Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Br[C:31]#[C:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]#[C:31][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:34][CH:35]=1
Reactant: Fc1ccc(C#CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(F)cc2)CCN(C)C1
Temperature: 82.5 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.00 mmol) was dissolved in toluene (5 mL). The mixture was stirred for 10 min, and copper sulfate (24.9 mg, 0.01 mmol) and 1,10-phenanthroline (36 mg, 0.2 mmol) were added, and the mixture further stirred for 10 min. To this was added 1-(bromoethynyl)-4-fluorobenzene compound (220 mg, 1.1 mmol) dissolved in toluene and the mixture purged with nitrogen. The reaction mixture was heated at 80-85° C. overnight. The progress of reaction was monitored by TLC and LCMS. The toluene was evaporated under reduced pressure and the crude product purified by column chromatography using silica (100-200 mesh) and 0-50% Ethylacetate:hexane as eluent. 1H NMR (DMSO, oxalate salt) δ (ppm): 7.70 (m, 2H), 7.55 (d, 1H), 7.30 (m, 3H), 7.20 (d, 1H), 4.30 (m, 2H), 3.16 (m, 4H), 2.90 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[C:13]1([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(Cl)(Cl)Cl>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:13]1([C:19]2[NH:20][C:21]3[CH:27]=[C:26]([S:28]([O:12][CH2:11][C@H:9]([C@@H:7]4[C:5]([OH:6])=[C:3]([OH:4])[C:2](=[O:1])[O:8]4)[OH:10])(=[O:29])=[O:30])[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=S(=O)(Cl)c1ccc2nc(-c3ccccc3)[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1O[C@H]([C@H](O)COS(=O)(=O)c2ccc3nc(-c4ccccc4)[nH]c3c2)C(O)=C1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
45.1 g of ascorbic acid (255.2 mmol; 3 eq.) are dissolved in 100 ml of DMF, 521 mg of 4-dimethylaminopyridine (4.27 mmol; 0.05 eq.) are added, and 25 g of 2-phenyl-3H-benzimidazole-5-sulfonyl chloride (85.4 mmol; 1 eq.), dissolved in 66 ml of DMF, are added dropwise at 0° C. The mixture is subsequently warmed to room temperature, and, after 6 hrs., 100 ml of water and 100 ml of chloroform are added, the mixture is extracted, dried, and the solvent is removed in vacuo. The residue is recrystallised from toluene, giving the product as a pale-beige solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1.[CH2:13]=[O:14]>>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][OH:14])=[N:10][CH:11]=1
Reactant: C=O
Reactant: COCOCc1ccc(C)nc1
Product: COCOCc1ccc(CCO)nc1
Yield: 32.8 %

Procedure:
A mixture of 5-methoxymethoxymethyl-2-methylpyridine (30.5 g) and formalin (37% aq., HCHO, 22.2 g) was heated in a sealed tube at 150° to 160° C. for 8 hours. The reaction mixture was concentrated under reduced pressure and the oily residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (20:1, v/v) gave 2-(5-methoxymethoxymethyl-2-pyridyl)ethanol (11.8 g, yield: 33%) as oil.
Reaction SMILES: [Cl:1][C:2]([Cl:18])([CH:8]1[CH:13](Cl)[C:12]([CH3:16])([CH3:15])[CH2:11][C:10](=[O:17])[O:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]([Cl:18])([CH:8]1[O:9][C:10](=[O:17])[CH:11]2[CH:13]1[C:12]2([CH3:16])[CH3:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)(Cl)C1OC(=O)CC(C)(C)C1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)(Cl)C1OC(=O)C2C1C2(C)C
Temperature: -20 °C
Yield: 59.9 %

