Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:14])[CH2:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>N1C=CC=CC=1>[OH:14][CH:11]([CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][O:13][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=1
Reactant: OCC(O)C(c1ccccc1)n1ccc2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=C(OCC(O)C(c1ccccc1)n1ccc2ccccc21)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol (EXAMPLE 1, step 1, 1.83 g, 6.9 mmol) in anhydrous pyridine (25 mL), p-nitrobenzoyl chloride (1.3 g, 6.9 mmol) in 1 mL of pyridine was added at −10° C. dropwise. After stirring for 30 minutes, the reaction mixture was cooled with an ice bath and quenched with water and a 2N aqueous solution of hydrochloric acid until the solution was pH=3 and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give (2RS,3RS)-4-nitro-benzoic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester quantitatively as a yellow solid. MS (ESI) m/z 417 ([M+H]+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([C@@H:26]4[CH2:28][C@H:27]4[CH3:29])[NH:23][N:22]=3)[C:17]([Cl:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[Cl:30][C:17]1[C:18]([NH:20][C:21]2[CH:25]=[C:24]([C@@H:26]3[CH2:28][C@H:27]3[CH3:29])[NH:23][N:22]=2)=[N:19][C:14]([C:11]2[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=2)=[N:15][CH:16]=1
Reactant: C[C@@H]1C[C@H]1c1cc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Cl)n[nH]1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@H]1c1cc(Nc2nc(-c3ccc(S(N)(=O)=O)s3)ncc2Cl)n[nH]1
Yield: 89.7 %

Procedure:
The solution of N-tert-butyl-5-(5-chloro-4-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (90 mg, 0.19 mmol) in TFA (5 mL) was heated to reflux for 0.5 h. After concentration, the resulting residue was dilute with EtOAc and washed with water, saturate NaHCO3, brine, dried (Na2SO4) and filtered. The filtrate was concentrated to afford the title compound 5-(5-chloro-4-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 320) (70 mg, 89%). LC-MS (m/z)=411 [M+H]% 1H NMR (400 MHz, DMSO-d6) δ 0.78-0.81 (m, 1H), 0.92-0.95 (m, 1H), 1.16 (m, 4H), 1.64-1.65 (m, 1H), 6.37 (s, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H), 7.81 (s, 2H), 8.45 (s, 1H), 9.42 (s, 1H), 12.26 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:37])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:36])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:3][C:4]([OH:6])=[O:5].[Na].O.Cl>CCCCCO>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:37])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:36])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:35])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O

Procedure:
82 g of 3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaenoic acid was dissolved in 1 l of n-amyl alcohol and 74 g of metallic sodium was added portionwise while the solution was vigorously stirred. After metallic sodium was completely dissolved, the reaction solution was poured into iced water and was made acidic by adding 300 ml of 6N hydrochloric acid. It was then extracted with 1 l of n-hexane, washed with water, dried and concentrated. 78 g of colorless, oily 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenoic acid was obtained as the crude product. The product was then added dropwise to 500 ml of an ethereal suspension of 10 g of lithium aluminum hydride while being cooled by ice and stirred. After stirring was continued for 30 minutes, 10 ml of water with 10 ml of a 15% caustic soda solution, and 30 ml of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 ml of ether. The filtrate was concentrated and the concentrate was defined by silica gel column chromatography, providing the captioned 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol as a colorless oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[OH:20])[CH3:2].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:6]([O:20][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:10]=1[CH3:11])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCCCc1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Ethyl-4-benzyloxy-2-hydroxy-6-methyl-benzoate (0.5 g, 1.8 mmol) is dissolved in DMF (10 mL) and 60% sodium hydride (0.07 g, 1.8 mmol) is added and stirred 20 minutes, forming a clear solution. Then 1-bromo-3-phenyl propane (0.27 mL, 1.8 mol) is added and this mixture is heated at 100° C. for 4 hours and stirred at room temperature overnight. The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 5% ethyl acetate in hexanes) to give the title compound: 1H NMR (300 MHz, CDCl3) δ 7.17-7.40 (m, 10H), 6.39 (d, 1H), 6.33 (d, 1H), 5.03 (s, 2H), 4.38 (q, 2H), 3.91 (t, 2H), 2.77 (t, 2H), 2.30 (s, 3H), 2.05 (m, 2H), 1.38 (t, 3H); MS (EI) 404 (M)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30](B(O)O)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[N:25]([CH3:24])[CH:26]=[CH:27]5)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: Cn1ccc2cc(B(O)O)ccc21
Product: COc1cc2ncn(-c3nc(-c4ccc5c(ccn5C)c4)c(C(=O)O)s3)c2cc1OC
Yield: 11.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and N-methylindole-5-boronic acid (26.2 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(1-methyl-1H-indol-5-yl)-thiazole-5-carboxylic acid (5.1 mg, 12%) as a white solid. MS 435 m/z (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].F[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1)=[N:10][CH:11]=[N:12]2>>[NH2:1][CH2:2][C@@H:3]([CH3:4])[O:5][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1)=[N:10][CH:11]=[N:12]2
Reactant: C[C@@H](O)CN
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN)c23)ccc1O
Yield: 65 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (R)-(−)-1-amino-propan-2-ol and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-methylphenol as a brown solid in 65% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.16 (s, 3H), 2.96 (m, 2H), 3.30 (s, 2H), 4.96 (m, 1H), 6.77 (d, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 7.67 (t, 1H), 8.39 (s, 1H), 9.16 (s, 1H), 10.50 (s, 1H); Mass spectrum MH+ 325.
Reaction SMILES: C([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#N.C(=O)([O-])[O-].[K+].[K+].CN(C)S(Cl)(=O)=O>C(#N)C>[N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][CH:3]=1
Reactant: N#Cc1nc2ccccc2[nH]1
Agent: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2[nH]cnc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 Grams of a 2-cyanobenzimidazole compound [compound (iii)] of the formula (II) in which X is Br and Z is OCF2CFHO was dissolved in 70 ml of acetonitrile. 1.5 Grams of potassium carbonate was added thereto. The resulting mixture was heated under reflux for 20 minutes. Thereafter, 1.2 g of dimethylsulfamoyl chloride was added thereto. Refluxing was continued for 1 hour with heating. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. Column chromatographying the resulting residue on silica gel with chloroform as an eluent and recrystallizing it from hexane/ethyl acetate gave 1.18 g of a benzimidazole derivative [present compound (3)]of the formula (I) in which X is Br, Z is OCF2CFHO, R is CN and Q is N(CH3)2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[CH:23]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: CCOc1ccccc1-c1cccs1
Product: CCOc1ccccc1-c1ccc(Cc2cc(Br)ccc2Cl)s1

