Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C([O:10][C:11]1[C:15]([C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:14]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:13]([CH:33]([CH3:35])[CH3:34])[N:12]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH:33]([N:13]1[C:14]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:11](=[O:10])[NH:12]1)([CH3:34])[CH3:35]
Reactant: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Oc2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2c(Oc3ccccc3)n(C(C)C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
Sodium borohydride (10 mg) was suspended in tetrahydrofuran (1 mL) and to the stirred suspension was added dropwise a solution of 3-benzyloxy-1-isopropyl-4-(4-methoxybenzoyl)-5-phenoxy-1H-pyrazole (24 mg) in tetrahydrofuran (4 mL) under ice cooling. The mixture was stirred at room temperature for 3 hours and 1 mL of 10% citric acid aqueous solution was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated sodium hydrogen carbonate and brine. After the solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the obtained residue was dissolved in ethanol (5 mL). To the stirred solution was added 10% palladium carbon powder under ice cooling and the suspension was stirred at room temperature for 6 hours under hydrogen atmosphere at normal pressure. Insoluble material was removed by filtration and the solvent of filtrate was removed under reduced pressure to give the title compound (10 mg).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C3(C)CCOCC3)cc2)cn1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 486 (M++1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[C:20]([I:21])=[C:19]([CH3:22])[NH:18][N:17]=1>C(Cl)Cl>[I:21][C:20]1[C:16]([CH3:15])=[N:17][N:18]([C:5](=[O:7])[CH3:6])[C:19]=1[CH3:22]
Reactant: Cc1n[nH]c(C)c1I
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1nc(C)c(I)c1C
Yield: 84.2 %

Procedure:
Acetic anhydride (0.51 mL, 5.4 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added to a solution of 3,5-dimethyl-4-iodopyrazole (1 g, 4.5 mmol) in CH2Cl2. After 1 h the reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with 1 N HCl, saturated NaHCO3, brine, dried over Na2SO4, and concentrated to give the title compound as a white solid (1 g, 85%).
Reaction SMILES: CN(C=O)C.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=O)=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:24])=O>ClCCl>[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([Cl:24])(=[O:20])=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)c1ccc(N2CCCC2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Yield: 19 %

Procedure:
DMF (0.5 mL) was added to solution of 4-(pyrrolidin-1-yl)benzenesulfonic acid (7.3 g, 32.16 mmol) in dichloromethane (40 mL). Oxalyl chloride (10 g, 78.74 mmol) was then dropwise and the resulting solution was maintained at room temperature for 1 hour. The reaction mixture was then quenched by the addition of 40 mL of iced water. The resulting solution was extracted using dichloromethane (3×20 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 1.5 g (19%) of 4-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.78 (d, 2H), 6.55 (d, 2H), 3.41 (t, 4H), 2.03 (t, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.C.OO.[C:11]([OH:14])(=[O:13])[CH3:12]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(=O)C=CC(=O)C=C1>[C:11]([O:14][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]=[C:2]1[CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CC1=CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)C=C1
Product: CC(=O)OC1CCCC=C1C
Reaction time: 2 h
Yield: 50 %