Procedure:
A solution of ethyl α,α,3-trichloro-3,4,5,6-tetrahydro-4,4-dimethyl-6-oxo-2H-pyran-2-acetate (3.43 g, 10.8 mmol) in 20 ml of tetrahydrofuran was cooled to -20° C. Potassium tert-butoxide was added in small portions while the mixture was stirred and maintained at -20° C. over a period of two hours. A total of 1.4 g (12.5 mmol) was added. Aqueous ammonium chloride was added and the mixture was extracted with methylene chloride. Purification by column chromatography gave 1.82 g of ethyl α,α-dichloro-6,6-dimethyl-4-oxo-3-oxabicyclo[3.1.0]hexane-2-acetate (60% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(OC(Cl)=O)C.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[CH2:26][CH2:27][CH:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCOC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(C=Cc1cccnc1)NCCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 ml (16.2 mmol) TEA are suspended in 50 ml abs. toluene and a solution of 1.5 ml (15.5 mmol) chloroformic acid ethyl ester in 20 ml abs. toluene are added dropwise under moisture exclusion and light cooling. This yellow suspension is stirred at RT for two hours and then a solution of 3.5 g (14.1 mmol) 3-(1-benzylpiperidin-4-yloxy)-propylamine in 20 ml abs. toluene is added dropwise. The mixture is stirred for two hours at RT and extracted by shaking three times in the heat, each with 10 ml water, 2 M sodium hydroxide and water again. The organic phase is concentrated under vacuum and the orange colored oily residue is chromatographically purified twice over silica gel with CHCl3/CH3OH/NH4OH (90/9/1 and 95/5/0 to 90/10/0) and crystallized from 10 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 100–102° C.; yield: 1.9 g (35%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH2:18][OH:19]>O1CCCC1>[N+:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:16][CH2:17][CH2:18][OH:19])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Reactant: NCCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CNCCO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a sealed tube, added 1-(chloromethyl)-2-nitro-4-(trifluoromethyl)benzene (2.0 g, 8.4 mmol), tetrahydrofuran (8.4 mL), and 2-aminoethanol (5.0 mL, 83.5 mmol). Stirred the mixture at room temperature for 45 minutes. Extracted the mixture into ethyl acetate, washed 2 times with water, 1 time with brine solution, dried over magnesium sulfate, filtered, concentrated to yield 2-(2-nitro-4-(trifluoromethyl)benzylamino)ethanol. MS (M+H)+=265; Calc'd 264.21 for C10H11F3N2O3.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[CH:40]([NH:41][C:42](=[O:77])[C:43]([C:52]3[N:53]=[C:54]([NH:57][C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[S:55][CH:56]=3)=[N:44][O:45][CH:46]3[CH2:50][CH2:49][O:48][C:47]3=[O:51])[C:39](=[O:78])[N:21]2[C:22]=1[C:23]([O:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:14])[CH3:13]>C(Cl)Cl>[O:9]=[S:19]1[C@@H:20]2[CH:40]([NH:41][C:42](=[O:77])[C:43]([C:52]3[N:53]=[C:54]([NH:57][C:58]([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:55][CH:56]=3)=[N:44][O:45][CH:46]3[CH2:50][CH2:49][O:48][C:47]3=[O:51])[C:39](=[O:78])[N:21]2[C:22]([C:23]([O:25][CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:17]([CH2:16][O:15][C:12](=[O:14])[CH3:13])[CH2:18]1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC3CCOC3=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC3CCOC3=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2S(=O)C1
Reaction time: 1 h

Procedure:
A solution of 0.420 g of m-chloro-perbenzoic acid in 8 ml of methylene chloride was added under an inert atmosphere to a stirred solution of 1.525 g of the product of Step A in 8 ml of methylene chloride cooled on an ice bath to 0° to 5° C. and the mixture was stirred for one hour at that temperature. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in 20 ml of ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution and then with aqueous sodium chloride until the wash waters were neutral, dried and evaporated to dryness under reduced pressure at a temperature less than 30° C. The residue was taken up in 10 ml of ether and the mixture was vacuum filtered at room temperature. The product was rinsed with ether to obtain 1.390 g of the syn isomer of diphenylmethyl 1-oxo-3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-oxo-3-tetrahydrofuranyloxyimino)-acetamido]-ceph-3-eme- 4-carboxylate in the form of a yellow product.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH:6]=1.CO.[H][H]>[Pt].CC(O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH:6]=2)=[C:2]([CH3:1])[C:20]=1[CH3:21]
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2C)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c(C)c2C)ccn1