Procedure:
The above 2-(2-ethoxyphenyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)benzene as colorless oil. APCI-Mass m/Z 407/409 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=O)=[CH:18][CH:17]=1.[NH3:28].CO>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH2:28])=[O:26])=[CH:18][CH:17]=1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: N
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Methyl 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate (600 mg, 1.64 mmol) obtained in Example 16 was added to ammonia/methanol (50 ml), and the mixture was stirred for 24 hr at room temperature. The solvent was evaporated under reduced pressure. Ethyl acetate (50 ml) and 1N aqueous sodium hydroxide solution (50 ml) were added for partition. The organic layer was washed with water (50 ml) and saturated brine (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (464 mg, yield 80%) as a white solid.
Reaction SMILES: C(OC)(=O)C1C=CC=CC=1.Cl[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.[I-:26].[Na+]>CC(C)=O.C(OCC)C>[I:26][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: COC(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OCCCI)cc1

Procedure:
4-[3-4-[(2-Benzothiazolyl )carbonyl]-1-piperidinyl]propoxy]benzoic acid, methyl ester ##STR22## Dissolve 4-(3-chloropropoxy)benzoic acid, methyl ester (6.97 g, 30.5 mmol) in anhydrous acetone (100 mL) and add powdered sodium iodide (16.0 g, 107 mmol). Heat at reflux under an argon atmosphere for 38 hours. Dilute with ethyl ether (100 mL) and filter through Celite® filter aid. Wash the filtrate with water and brine, then dry (MgSO4). Evaporate the solvent in vacuo to give 4-(3-iodopropoxy)benzoic acid, methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][NH:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10].[CH2:17]=[O:18].O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][N:5]([CH2:17][OH:18])[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10]
Reactant: C=O
Reactant: CCCNC(=O)NOc1cc(Cl)ccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)N(CO)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.0 g (7.6 mmoles) of 3-(2,5-dichlorophenoxy)-1-n-propyl-urea, and then 1.87 g (22.8 mmoles) of 37% aqueous formalin solution was added The mixture was stirred at 25° C. for 3 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure The residue was recrystallized from ethyl acetate and toluene to give 1.4 g (yield 63%) of the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([OH:10])[CH:7]=2)[O:2]1.[OH-].[Na+].S(Cl)([Cl:16])(=O)=O>C(OCC)C>[Cl:16][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[OH:10]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Oc1cc2c(cc1Cl)OCO2