Procedure:
Acetoxylation of 1-methylcyclohexene A 500 ml three-neck flask is charged with 15 g of 1-methylcyclohexene (0.15 moles), 150 g of acetic acid, 0.77 g of benzoquinone (7 mmoles), 1 g of active charcoal and 80 mg of palladium acetate (0.35 mmoles). The temperature is taken to 50°, then 8 g (0.17 moles) of 70% by weight hydrogen peroxide are introduced in 8 h, and the reaction is allowed to proceed for a further 2 h while maintaining the temperature at 50°. The acetic acid is then distilled (35°, 20×102Pa). The residue is distilled under vacuum (75°-80°, 15×102Pa) to provide 2-methyl-cyclohex-2-en-1-yl acetate (11 g, yield 50%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[CH2:19][C:20](OC)=[O:21]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:20](=[O:21])[CH:19]=1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: COC(=O)CC(=O)c1ccco1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccco2)[nH]c2cc(-c3ccccc3)nn12
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-amine (90: 0.318 g, 2.0 mmol, 1.0 eq) and methyl 3-(furan-2-yl)-3-oxopropanoate (0.370 g, 2.2 mmol, 1.10 eq) was heated in acetic acid (2.0 mL) at 100° C. for 4 hr. After cooling down to rt, the precipitate was collected by filtration. The precipitate was rinsed with EtOH (15 mL) and dried under air to afford 5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.358 g, 65%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.06 (m, 1H), 8.00 (m, 1H), 7.98 (m, 1H), 7.51-7.47 (m, 3H), 7.44-7.42 (m, 1H), 6.81 (dd, J=3.7, 1.8 Hz, 1H), 6.64 (s, 1H), 6.15 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][CH:23]3[CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccc(C#CC3CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(CCC3CC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopropylethyl)-3-methylnaphthalen-2-yl)acetic acid (92) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.60 (m, 3H), 7.35 (m, 2H), 7.06 (s, 1H), 5.21 (s, 1H), 2.72 (t, J=7 Hz, 2H), 2.62 (s, 3H), 1.48 (m, 2H), 0.94 (s, 9H), 0.65 (m, 1H), 0.37 (m, 2H), 0.01 (m, 2H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5.0 min run): tR (min)=4.02.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:8]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(OCC)(=O)C>C(Cl)Cl>[C:39]1([S:45]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([C:14]4[C:15]([C:20]5[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=5)=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:8]=3)[CH2:3]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a solution of the title F compound (4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide, 0.100 g, 0.250 mmol) in methylene chloride (10 mL) is added diisopropylethyl amine (0.036 g, 0.280 mmol) followed by benzenesulfonyl chloride (0.046 g, 0.260 mmol). After 1 h, the reaction mixture is poured into ethyl acetate and washed with 1 N HCl, 8% NaHCO3 solution, water, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give an oil which is purified by silica gel chromatography. Drying under vacuum at 60° C. gives 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)-amide as a non-crystalline solid; mp 96° C. sinters. MS (ES+), m/z 537 (M+1), 554 (M+NH4+).
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[C:4]([OH:9])(=[O:8])[C@H:5]([CH3:7])[OH:6]>O>[C:4]([O-:9])(=[O:8])[CH:5]([CH3:7])[OH:6].[Ca+2:2].[C:4]([O-:9])(=[O:8])[CH:5]([CH3:7])[OH:6]
Reactant: C[C@H](O)C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(O)C(=O)[O-]

Procedure:
External skeletons of Hemicentrotus pulcherrimus, from which ovaries had been already extracted, were washed with water and dried spontaneously, and then baked in a baking furnace at about 1,100° C. for one hour to give calcium oxide, which was fully hydrated and converted into calcium hydroxide. 1,000 g of thus obtained calcium hydroxide was dissolved in 10 liter of water, about 5,000 g of 50% L-lactic acid was added and reacted at a temperature of 75° C. for 15 min to produce calcium lactate from sea urchin shells. In this case, lactic acid was added in such a little stoichiometrically excessive amount that the pH value of the aqueous solution be at a prescribed value in a range of about 5 to 6 after the reaction, and the reaction process was finished at the time the pH value was settled. To this aqueous solution, 150 g of reducing maltose and about 15 g of chondroitin sulfate composition at 20% purity (ratio of 20% chondroitin sulfate composition to calcium: about 0.5%, ratio of chondroitin sulfate (100%) to calcium: about 0.6%) were added, and dried by a spray-drier to give highly water-soluble particles of 60 μm or less in average diameter which were almost white and had a slightly peculiar taste.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C@@:20]([OH:32])([CH3:31])[CH2:21][N:22]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[N:24]=[C:23]3Cl)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C@:20]3([CH3:31])[O:32][C:23]4=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:22]4[CH2:21]3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: C[C@](O)(COC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate prepared in Example 93 (1.29 g, 2.5 mmol) in DMF (13 ml), sodium hydride (0.12 g, 3 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice water was added, and the precipitates were filtered off, washed with water and recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate (0.70 g, yield 59%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:28][N:29]([CH3:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.C(O)(=O)C>CN(C=O)C>[CH2:17]([NH:16][C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:29]([CH3:28])[CH3:39])=[CH:38][CH:37]=3)[CH:20]=[CH:19][C:9]=2[N:10]=1)=[O:15])[CH3:18]
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)c3ccc(N(C)C)cc3)cc2s1
Yield: 25 %

