Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1.[Br:22][CH2:23][CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]1
Reactant: OCCCBr
Reactant: COc1ccc(O)c(C2Sc3ccccc3N(C)C2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCCCBr)c(C2Sc3ccccc3N(C)C2=O)c1
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of (-)-3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (6.3 g), which was prepared by the process (ii), in anhydrous tetrahydrofuran (70 ml), 3-bromo-1-propanol (8.8 g), triphenylphosphine (16.6 g) and then diethyl azodicarboxylate (10.0 ml) were added. The mixture was stirred for 2 hours under nitrogen atmosphere and concentrated in vacuo. The residue was purified by the silica gel column chromatography to give 4.5 g (51%) of (-)-3,4-dihydro-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[ClH:19]>[Pd].C(O)C>[ClH:19].[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]2[CH:15]=[C:16]([CH3:18])[N:17]=[C:10]12
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cn2c(n1)C(O)CCC2
Reaction time: 45 h

Procedure:
A mixture of 8-benzyloxy-2-methyl-imidazo[1,2-a]pyridine (5.9 g), 6.1 N HCl(4.2 ml), 10% Palladium-on-charcoal (5.9 g) and 240 ml ethanol was hydrogenated under a H2 -pressure of about 3.5 kg/cm2 for 22 hrs. at room temperature, after which period a further 2 g of fresh catalyst was added and hydrogenation continued for another 45 hrs. After filtration and evaporation of the solvent at the reduced pressure, the title compound is obtained as a pale yellow solid with m.p. 140°-152° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]([C:9]([OH:11])=O)[NH:3]1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1>CN(C)C=O>[O:1]=[C:2]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]([C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]([CH3:26])[CH2:21][C:22](=[O:25])[NH:23][N:24]=3)=[CH:15][CH:14]=2)=[O:11])[NH:3]1
Reactant: O=C1CCSCC(C(=O)O)N1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CSCCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.3 g (0.03 mole) of 5-oxo-perhydro-(1,4)-thiazepine-3-carboxylic acid and 6.1 g (0.03 mole) of N,N'-carbonyl-diimidazole are stirred in 15 ml of dimethylformamide at 50° c. for 15 minutes. After addition of 4.9 g (0.03 mole) of 6-(4-amino-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, the mixture is stirred at room temperature for 12 hours and the product is filtered off with suction and dried.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:20])/[CH:17]=N/O)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:22]>>[C:11]([C:9]1[CH:8]=[C:7]2[C:6](=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)[NH:15][C:16](=[O:20])[C:17]2=[O:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(NC(=O)/C=N/O)c(C(C)(C)C)c1
Reactant: O=S(=O)(O)O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)NC(=O)C2=O
Temperature: 0 °C
Yield: 42 %

Procedure:
N-(2,4-Di-tert-butyl-phenyl)-2-[(E)-hydroxyimino]-acetamide (500 mg, 1.7 mmol) in concentrated sulfuric acid (3.8 mL) was heated at 90° C. for 2 h. This solution was cooled at 0° C. and slowly added to ice-water (15 mL), the brown precipitate was filtered off and purified by chromathography on silica gel with a gradient of 0% to 25% of ethyl acetate in heptane to afford 200 mg (42%) of an orange powder. MS: m/z=259 (M).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7](/[C:12](/[C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[CH:13]/[C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH2:13][C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10][CH3:11])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc3c(c2)CCO3)ccc1C1CC1
Agent: [Pd]
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc3c(c2)CCO3)ccc1C1CC1

Procedure:
10% palladium-activated carbon (50 mg) was added to a solution of (5R)-5-[(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethenyl]pyrrolidin-2-one (240 mg) in methanol (3 mL), and the mixture was stirred at room temperature for four hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-2-one as an amorphous (200 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[CH3:10].[K+].[Br-]>>[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(N)cc1
Reactant: N#Cc1cccnc1
Agent: [Br-]
Agent: [K+]
Product: CCc1ccc(NC(=N)c2cccnc2)cc1
Yield: 84.9 %

Procedure:
The title compound was prepared from 3-cyanopyridine (8.5 g, 83 mmol) and 4-ethylaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (15.8 g, yield 84.9%, mp 134-136 C, purity 99.8% by HPLC). 1H-NMR (CDCl3):δ 1.22-1.26 (t, 3H), 2.60-2.65 (q, 2H), 5.09 (bs, 2H, D2O exchangeable), 6.88-6.89 (d, 2H), 7.18-7.19 (d, 2H), 7.32-7.35 (m, 1H), 8.18-8.20 (d, 1H), 8.64-8.65 (d, 1H), 9.03 (s, 1H). IR (KBr) cm−1: 3302, 3108, 2965, 2928, 2844, 1655. MS m/z: 227.1 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2ccccc2n1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of quinoline-2-carboxylic acid 3.1 (10 g, 0.0578 mol) in 100 mL of absolute methanol was added dropwise thionyl chloride (20 g, 0.173 mol). After the addition was completed, the mixture was heated to reflux for 2 h. The solvent was then evaporated to dryness under reduced pressure and treated with 100 mL of 10% aqueous solution of K2CO3. The mixture was extracted with ethyl acetate; combined organic extracts were dried over sodium sulfate and evaporated to dryness to afford of methyl quinoline-2-carboxylate. Yield: 10.1 g (93%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:13]1[C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][S:16][C:12]1=[N:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc(N=C2NC3(CCCC3)CS2)ccc1[N+](=O)[O-]
Reactant: CC(C)CBr
Product: Cc1cc(N=C2SCC3(CCCC3)N2CC(C)C)ccc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(Cc2ccccc2)cc1