Procedure:
To a solution of 0.18 mol (25 g) of 4,5-methylenedioxyphenol in 125 ml of ethyl ether, 17 ml of sulphuryl chloride are added at a temperature below 35° C. As soon as the addition is complete, the ethyl ether is evaporated off at room temperature. The dry residue thereby obtained is taken up with 2N sodium hydroxide. The mixture is filtered to remove a resin. The filtrate is acidified with 2N hydrochloric acid; the expected product precipitates. After being washed with water and dried under vacuum in the presence of phosphorus pentoxide, it is recrystallized from a cyclohexane/benzene mixture. It melts at 95° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[CH3:24][NH:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][N:27]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:24][NH:25][C:26]1[C:31]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][C:9]([C:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=4)=[CH:10][C:3]=23)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1
Reactant: CNc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNc1ncccc1-c1ccnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 100 °C

Procedure:
A mixture of Example 135D (170 mg, 0.45 mmol), N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (105 mg, 0.45 mmol), bis(triphenylphosphine)palladium(II) chloride (31 mg, 0.045 mmol), tricyclohexylphosphine (13 mg, 0.045 mmol) and cesium carbonate (443 mg, 1.34 mmol) in a round bottom flask was purged with nitrogen. Dioxane (10 mL) was added and the mixture was heated at 100° C. overnight. After cooling, the mixture was triturated with dichloromethane (200 mL) and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 406 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[CH:4][C:3]=1[CH3:36].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][C:3]=1[CH3:36]
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)ccc1F
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 65.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-3-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.067 g, 0.61 mmol), the title compound (0.038 g, 64%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[CH:4][N:3]=1.[CH:10]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:12][CH2:11]1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH:17]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[N:14]=[CH:15]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: Fc1cnc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [Cs+]
Solvent: CCCC#N
Product: Fc1cnc(Cl)cc1-n1cnc(C2CC2)c1

Procedure:
A suspension 2-chloro-5-fluoro-4-iodopyridine (1.8 g, 1.00 mmol), 4-cyclopropyl imidazole (982 mg, 9.10 mmol), Cu2O (100 mg, 0.700 mmol), 8-hydroxyquinoline (152 mg, 1.05 mmol), cesium carbonate (4.60 g, 14.0 mmol), and PEG-3350 (1.4 g) in butyronitrile (50 mL) was heated at 65° C. for 16 hours. The reaction mixture was filtered through Celite, concentrated and the residue was partitioned between dichlormethane and water. The layers were separated and the aqueous layer washed twice with dichloromethane. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (15→60% EtOAc in hexanes) to afford 2-chloro-4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+]([O-])([O-])=[O:11].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
Into a reactor are placed 1.22 g of p-methyl anisole and 23.0 g of ammonium cerium(IV) nitrate, and 150 ml of water is further placed into the reactor. The mixture is stirred at room temperature for 6 hours. The same extraction and purification steps as in Example 1 are performed for the reaction mixture, affording anisaldehyde in a yield of 20% and a large amount of tar-like compound of unidentified structure.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([NH2:32])([CH3:31])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[N:21]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:32][C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)([CH3:31])[CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Agent: Br
Agent: Cl
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid;hydrochloride (example 145d) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer A) (example 124b) as starting materials and isolated (16 mg, 20%); MS (ESI, m/z): 445.3 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CS(Cl)(=O)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:1][CH2:2][CH:3]4[NH:7][C:6](=[O:8])[CH2:5][CH2:4]4)=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: O=C1CCC(COc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)N1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (315 mg, 2.74 mmol) in N,N-dimethylformamide (3 mL) is treated with methansulfonyl chloride (320 mg, 2.74 mmol) and heated at 60° C. for 5 h. The reaction mixture is diluted with N,N-dimethylformamide (1 mL) and 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (200 mg, 0.91 mmol) added. The mixture is stirred at 60° C. for additional 16 h, cooled to room temperature, and partitioned between ethyl acetate and water. The organic portion is washed three times with water, once with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude residue is chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 32 mg (8%), as a light red solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[CH:9][CH:10]=1>CO>[CH3:1][O:2][C:5]1[N:6]=[N:7][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1

Procedure:
A solution of sodium methoxide in methanol (28%, 411 mg) was added to a mixture of 3-(3-chloropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (436 mg) and methanol (4 ml) at room temperature. The reaction mixture was heated under reflux for 3 hours. After evaporating the solvent in vacuo, a saturated aqueous solution of sodium chloride (20 ml) was added to the residue and extracted with chloroform (20 ml×3). The combined extract was washed with a saturated aqueous solution of sodium chloride (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (10 g) using chloroform as an eluent and recrystallized from 95% EtOH to give 3-(3-methoxypyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (165 mg).