Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][NH2:14]>O.Cl.C(OCC)C>[N:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])=[N+:14]=[N-:1]
Reactant: NNc1ccccc1F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
Sodium nitrite (510 mg) dissolved in 2 ml of water was dropped, under cooling with ice, into a solution of 1.0 g of 2-fluorophenylhydrazine hydrochloride in 5 ml of concentrated hydrochloric acid and 6 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 2 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 400 mg of the title compound as a brown oily crude product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[I-].[K+]>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:11]=[CH:12][C:5]=12
Reactant: COCCCBr
Reactant: Fc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCn1ccc2c(F)ccnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
60% Oily sodium hydride (135 mg) was added to a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (384 mg) in N,N-dimethylformamide (6 ml) and the mixture was stirred at room temperature for 1.5 hours. 1-Bromo-3-methoxypropane (518 mg) and potassium iodide (468 mg) were added to the mixture and the reaction mixture was stirred at 50° C. for 1.5 hours. Ice water was added to the reaction mixture slowly and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=90/10 to 70/30) to give 4-fluoro-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridine (520 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[C:5]([C:15]([NH2:17])=[O:16])=[C:4]2[CH2:18][CH2:19][CH2:20][C:3]=12.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.Cl.[CH:38]12[CH2:44][C:43]1([CH2:45][OH:46])[CH2:42][CH2:41][NH:40][CH2:39]2>O>[OH:46][CH2:45][C:43]12[CH2:44][CH:38]1[CH2:39][N:40]([C:2]1[N:10]3[C:6](=[N:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[C:5]([C:15]([NH2:17])=[O:16])=[C:4]3[CH2:18][CH2:19][CH2:20][C:3]=13)[CH2:41][CH2:42]2
Reactant: OCC12CCNCC1C2
Reactant: NC(=O)c1c2c(c(Cl)n3c1nc1ccccc13)CCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1c2c(c(N3CCC4(CO)CC4C3)n3c1nc1ccccc13)CCC2
Yield: 74.8 %

Procedure:
11-chloro-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (800 mg) and DIPEA (1.95 ml) were added to an NMP suspension of 3-azabicyclo[4.1.0]hept-6-ylmethanol hydrochloride (1.01 g), and stirring was performed at 220° C. for 60 minutes under microwave irradiation. The reaction liquid was added to water and the precipitate was collected by filtration. The resulting solid was purified by silica gel column chromatography (MeOH/chloroform) to obtain 11-[6-(hydroxymethyl)-3-azabicyclo[4.1.0]hept-3-yl]-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (788 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=3)[CH:7]=2)=[CH:9]1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(-c2ccsc2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Yield: 57.2 %

Procedure:
Following general procedure B1, 4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.070 g, 0.30 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.064 g, 0.36 mmol) to afford the title compound (0.065 g, 57%) as an orange-brown oil. MW=378.49. APCI MS m/z 379 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:25]>CN(C)C=O.[Cl-].[NH4+]>[Cl:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1c(Cl)cccc1[N+](=O)[O-])C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (1.8 g, 0.077 mol) was suspended in N,N-dimethylformamide (150 mL) at 0° C. Diethyl malonate (9.9 g, 0.0623 mol) was added in three portions and the resulting suspension was stirred at 0° C. for 10 min. A solution of 2-(bromomethyl)-1-chloro-3-nitrobenzene (147-1; 13 g, 0.0519 mol) in N,N-dimethylformamide (150 mL) was added drop wise. The reaction mixture was stirred for 45 min at 0° C., then diluted with saturated ammonium chloride and extracted with ethyl acetate (2×250 mL). The combined organics were dried over anhydrous sodium sulphate and concentrated to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.762-7.741 (d, J=8.4 Hz, 1H), 7.635-7.616 (d, J=7.6 Hz, 1H), 7.365-7.324 (t, J=8.4 Hz, 1H), 4.195-4.142 (q, J=7.2 Hz, 4H), 3.817-3.779 (t, J=7.6 Hz, 1H), 3.675-3.656 (d, J=7.6 Hz, 2H), 1.236-1.201 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:25][C:26]([C:29]([NH2:31])=[O:30])([CH3:28])[NH2:27]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][NH:27][C:26]([CH3:28])([C:29]([NH2:31])=[O:30])[CH3:25])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)C(N)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)(C)C(N)=O
Yield: 49.1 %