Procedure:
A solution of N-(4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-yl)-2-methoxyacetamide (90 mg, 0.272 mmol) in a mixture MeOH (30 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 50° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H5, (82 mg, 100%); Rt 1.21 min (Method 2); m/z 302 (M+H)+ (ES+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[C:17]([Cu])#[N:18]>CN1CCCC1=O.CCOC(C)=O>[C:17]([C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8])#[N:18]
Reactant: CCOC(=O)CCCc1ccc(O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCc1ccc(O)c(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-(3-bromo-4-hydroxyphenyl)butanoate (19.8 g, 69 mmol) in 172 mL of N-methyl-2-pyrrolidinone was added CuCN (6.49 g, 72.4 mmol). The solution was heated to reflux for 4 hours then cooled to room temperature. The reaction was diluted with EtOAc and washed twice with 5% HCl and once with brine, then dried over sodium sulfate and concentrated. Purified on silica gel using 60:40 hexanes:EtOAc as the elutant. The yield of ethyl 4-(3-cyano-4-hydroxyphenyl)butanoate was 9.84 g (61%): 1H-NMR (CDCl3) 7.67 (1H, s), 7.24-7.29 (2H), 7.94 (1H, d), 4.14 (2H, q), 2.59 (2H, dd), 2.34 (2H, dd), 1.91 (2H, m), 1.28 (3H, t).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:17][N:18](C)C=O>O>[C:17]([C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(Br)ccnc12
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)c2c(C#N)ccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-5,8-dimethyl-6-nitroquinoline (3.87 g, 13.77 mmol), cuprous cyanide (3.67 g, 41.31 mmol) and dimethylformamide (70 mL) is stirred at room temperature for 30 minutes and then heated to 155° C. and stirred at this temperature for 1 hour. Water is added, and the reaction mixture is filtered. The precipitate is washed with water and methylene chloride. The filtrate is extracted with methylene chloride (3×125 mL), and the combined organic layers are dried (sodium sulfate) and evaporated. Purification by chromatography through a short column consisting of layers of sand/flash silica gel/sand, using chloroform as eluent, provides 4-cyano-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[I:40]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[C:10]=3[I:40])[CH2:2][CH2:3]1
Reactant: II
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2I)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (803 mg) in THF (6 mL) was added dropwise a THF solution (1.11 M, 3.3 mL) of lithiumdiisopropylamide at −78° C. under an argon atmosphere, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added a solution of iodine (933 mg) in THF (3 mL), and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol to give the title compound as colorless crystals (782 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:16][CH2:15]1)[CH3:2]>CCOC(C)=O.CCO.[Pt]>[CH2:1]([C:3]1[C:4]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:19]2)=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1-[2-Ethyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (1.7 g, 4.7 mmol) was taken up in EtOAc (30 mL) and EtOH (15 mL). The catalyst, 5% sulfided platinum on carbon (300 mg) was added. The reaction was placed under 1 atm of H2 gas and was allowed to stir at room temperature for 5 days. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound without further purification (1.4 g, 4.1 mmol, 86%). MS (M+H, ES+) 342.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][C:49]([F:53])([F:52])[CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:54])=[C:37]([OH:55])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([CH:46]5[CH2:51][CH2:50][C:49]([F:53])([F:52])[CH2:48][CH2:47]5)=[CH:44][CH:45]=4)[C:38]([CH3:54])=[C:37]([O:55][CH3:3])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(C2CCC(F)(F)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OCCO
Product: COC1=C(C)C(c2ccc(C3CCC(F)(F)CC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2.5 v/v, 28 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(4-(4,4-difluorocyclohexyl)-phenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.800 g, 1.88 mmol, 1 eq) and MeOH (10 ml); yield: 0.060 g (7.3%); MS m/z: 438.3 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.39 (s, 1H), 8.14 (d, 1H), 7.69 (d, 1H), 7.49 (d, 1H), 7.26-7.15 (m, 4H), 5.79 (s, 1H), 3.93 (s, 3H), 2.67-2.54 (m, 1H), 2.03-1.88 (m, 3H), 1.83-1.76 (m, 3H), 1.69 (s, 3H), 1.59-1.50 (m, 2H); HPLC (METHOD [A]): rt 14.64 min (95.14%)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:30]1([C@@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C@@H:36]([NH:38][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[CH:29]=[N:28][NH:27][C:14]4=[N:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[CH:8]=[CH:7][N:6]=2)[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Product: C[C@H](Nc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 100 °C
Yield: 16.7 %

