Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]
Reactant: CN(C)C=O
Reactant: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21

Procedure:
(S)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 ml:1 ml) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reverse-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vacuum-oven overnight. The solid product was collected as 87 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br. s., 1 H), 8.23 (t, J=4.67 Hz, 1 H), 7.77 (d, J=1.01 Hz, 1 H), 7.60-7.64 (m, 2 H), 7.40 (t, J=7.58 Hz, 1 H), 7.30 (s, 1 H), 7.20-7.26 (m, 2 H), 5.87 (s, 1 H), 4.59-4.68 (m, 1 H), 4.36 (s, 1 H), 4.35 (s, 1 H), 3.46 (s, 2 H), 2.24 (s, 3 H), 2.18 (s, 9 H), 2.11 (s, 3 H), 1.76-1.88 (m, 2 H), 1.41 (d, J=6.57 Hz, 3 H), 0.74 (t, J=7.33 Hz, 3 H); LCMS: 499.4 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:23]1([S:33](Cl)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([S:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)(=[O:35])=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCCCSc1cccc2nccn12)c1cccc2ccccc12
Yield: 53.3 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (300 mg, 1.36 mmoles) and triethylamine (0.29 ml, 2.08 mmoles) in methylene chloride (15 ml) was added 1-naphthalenesulfonyl chloride (307 mg, 1.35 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 296 mg of the desired product (53.0%, colorless solid).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([CH2:19][CH2:20][NH:21][NH2:22])#[N:18]>>[C:17]([CH2:19][CH2:20][NH:21][N:22]=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)#[N:18]
Reactant: N#CCCNN
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Product: N#CCCNN=Cc1ccc(OCc2ccccc2)cc1
Yield: 86 %

Procedure:
4-(benzyloxy)benzaldehyde (2-cyanoethyl)hydrazone is prepared by condensation of 4-(benzyloxy)benzaldehyde with (2-cyanoethyl)hydrazine according to the following procedure:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)[C:13]([N:15]([CH2:26][C:27](O)=[O:28])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:56][C:57]([CH3:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:58][NH2:59].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:13](=[O:14])[N:15]([CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:26][C:27](=[O:28])[NH:59][CH2:58][C:57]([CH3:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:56])[CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Reactant: CC(C)(CN)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The compound from Step 3 (1.3 g, 1.8 mmol) was dissolved in methylene chloride (10 mL). β,β-dimethylphenethylamine hydrochloride (Example 1, Step 6) (0.370 g, 2 mmol) was added followed by diisopropylethylamine (1 mL, 5.7 mmol) and PyBOP (1.04 g, 2 mmol) dissolved in methylene chloride (10 mL). The reaction was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to give a white solid; 1.09 g (70% yield). MS-APCI: M+1=863.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(N2CCNCC2)cc1Cl
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(C)c(Cl)c3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-4-methyl-phenyl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]2[C:26](=[CH:27][CH:28]=1)[O:25][C:12]1([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:29]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:26](=[CH:27][CH:28]=1)[O:25][C:12]1([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH2:11][C:10]2=[O:29])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl chloridocarbonate was added to a solution of tert-butyl 6-amino-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate in pyridine and stirred at room temperature for 6 hours. The solvent was removed under reduced pressure and the residue was purified by silicagel column chromatography (hexane/EtOAc) to obtain the intended compound as pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:13](Cl)(Cl)=[S:14]>O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[C:13]=[S:14]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1ccc(N=C=S)cc1