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.2 g, 0.568 mmol) was coupled with 2-methylalaninamide hydrochloride using an analogous method to that described for the equivalent step in Example 62 to give the title product (0.12 g, 49.1%); Mass Spectrum: (M+H)+ 418.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16]S(C3C=C(C)OC=3C)(=O)=O)[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31]1.FC1C=CC(OC)=C(C2C=CC(C(N)C)=CC=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:33]3[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31][N:30]([CH3:29])[CH:34]=3)(=[O:37])=[O:36])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Agent: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride and 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.40, 7.16 (a/b, 4H), 7.05-6.88 (m, 3H), 4.89 (m, 1H), 4.60 (t, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 480 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.CC[N:27]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:27])=[O:24])[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Yield: 86.9 %

Procedure:
A solution of 4-(4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (105 mg) obtained in Example 23, HOBt ammonium salt (139 mg) and EDCI hydrochloride (175 mg) in DMF (15 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (91 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]([CH3:34])=[C:16]([CH2:18][CH2:19][O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH2:23][CH2:24][CH:25]=[C:26]5[CH2:31][CH2:32][OH:33])[N:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(OCC)(=O)C.CS(C)=O.C(N(C(C)C)CC)(C)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:14][C:15]([CH3:34])=[C:16]([CH2:18][CH2:19][O:20][C:21]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:22]=4[CH2:23][CH2:24][CH:25]=[C:26]5[CH2:31][CH:32]=[O:33])[N:17]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(C3CCCCC3)cc2)nc1CCOc1cccc2c1CCC=C2CCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1oc(-c2ccc(C3CCCCC3)cc2)nc1CCOc1cccc2c1CCC=C2CC=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 131.4 %

Procedure:
To a mixed solution of the compound (1.20 g) prepared in Example 3 in ethyl acetate (12 ml) and dimethylsulfoxide (5.0 ml), diisopropylethylamine (2.7 ml) was added, and a dimethylsulfoxide (6.5 ml) solution of sulfur trioxide-pyridine complex (1.25 g) was added dropwise thereto at −10° C., followed by stirring at −10° C. for 2 hours. The reaction mixture was poured into cold water, and extracted with ethyl acetate. The extract was washed with a saturated saline, dried with anhydrous magnesium sulfate, and concentrated to thereby obtain the crude title compound (1.57 g) having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH:16]1([N:15]2[C:9]3[N:10]=[C:11]([NH2:14])[N:12]=[CH:13][C:8]=3[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([F:21])[C:2]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ncc(-c2ccnc(F)c2Br)c(NC2CCCC2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Temperature: 120 °C
Yield: 84.5 %

Procedure:
Compound 244 (0.143 g, 0.41 mmol), and cesium carbonate (0.40 g, 1.2 mmol) were combined in 5 mL of anhydrous 1,4-dioxane. Nitrogen was bubbled through the solution briefly before adding Pd2(dba)3 (0.037 g, 0.041 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.047 g, 0.081 mmol). The solution was heated at 120° C. with microwave irradiation for 1 hour. The solution was purified on CombiFlash column (dry loaded) eluting with a gradient of 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 7% methanol/0.35% NH4OH (˜28% in water)/DCM. The fractions containing the pure product were combined and concentrated under vacuum to give compound 245 (94 mg, 85%) as a light brownish solid. 1H NMR (500 MHz, DMSO-d6) δ 9.10 (1 H, s), 7.94 (1 H, dd, J=5.2, 1.5 Hz), 7.91 (1 H, dd, J=5.1, 2.9 Hz), 7.10 (2 H, br. s.), 5.38-5.49 (1 H, m), 2.10-2.23 (2 H, m), 1.93-2.08 (4 H, m), 1.64-1.79 (2 H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 272.0.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])O.[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C1C=CC=CC=1>O>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH:2]([CH3:4])[C:1]#[N:5])[CH2:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: CC(O)C#N
Solvent: c1ccccc1
Solvent: O
Product: CC(C#N)N1CCN(C)CC1