Procedure:
Similar to the synthesis of Example 248, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 4-dimethylaminobenzoyl chloride in DMF was reacted to give the desired compound 0.025 g (25%) as an acetic acid salt. LC/MS 440.1 (M+1); LC retention time 2.86 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.Cl.[CH3:33][P:34]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[C:39]([O:44][CH3:45])[CH:38]=1)([CH3:36])=[O:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:36][P:34]([C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:2]2[N:3]=[C:4]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:6]=3[N:7]=2)=[C:39]([O:44][CH3:45])[CH:38]=1)([CH3:33])=[O:35]
Reactant: COc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: COc1cc(P(C)(C)=O)ccc1Nc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c2ccn(COCC[Si](C)(C)C)c2n1
Yield: 54 %

Procedure:
To a microwave reaction tube was charged with 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (180 mg, 0.374 mmol), 4-(dimethylphosphoryl)-2-methoxyaniline hydrochloride (105 mg, 0.45 mmol), Pd2(dba)3 (34 mg, 0.0374 mmol), Xanthphos (26 mg, 0.045 mmol), and t-BuONa (129 mg, 1.346 mmol). This mixture was degassed via 3-cycle of vacuum and re-fill with N2. Anhydrous 1,4-dioxane (2 mL from sure-seal bottle) was added and the reaction was then run under microwave irradiation at 140° C. for 20 min. Water and EtOAc was added to facilitate extraction. Chromatography on silica gel (10% MeOH in CH2Cl2 as eluent) gave the desired product in 54% yield (130 mg). MS/ES+: m/z=644.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2.C(N(CC)CC)C.O>CO>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([NH:13][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=3)=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc3[nH]ncc3c2)n1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To the solution of 2-chloro-6-methoxy-3-nitropyridine (5 g) and 5-aminoindazole (3.7 g) in methanol (60 ml) was added triethylamine (4.1 ml), and then the solution was reacted at 25-30° C. for 5 hr. The reaction mixture was cooled at room temperature with slowly adding H2O (30 ml), and then stirred for 0.5 hr. The reaction mixture was filtered, washed with methanol (10 ml), obtained a solid product. The solid product was dried at 50° C. in vacuo to obtain the desired compound (6.5 g, 86%).
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:31])(=O)=O>>[Cl:31][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(NCc1ccc(CO)cc1)c1ccccn1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccc(CCl)cc1)c1ccccn1
Yield: 45.2 %