Procedure:
4-amino-benzenesulfonamide Compound 2a (40 g, 240 mmol) in water (400 mL) in the presence of concentrated hydrochloric acid (100 mL) was reacted with thiophosgene (26.8 g, 240 mmol) at r.t. for 30 mins to provide 4-isothiocyanato-benzenesulfonamide Compound 2b (85% yield) (procedure described in McKee R L and Bost R W, J. Am. Chem. Soc., 1946, 68, 2506-7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[C:23]([O:25]C)=[O:24])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[C:23]([OH:25])=[O:24])(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of methyl 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylate (164 mg, 0.41 mmol), [prepared as described in Example 3] and NaOH (33 mg, 0.82 mmol) in methanol/water (5 ml of 9:1 ratio) was heated at reflux. After 2 h, the reaction mixture was concentrated in vacuo, diluted with water (5 ml) and extracted with diethyl ether. The aqueous phase was acidified to pH 3 with 5% potassium bisulfate solution and the product was extracted into ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated to yield 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid as a foam (125 mg, 79%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[S:18]1[CH2:22][CH:21]([C:23]([NH2:25])=[O:24])[NH:20][CH2:19]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:20]3[CH:21]([C:23]([NH2:25])=[O:24])[CH2:22][S:18][CH2:19]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)C1CSCN1
Product: NC(=O)C1CSCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 4-thiazolidinecarboxamide (CAN 103749-87-7, 62.3 mg, 472 μmol) as starting materials and isolated (114 mg, 77%) as white solid; LC-MS (UV peak area, ESI) 100%, 348.1377 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16][O:17][CH2:18][CH2:19]O>>[CH3:16][O:17][CH2:18][CH2:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COCCO
Agent: O=S(=O)(O)O
Product: COCCOC(=O)c1ccc(O)cc1

Procedure:
A mixture of 25.0 g of p-hydroxybenzoic acid, 170 g of methyl glycol (methoxyethanol) and 1 ml of sulfuric acid (conc.) was heated for 8 hours to 110°-115° C. and, after the excess methyl glycol had been distilled off under reduced pressure, was poured onto ice/water. After neutralization with sodium hydrogen carbonate, the aqueous phase was extracted by shaking several times with methylene chloride. The methylene chloride solution was treated with active carbon, concentrated by evaporation and the residue recrystallized from toluene. p-hydroxybenzoic acid 2-methyloxy-ethyl ester melting at 90°-93° C. was obtained in a yield of 27.6 g (78%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(CCCl)Nc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-3-chloroaniline (6.0 g, 29.1 mmol) and pyridine (3.45 g, 43.6 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (5.53 g, 43.6 mmol) dropwise at 15° C. After stirring for 2 hours at room temperature, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The product N-(4-bromo-3-chloro-phenyl)-3-chloro-propionamide (8.20 g, yield: 95%) was obtained as an oil. MS: 298.0 (M+H+)+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:26][OH:27])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:26]=[O:27])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH:18]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
Pyridiniumchlorochromate (1.67 g, 7.77 mmol) was added to N-(5-chloro-2-(hydroxymethyl) phenyl) pivalamide (1.34 g, 5.55 mmol) in CH2Cl2 (100 mL) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 3 hrs. Then it was passed through a thin silica gel pad with CH2Cl2(100 mL), concentrated on rotary vacuum and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (800 mL) to afford the expected product as a white solid (937 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.28-1.34 (s, 9 H), 7.15 (dd, J=8.31, 2.01 Hz, 1 H), 7.53-7.59 (m, 1 H), 8.87 (d, J=2.01 Hz, 1 H), 9.84-9.88 (m, 1 H), 11.42 (s, 1 H); Mass spec. 240.07 (MH+), Calc. for C12H14ClNO2 239.07.
Reaction SMILES: C([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)CC1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:20]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:43])=[O:44])[CH:15]=2)[CH:11]=[N:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 205 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.290 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 175 mg (85.7% yield) of the titled compound. MS: m/z=589.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([O:14]C(C)(C)C)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19]1[CH:24]=[C:23]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH:28]=[C:27]([CH2:39][OH:40])[C:26]=2[CH2:41][OH:42])[CH:22]=[CH:21][N:20]=1.Cl>O1CCOCC1>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19]1[CH:24]=[C:23]([C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=3)[CH:28]=[C:27]([CH2:39][OH:40])[C:26]=2[CH2:41][OH:42])[CH:22]=[CH:21][N:20]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(C(=O)OC(C)(C)C)c5ccccc54)c3)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)cc(C(=O)O)c5ccccc54)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
1-[2-(2-Oxo-4-tert-butoxycarbonyl-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.96 g) is added to a 4 M solution of hydrogen chloride in dioxane (25 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; chloroform:methanol:acetic acid=90:10:3), and crystallized from ethyl acetate to give 1-[2-(2-oxo-4-carboxy-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.41 g) which is listed in Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5](OC)=[O:6].[NH3:13]>CCOCC>[CH3:1][O:2][C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([NH2:13])=[O:6]
Reactant: COC(=O)C(F)(F)C(F)(F)OC
Reactant: N
Solvent: CCOCC
Product: COC(F)(F)C(F)(F)C(N)=O
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A solution of 140 g (0.74 mol) of methyl 3-methoxytetrafluoropropionate in 100 ml of ether was treated at 0° with 15.3 g (0.90 mol) of NH3. The resulting viscous mixture was stirred at 25° overnight and evaporated to dryness at 25° (10 mm). The crude residue was then recrystallized from ether/hexane to give 123.6 g (95%) of 3-methoxytetrafluoropropionamide, mp 78°-80°. An analytical sample was recrystallized from ether/hexane, mp 83°-85°. IR (KBr): 2.95, 3.02 and 3.10 (NH2), 3.37 and 3.49 (sat'd CH), 5.92 (C=O), 6.19 (NH2), 7.5-10μ (CF, C-O). NMR ((CD3)2CO): 1H 6.67 (broad, 2H, NH2) and 3.66 ppm (s, 3H, OCH3); 19F-120.6 (t, JFF 4.7 Hz, 2F, CF2) and -121.8 ppm (t, JFF 4.7 Hz, of d, JHF 2.1 Hz, 2F, CF2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[OH:25].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]
Reactant: CN(C)CCCCl
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(O)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1
Yield: 89.6 %