Procedure:
Lactonitrile (71.08 g.) is added in a dropwise manner to a stirred solution of 100.1 g. of 1-methyl-piperazine in 500 ml. of benzene. The resulting warm solution is heated at reflux under a water separator until the theoretical amount of water is collected (about 4 hours). The solution is evaporated at reduced pressure and the residue is fractionated. The product, 2-(4-methyl-1-piperazinyl)propionitrile, is obtained as an oil, b.p. 128°-130° C./23 mm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=2[CH3:27])[CH:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[CH3:27])[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Reaction time: 8 h

Procedure:
[1-(6-Amino-pyrimidin-4-yl)-1H-benzoimidazol-2-yl]-(2-methyl-5-nitrophenyl)-amine (135 mg, 0.37 mmol) is dissolved in ethanol (30 mL). After hydrogenation catalyzed by palladium (10 wt % on activated carbon, wet, Degussa type, 22 mg) under 1 atm H2 balloon overnight, the reaction mixture is filtered through a pad of celite and washed with ethanol. The combined filtrate and washings are concentrated to afford the title compound, which is used for next reaction without any further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1nc(N)sc1C
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: COC(=O)Cc1nc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (27.2 mg) with purity >80%. MS (pos) m/z 409.0, 411.0.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[OH:14]C1C=C2C(C(=O)CCO2)=CC=1>>[OH:14][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[O:10][CH2:9][CH2:8][C:7]2=[O:13]
Reactant: O=C1CCOc2cc(O)ccc21
Reactant: COc1ccc2c(c1)OCCC2=O
Product: O=C1CCOc2ccc(O)cc21

Procedure:
By the same method, 7-methoxy-4-chromanone was converted to 7-hydroxy-4-chromanone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:13]([CH:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)([CH3:15])[CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[CH2:24][CH:25]([O:27][CH:28]([CH3:31])[CH2:29]Cl)[CH3:26].O>C1(O)CCCCC1>[CH3:24][CH:25]1[O:27][CH:28]([CH3:31])[CH2:29][N:22]([CH:19]2[CH2:18][CH2:17][CH:16]([C:13]([CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)([CH3:15])[CH3:14])[CH2:21][CH2:20]2)[CH2:26]1
Reactant: CC(CCl)OC(C)CCl
Reactant: CC(C)(C1CCCCC1)C1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OC1CCCCC1
Product: CC1CN(C2CCC(C(C)(C)C3CCCCC3)CC2)CC(C)O1

Procedure:
41.4 g (0.3 mole) of potassium carbonate is added to a solution of 23.3 g (0.1 mole) of 4-(2-cyclohexylprop-2-yl)-cyclohexylamine and 17.1 g (0.1 mole) of di-(1-chloro-2-propyl)-ether in 200 ml of cyclohexanol, and the mixture is refluxed for 8 hours while stirring. After cooling, approx. 100 ml of water is added, and the organic phase is separated and dried over a small amount of Na2SO4. The residue remaining after the cyclohexanol has been distilled off is fractionally distilled under reduced pressure. At 160°-164° C./0.2 mm there is obtained 16 g (50% of theory) of the captioned compound as a colorless oil (isomer mixture; compound no. 1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:16][C:17]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:22]([CH3:27])=[C:21]([CH3:28])[C:18]=1[CH2:19]Br>CCO>[CH3:19][C:18]1[C:17]([CH3:16])=[C:24]([CH3:25])[C:23]([CH3:26])=[C:22]([CH3:27])[C:21]=1[CH2:28][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: Cc1c(C)c(C)c(CBr)c(C)c1C
Solvent: CCO
Product: Cc1c(C)c(C)c(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c(C)c1C