Procedure:
The product (1.01 g) is obtained according to the method of stage 1 of Example 4, by using 1.13 g of 2-fluoro-3-methyl-nitrobenzene and 2 g of 4-benzyl-aniline in the presence of 1.31 g of potassium tert-butanolate in 30 mL of DMSO.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:18][C:17]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]2[NH:14][C:13](=[O:15])[CH2:12][O:11][C:10]=2[N:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1COc2ncc(-c3ccccc3)cc2N1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
In a 10 ml microwave vial was 7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.221 mmol) and N-bromosuccinimide (78.6 mg, 0.441 mmol) in dimethylformamide (1 ml). The reaction mixture was heated to 80° C. under microwave irradiation for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 ml). The organic solution was washed with water (2×10 ml) and brine (2×10 ml). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified via Biotage chromatography (gradient 0% to 5% methanol in dichloromethane) to give the title compound as a yellow solid (61 mg, 90%). 1H NMR (500 MHz, CD3OD) δ 7.48-7.32 (5H, m), 7.12 (1H, s), 4.82 (2H, s).
Reaction SMILES: C(C1[C:12]2[C:7](=[CH:8][C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:10]([Cl:13])[CH:11]=2)[C:6](=[O:20])[CH2:5][CH2:4]1)#N.[C:21]([OH:24])(=[O:23])[CH3:22].S(=O)(=O)(O)O>O>[O:20]=[C:6]1[C:7]2[C:12](=[CH:11][C:10]([Cl:13])=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:8]=2)[CH:22]([C:21]([OH:24])=[O:23])[CH2:4][CH2:5]1
Reactant: CC(=O)O
Reactant: N#CC1CCC(=O)c2cc(C3CCCCC3)c(Cl)cc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCC(C(=O)O)c2cc(Cl)c(C3CCCCC3)cc21

Procedure:
A mixture of 19 g of 4-cyano-6-chloro-7-cyclohexyl-3,4-dihydro-naphthalene-1(2H)-one, 36 ml of glacial acetic acid, 43 ml of concentrated sulfuric acid, and 29 ml of water is refluxed overnight. It is then poured into water, and the aqueous mixture is extracted with ethyl acetate. After drying and evaporation of the solvent, the residue is crystallized from toluene. There are obtained 14.3 g of 4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydro-naphthalene-1 -carboxylic acid melting at 204°-205°C, which product is identical with the compound of Example 3.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:5]([CH2:7][C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[K+]>O>[CH3:1][C:2]1[O:3][C:4]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1nc(C)oc1-c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(CC(=O)O)c(-c2ccco2)o1
Yield: 56.8 %

Procedure:
1.1 g of ethyl 2-[2-methyl-5-(2-furyl)-4-oxazolyl]acetate, 20 ml of methanol, 5 ml of water and 0.7 g of potassium hydroxide are treated in the same manner as described in Example 16. 0.55 g of 2-[2-methyl-5-(2-furyl)-4-oxazolyl]acetic acid is obtained. Yield: 56.5%
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C:34](C)([OH:36])[CH3:35])N>>[CH3:33][C:34]([OH:36])([CH3:35])[CH2:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CC(C)(O)CNN
Product: CC(C)(O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Hydrazino-2-methyl-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.2 Hz, 2H), 8.19 (d, J=8.7 Hz, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.74 (t, J=8.3 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.62 (s, 1H), 7.55 (t, J=7.1 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.17 (m, 2H), 7.01 (d, J=8.7 Hz, 2H), 5.39 (s, 2H) 4.09 (s, 2H), 1.23 (s, 2H); MS: (M+H m/z=451.2).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[Cl:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:15][C@H:3]1[C@@H:2]([NH:1][C:24]([C:19]2[NH:20][C:21]([CH2:22][CH3:23])=[C:17]([Cl:16])[N:18]=2)=[O:25])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](Cl)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2Cl)nc1Cl
Yield: 73.4 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl cis(±)-4-amino-3-chloropiperidine-1-carboxylate obtained in Example (198a) (134 mg, 0.571 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (99.7 mg, 0.571 mmol), 1-hydroxybenzotriazole hydrate (116 mg, 0.856 mmol), WSC hydrochloride (164 mg, 0.856 mmol) and triethylamine (119 μL, 0.856 mmol), to obtain 164 mg of the title compound (73%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)Nc1cc(-c2cc(-c3nnc(CN4CCOCC4)o3)c3cn[nH]c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
N-(2-Chloro-5-{1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (52 mg, 0.081 mmol) was placed in isopropanol (3 ml) and 2M sodium hydroxide (1 ml, 2.0 mmol) added. The mixture was stirred at room temperature overnight and blown to dryness under a stream of nitrogen. The mixture was dissolved in water (10 ml) and washed with dichloromethane (10 ml). The organic layer was acidified by the addition of 2M hydrochloric acid and the solvent removed. The residue was purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.I[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:17][CH2:18][CH3:19])[C:4]=2[N:3]=1
Reactant: CCCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Temperature: 50 °C
Yield: 46.2 %