Procedure:
According to the method described in example 1.6, starting from 5.4 g (15.26 mmol) of methyl 6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate, 9.95 g (30.53 mmol) of caesium carbonate and 2.9 g (18.3 mmol) of 3-chloro-N,N-dimethylpropan-1-amine hydrochloride in 60 mL of DMF, we obtain 6 g of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH2:9][S:10]([C:13]3[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][N:14]=3)(=[O:12])=[O:11])=[C:7]([CH3:20])[O:6][N:5]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:27][CH:9]([S:10]([C:13]1[CH2:17][C:16]([CH3:18])([CH3:19])[O:15][N:14]=1)(=[O:11])=[O:12])[C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][O:6][C:7]=1[CH3:20]
Reactant: Cc1onc(C2CC2)c1CS(=O)(=O)C1=NOC(C)(C)C1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C2CC2)c1C(Cl)S(=O)(=O)C1=NOC(C)(C)C1
Temperature: -78 °C
Yield: 44.2 %

Procedure:
3-Cyclopropyl-4-(5,5-dimethyl-4,5-dihydroisoxazol-3-ylsulfonylmethyl)-5-methyl-isoxazole (108 mg, 0.36 mmol) was dissolved in THF (5 ml) under nitrogen. The solution was cooled to −78° C. and potassium tert-butoxide (0.4 ml, 0.4 mmol) added, followed by hexachloroethane (90 mg, 0.4 mmol). The solution was allowed to warm to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 3.07 of Table 29) as a white solid (53 mg, 44% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
3-(4-Hydroxyphenyl)propionitrile (1.47 g, 0.01 mol) was dissolved in DMF (24 ml), and to this solution were successively added benzyl bromide (1.31 ml, 0.011 mol, 1.1 eq) and anhydrous potassium carbonate (4.15 g, 0.030 mol, 3.0 eq). The mixture was stirred under heating at 90° C. for 3 hours. This reaction mixture was cooled to room temperature, and water (100 ml) was added. The mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed with saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-(4-benzyloxyphenyl)propionitrile (2.39 g, 100%) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH2:48])[CH2:44][CH2:43]1>ClCCl>[NH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH:48][C:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@H:23]3[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]3)=[C:10]([NH:9][CH2:8][CH:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:18]=2)=[O:20])[CH2:44][CH2:43]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)N[C@H]4CC[C@H](N)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (0.35 g, 0.64 mmol) and trans-1,4-diaminocyclohexane (0.6 g, 6.14 mmol) was heated at 105° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:1.2, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (88:12:2, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.32 g, 79%).