Procedure:
A mixture of 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (0.55 g, 0.13 mmol, obtained in example 127) and (1S)-1-phenylethylamine (0.16 g, 1.3 mmol) was heated to 100° C. for 1 h. It was allowed to cool and the crude product obtained was purified by chromatography on silica gel using increasing polarity mixtures of EtOAc-hexane as eluent, to afford 10 mg of the title compound (yield: 16%).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1>CC(O)=O>[CH2:14]([O:13][C:11]([CH2:10][N:8]1[C:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][C:18]=2[C:7]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)CN(N)c1ccccc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)O)CC2
Temperature: 70 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of ethyl (N-phenyl-hydrazino)-acetate hydrochloric acid salt (2.3 g, 10 mmol) and 4-oxo-cyclohexanecarboxylic acid (1.42 g, 10 mmol) in glacial AcOH (20 ml) is stirred at 70° C. for 1 h. The suspension is allowed to cool to rt, poured onto H2O and stirred for 1 h. The resulting precipitate is filtered, washed with H2O and dried under high vacuum to give pure 9-ethoxycarbonylmethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid as a white solid (2.85 g) in 93% yield.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[S:13][CH:14]=1.CCCCCC>C(OCC)(=O)C>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[S:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3F)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (3.80 g, 9.96 mmol) in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 14 hours. Hexane was poured to the reaction mixture, and crystals were collected by filtration to give 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine hydrochloride. The hydrochloride was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.06 g, (73.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:68])[CH3:2].F>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C(C)C)(C(C)C)C(C)C)C2C)C(OC)CC3C)CCC1=O
Agent: F
Solvent: CC#N
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1=O

Procedure:
To a stirred solution of 17-ethyl-1-hydroxy-12-[2'-(3"-allyloxy-4"-oxocyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in acetonitrile was added hydrofluoric acid at room temperature. The reaction progress is monitored by tlc analysis. The reaction mixture is quenched with sat'd aqueous sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate three times. Combined organic layers are washed (sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography), gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH:20](O)[C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:26]([CH3:27])=[C:19]([CH3:20])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:17]=4[C:16]=3[CH3:29])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: C1CCNC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(N3CCCC3)C(C)(C)O4)CC2)cc1
Yield: 48 %

Procedure:
Using 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol and pyrrolidine obtained in Reference Example 18, the title compound was obtained in the same manner as in Example 57. Yield 48% mp. 124–126° C. (methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].C(O)(=O)C.O>C1C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)CCC(C)=O
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cccc(-n2c(C)ccc2C)c1

Procedure:
The mixture of ethyl 3-aminobenzoate (2.0 g), hexane-2,5-dione (1.8 ml) and acetic acid (0.7 ml) in benzene (10.0 ml) was heated under reflux for 5 hours, while water was removed in a Dean-Stark apparatus. To the mixture was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with a brine, dried over magnesium sulfate and evaporated in vacuo to give ethyl 3-(2,5-dimethylpyrrol-1-yl)benzoate (2.9 g) as an oil.