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 2,3,4,5,6-pentamethylbenzylbromide (0.295 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](O)([C:21]([F:24])([F:23])[F:22])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:17]([F:20])([F:19])[F:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=[C:6]1[C:17]([F:19])([F:20])[F:18])[C:21]([F:24])([F:23])[F:22]
Reactant: COC(=O)C(O)(c1c(C(F)(F)F)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C(F)(F)F)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-3-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (192 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (183 mg).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3[nH]2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3[nH]2)cc1
Yield: 31.2 %

Procedure:
A solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.44 mmol) in methanol (70 mL) was passed through a H-Cube reactor (10% palladium on activated carbon, 50° C., 50 bar of hydrogen pressure, 1 mL/minute). The reaction solution was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 41%) as a white solid: LC/MS m/e calcd for C22H23F3N2O2S [M+H]+ 437.50, observed 436.9; 1H NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1H), 8.23 (s, 1H), 7.93-7.98 (m, J=8.3 Hz, 2H), 7.63-7.69 (m, J=8.3 Hz, 2H), 6.59 (s, 1H), 4.40 (t, J=7.8 Hz, 1H), 3.14 (s, 3H), 2.30-2.38 (m, 1H), 2.15-2.24 (m, 1H), 1.65-1.92 (m, 5H), 1.49-1.61 (m, 2H), 1.21-1.38 (m, 2H).
Reaction SMILES: [C:1](=[O:8])([S:5][CH2:6][CH3:7])[O:2][CH2:3]I.[C:9]([O-:14])(=[O:13])[CH2:10][CH2:11][CH3:12].[Na+]>CN(C=O)C>[C:1](=[O:8])([S:5][CH2:6][CH3:7])[O:2][CH2:3][O:14][C:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCSC(=O)OCI
Reactant: CCCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)SCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Crude 5b (23.6 g, 96 mmol) is added during 30 min to a stirred suspension of sodium butanoate (10.5 g, 96 mmol) in dry DMF (125 mL) at -20° C. followed by stirring overnight at ambient temperature. After filtration and washing with DMF (5 mL) and Et2O (10 mL),Et2O (250 mL) and ice-cold H2O (100 mL) are added to the combined filtrates. The aqueous phase is separated and extracted with Et2O (100 mL). The combined organic phases are washed (all solutions ice-cold) with 5% aqueous NaHCO3 (50 mL), H2O (50 mL), 0.01N HCl (100 mL), and H2O (2×50 mL). After drying (MgSO4) and evaporation of solvents the residue is distilled to yield 15.0 g (76%) of 6db, bp 75°-80° C./0.5 mbar.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]([CH:17]2[CH2:20][C:19](OC)([O:21]C)[CH2:18]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.C(Cl)Cl>[C:1]([N:5]1[C:9]([NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[CH:8][C:7]([CH:17]2[CH2:18][C:19](=[O:21])[CH2:20]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1(OC)CC(c2cc(NC(=O)C(F)(F)F)n(C(C)(C)C)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)n1nc(C2CC(=O)C2)cc1NC(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a stirring solution of N-[2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-yl]-2,2,2-trifluoro-acetamide (6.5 g, 18.5 mmol) in acetone (182 mL) and water (61 mL) was added p-toluenesulfonic acid monohydrate (1.8 g, 9.5 mmol) and the reaction mixture was heated to 65° C. After 1.5 hr, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (250 mL), and water (50 mL). The layers were separated and the aqueous layer was back-extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the resulting material was accomplished by trituration with isopropyl ether. The product was collected and dried under reduced pressure to yield the title compound (4.2 g, 76% yield, two crops) as a yellow solid. 400 MHz 1H NMR (CDCl3) d 7.86 (bs, 1H), 6.33 (s, 1H), 3.62 (dddd, J=7.6, 7.6, 7.6, 7.6 Hz, 1H), 3.46-3.30 (m, 4H), 1.62 (s, 9H). LRMS m/z (APCI+) 304 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC1(C)C(C)(C)OB(/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2](/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(C)c(Br)c1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C(=O)OC)cc(Br)c1C
Temperature: 100 °C

Procedure:
To a solution of methyl 3,5-dibromo-4-methylbenzoate (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.02 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.