1.C(N(CC)CC)C>C(OCC)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:1]5[C:37](=[O:38])[CH2:36][CH2:35][C:34]5=[O:39])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)O1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)N1Cc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 80 °C

Procedure:
A mixture of 200 mg (0.537 mmol) of 3(3-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5) and 10 ml of toluene is concentrated by evaporation in vacuo for the purpose of removing water and, after repetition of that operation, the residue is taken up in 10 ml of toluene. After the addition of 59 mg (0.59 mmol) of succinic anhydride and 0.082 ml (0.59 mmol) of triethylamine, the reaction mixture is heated for 1 hour at 80° C. and for 18 hours under reflux. A further 21 mg (0.21 mmol) of succinic anhydride and 0.041 ml (0.2949 mmol) of triethylamine are added to the reaction mixture which is heated for a further 6 hours under reflux, then cooled to room temperature and 10 ml of diethyl ether are added. Filtration, purification of the filter residue by flash chromatography (silica gel having a particle size of 0.04-0.06 mm; eluant: ethyl acetate), concentration of the product-containing fractions by evaporation in vacuo and recrystallization of the residue from methanol yield 4-(3-chloro-phenylamino)-3-(3-[succinimido-methyl]-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 7.72%; m.p. 140-142° C.; ESI-MS: (M−H)−=446.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][C:20]2[S:21][C:22]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.CSC.N>ClCCl>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:23]1[N:24]=[C:20]([NH:19][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:18])[S:21][C:22]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N
Solvent: CSC
Solvent: ClCCl
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Compound 43 (4.71 g, 9.50 mmol) was dissolved in dichloromethane (100 mL), and dimethyl sulfide (29.4 mL, 400 mmol) and boron trifluoride-diethyl ether complex (24.6 mL, 200 mmol) were added thereto, followed by stirring overnight at room temperature. The reaction mixture was poured into 28% aqueous ammonia, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford the entitled Compound 44 (1.36 g, 38%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:30]=[CH:29][O:28][N:27]=1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:25][C:26]5[CH:30]=[CH:29][O:28][N:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reactant: Nc1ccon1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CNc3ccon3)ccc1-2
Yield: 52 %

Procedure:
Following the procedure for 119, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and 3-amino-isoxazole were reacted. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) gave 284 as a white solid (154 mg, 52%). LCMS: RT=10.79 min, [M+H]+=409. 1H NMR δ (ppm) (CDCl3): 8.33 (1H, d, J=8.10 Hz), 8.04 (1H, d, J=1.68 Hz), 7.90 (1H, s), 7.16 (1H, d, J=8.19 Hz), 7.06 (1H, s), 5.93-5.84 (1H, m), 5.85-5.83 (1H, m), 4.42 (2H, s), 4.38 (2H, t, J=5.02 Hz), 3.42-3.36 (2H, m), 1.60 (6H, d, J=6.62 Hz). 1 Exchangeable proton not seen.