Procedure:
Reaction of pyridine-2-sulfonic acid 4-hydroxymethyl-benzylamide (140 mg, 0.50 mmol), Et3N (88 uL, 0.60 mmol), and MsCl (47 uL, 0.60 mmol) for 2 h at reflux followed by column chromatography on silica gel (CH2Cl2/MeOH 99:1) gave the title compound (67 mg, 45%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.28 (d, 2H, J=6.0 Hz), 4.54 (s, 2H), 5.17 (br s, 1H), 7.23-7.49 (m, 4H), 7.47-7.52 (m, 1H), 7.88 (ddd, 1H, J=7.5, 7.5, 1.7 Hz), 7.97 (d, 2H, J=7.5 Hz), 8.69 (d, 1H, J=4.8 Hz). ES-MS m/z 319 (M+Na).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CO.O>[CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=[N:22][OH:23])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCc1oc2ccccc2c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of 2-butyl-1-benzofuran-3-carbaldehyde (25 g, 0.124 mol) and sodium acetate (12.2 g, 0.124 mol) in methanol (100 mL) was added hydroxylamine hydrochloride (10.3 g, 0.149 mol) in water (25 mL) at 0° C. The mixture was stirred at rt for 2 h. Water (300 mL) was added to the reaction mixture and the product was extracted with EtOAc. The organic layer was dried and concentrated under vacuum to give crude 2-butyl-1-benzofuran-3-carbaldehyde oxime (25 g, 93%) as a light brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.I[CH:16]([CH3:18])[CH3:17].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH:16]([CH3:18])[CH3:17])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(Cc1cncc(Br)c1)C(C)C

Procedure:
In analogy to the procedure described for the preparation of intermediate A-42, ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11) was reacted with 2-iodopropane in presence of NaH (60% in mineral oil) to give the title compound as white solid after purification by reverse phase HPLC on a Gemini-NX column. MS: 323.1 (M+H+).
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([O:11]C)=O)(=[O:5])=[O:4])[CH3:2].[Cl:13][C:14]1[CH:32]=[CH:31][C:17]2[O:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH2:21][N:22]([C:23]([NH:25][NH2:26])=[O:24])[C:16]=2[CH:15]=1>>[CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([NH:26][NH:25][C:23]([N:22]1[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:11])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)NCCC(=O)OC
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CCS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(ethylsulfonyl)amino]-1-oxopropyl]hydrazide (22) was prepared from N-(ethylsulfonyl)-β-alanine, methyl ester (21), prepared as described above in Example 21, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in the manner described in Example 18 above on a 2.0 mmol scale to yield 0.25 g (28%) of product. Analysis calculated for C19H21N4O5SCl. 0.75 H2O (M.W. 466.43): C, 48.93; H, 4.86; N, 12.01; Cl, 7.60; S, 6.87. Found: C, 49.05; H, 4.61; N, 11.78; Cl, 8.34; S, 6.69.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH:28]2[CH2:33][C:32](=[O:34])[NH:31][CH:30]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:29]32[C:50]2[C:45](=[CH:46][C:47]([Cl:51])=[CH:48][CH:49]=2)[NH:44][C:43]3=[O:52])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:51][C:47]1[CH:46]=[C:45]2[NH:44][C:43](=[O:52])[C:29]3([CH:28]([C:22]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=4[N:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH2:33][C:32](=[O:34])[NH:31][CH:30]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:50]2=[CH:49][CH:48]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 2 h
Yield: 96.6 %

Procedure:
At room temperature, trifluoroacetic acid (2 mL) was added into a solution of racemic (2′S,3S,4′R)-4′-[2-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (280 mg, 0.43 mmol) in DCM (10 mL). After stirred for 2 h, the mixture was concentrated. The residue was dissolved in EtOAc, washed with 1 N NaOH and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (230 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:25]([C:26]([O:28]CC=C)=[O:27])=[C:16]3[C:17]([C:21]([CH2:23][CH3:24])=[S:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1.CC1(C)CC(=O)CC(=O)C1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:25]([C:26]([OH:28])=[O:27])=[C:16]3[C:17]([C:21]([CH2:23][CH3:24])=[S:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2oc(C)c(C(=S)CC)c12
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: C1CCOC1
Product: CCC(=S)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
1.60 g of allyl 5-(4,6-dimethoxypyrimidin-2-yl)oxy-3-ethylthiocarbonyl-2-methylbenzofuran-4-carboxylate and 0.54 g of dimedone were dissolved in 14 ml of tetrahydrofuran, and 40 mg of tetrakistriphenylphosphine palladium (0) was added thereto under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to obtain 1.33 g (yield: 91%) of the desired compound.