Procedure:
A mixture of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.6 mmol), 1-iodopropane (1.2 g, 6.9 mmol) and sodium carbonate (0.9 g, 8.5 mmol) in DMF (40 ml) was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and the residue treated with water (60 ml) and extracted with ethyl acetate (3×80 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated. The residue was triturated with ether/cyclohexane, the solid was filtered off and dried to afford the title compound (0.82 g, 46%); m/z 269.1 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=2[Cl:19])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])(=[O:37])=[O:36])=[CH:30][CH:29]=2)O1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])(=[O:36])=[O:37])=[CH:30][CH:29]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[Cl:19]
Reactant: CCN(CC)CCS(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1ncc(Br)cc1OCc1c(F)ccc(F)c1Cl
Product: CCN(CC)CCS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3c(F)ccc(F)c3Cl)c2)cc1
Yield: 60 %

Procedure:
2-diethylamino-ethanesulfonic acid {4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide was prepared following the general Suzuki coupling procedure 3 from 5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and 2-diethylamino-ethanesulfonic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide prepared in part 2 as a white solid in 60% yield.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[C:16]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])#[N:17]>>[C:16]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3][CH:2]1[CH3:1])=[O:22])#[N:17]
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Reactant: CC(C)(CCC#N)C(=O)O
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)C(C)(C)CCC#N
Yield: 17 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 4-cyano-2,2-dimethylbutanoic acid as described for example 37 step 3 (400 mg, yield 17%) as yellow viscous liquid. 1H NMR (300 MHz, MeOD) δ 8.40-8.39 (dd, J=2.2 Hz, 0.7 Hz, 1H), 7.76-7.72 (dd, J=9.1 Hz, 2.3 Hz, 1H), 6.86-6.83 (d, J=9.0 Hz, 1H), 4.69-4.65 (m, 1H), 4.32-4.22 (m, 3H), 3.41-3.35 (m, 2H), 3.20-3.14 (m, 1H), 2.50-2.45 (m, 2H), 2.04-1.95 (m, 2H), 1.33 (s, 6H), 1.20-1.18 (m, 3H). MS (ESI) m/z: Calculated for C18H23N5O: 325.19. found: 326.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=NO)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-:36].[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[O:36])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: O=C([O-])[O-]
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Temperature: 65 °C
Yield: 76.2 %

Procedure:
A mixture of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde oxime (14.20 g, 31.34 mmol), triethyl silane (10.3 mL, 7.53 g, 62.8 mmol), sodium carbonate (5.43 g, 39.3 mmol), palladium bis(diphenylphosphine)-ferrocene dichloride CH2Cl2-complex (1.28 g, 1.57 mmol) and DMF (250 mL) were stirred under an atmosphere of carbon monoxide at 65° C. over night. After cooling to room temperature, the solvent was evaporated and the residue taken up in MTBE, filtered and the filtrate was concentrated in vacuum. Purification of the residue on silica gel afforded the title compound (9.60 g, 76%).
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.C([O:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26](O)=[O:27])[C:21]1=[O:29])(=O)C.ON1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH2:7])=[O:27])[C:21]1=[O:29]
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Product: NC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.64 g of dicyclohexylcarbodiimide dissolved in 20 ml of chloroform are added at room temperature to 1.5 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid, 40 ml of chloroform and 0.86 g of N-hydroxysuccinimide. After 4 hours, the solid is filtered, whereupon the filtrate is concentrated and again filtered. The filtrate is evaporated. The residue is treated at room temperature with 40 ml of a saturated solution of ammonia in methanol. The mixture is stirred at room temperature for 5 minutes, 10 ml of ion-free water are then added thereto and the mixture is stirred at room temperature for an additional minutes. The precipitated solid is filtered. The filtrate is evaporated, the residue is stirred in 30 ml of acetonitrile and the crystallized-out product is recrystallized two more times from acetonitrile. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 162°-164°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1([CH2:19][C@H:20]([N:24]2[C:28](=[O:29])[C@H:27]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:26][C:25]2=[O:37])[C:21](O)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:21](=[O:22])[C@@H:20]([N:24]2[C:28](=[O:29])[C@H:27]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:26][C:25]2=[O:37])[CH2:19][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[S:3][CH:4]=1)[CH3:12]
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)n1

Procedure:
By using the conditions described in Step (iv) of Example 17, ethyl 2-amino-4-thiazoleacetate was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd. for C26H38N4O5S (M+) 519.2641, found 519.2620.