Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:20])([F:19])[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:10]#[N:11]>[Br-].[Zn+2].[Br-].O>[F:5][C:6]([F:19])([F:20])[C:7]1[CH:8]=[C:9]([C:10]2[NH:11][N:3]=[N:2][N:1]=2)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: N#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: FC(F)(F)c1cc(-c2nnn[nH]2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
Anhydrous zinc bromide (93.5 g, 415 mmol, 0.99 equiv.), sodium azide (29.8 g, 458 mmol, 1.1 equiv.) and water (750 ml) were added to 3,5-bis(trifluoromethyl)benzonitrile (100.0 g, 418 mmol, 1.00 equiv.). The resulting suspension was stirred for 10 days at ambient temperature. The completion of the reaction was confirmed by reversed phase HPLC on a Waters Novapak C18 column (3.9×150 mm) eluting with a linear gradient from 40% to 100% acetonitrile in 250 mM triethylammonium acetate buffer pH 6.5 in 15.00 minutes with a flow rate of 1.0 mL/min, detection at λ=270 nm, product retention time 2.0 min., educt retention time 6.5 min. Ethyl acetate (3.8 ltr.) and 10% citric acid in water were added and the resulting mixture was vigorously stirred for 15 minutes. The aqueous phase was separated and extracted with ethyl acetate (2×900 ml). The organic phases were combined and evaporated to dryness. The resulting solid was stirred in aqueous NaOH solution (0.25 M, 3.8 ltr.) for 30 minutes to give a suspension, which was filtered. The filtrate was acidified with aqueous HCl (375 ml conc. hydrochloric acid and 375 ml water) which caused the product to precipitate as a fine white powder. The product was collected by filtration after one hour, washed with cold hexanes (100 ml) and dried in a desiccator under vacuum, yield 72.7 g (62%) of compound (8) as white crystalline powder. The purified product had a purity of 100% by reversed phase HPLC as depicted in FIG. 4. 1H NMR (300 MHz, d6-DMSO) δ 8.26 (s, 1H), 8.59 (s, 1H), m.p. 179° C. The product can be recrystallized from toluene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][Se]C2C=CC=CC=2[N+]([O-])=O)[C@@H:12]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:11]([CH3:36])[O:10][C:9]1=[O:37])([CH3:4])([CH3:3])[CH3:2].OO>C1COCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH:17]=[CH2:18])[C@@H:12]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@H:11]([CH3:36])[O:10][C:9]1=[O:37])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CC[Se]c2ccccc2[N+](=O)[O-])[C@H]1Oc1ccccc1
Agent: OO
Solvent: C1CCOC1
Product: C=C[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-9-methyl-7-(2-((2-nitrophenyl)-selanyl)ethyl)-2-oxo-8-phenoxyoxonan-3-yl)carbamate (284 mg, 0.480 mmol) in THF (4.8 mL) was added 30% aqueous hydrogen peroxide (H2O2 392 μl, 3.84 mmol), and the resulting bright yellow solution was stirred at room temperature for 3 d. The reaction was cooled to 0° C. (icewater bath), quenched with sat. aqueous NaHSO3 solution (4 mL), diluted with H2O (20 mL), and extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered, and concentrated to the title compound as an orange solid (134.9 mg, 72%): 1H NMR (400 MHz, CDCl3) δ 7.34-7.19 (m, 2H), 7.02-6.86 (m, 3H), 5.76 (ddd, J=17.2, 10.3, 8.0 Hz, 1H), 5.17-5.06 (m, 2H), 5.03 (d, J=17.1 Hz, 1H), 4.94 (d, J=10.4 Hz, 1H), 4.28 (t, J=8.8 Hz, 1H), 4.25-4.17 (m, 1H), 2.56-2.41 (m, 1H), 2.27 (dt, J=13.5, 6.6 Hz, 1H), 1.85 (td, J=14.6, 7.1 Hz, 1H), 1.75 (dt, J=14.8, 7.3 Hz, 1H), 1.65 (s, 1H), 1.44 (s, 9H), 1.33 (d, J=6.4 Hz, 3H), 1.31-1.17 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 173.35, 159.33, 138.51, 129.49, 121.10, 116.18, 115.78, 99.98, 80.46, 74.39, 53.05, 47.47, 34.13, 31.07, 28.34, 19.66, 18.36; HRMS-ESI (m/z) ([M+Na]+) calcd for C22H31NO5Na, 412.2094, found 412.2106.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[NH:27][CH2:26][CH2:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:22]=3[CH:32]=2)=[CH:14][CH:13]=1)[CH2:9][CH3:10].C(OC=O)=O>C1COCC1>[CH:1]([N:27]1[C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:8][CH2:9][CH3:10])=[CH:17][CH:16]=3)=[CH:32][C:22]=2[CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:26]1)=[O:3]
Reactant: CC(=O)O
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: O=COC=O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.65 ml) was added formic acid (0.32 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, air-cooled and diluted with THF (10 ml). In THF (10 ml) was dissolved methyl 7-(4 propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (520 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (563 mg) as white crystals.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:52])[C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)[CH:9]=[CH:8][C:7]=1[F:51].Cl>CO>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:7]([F:51])=[C:6]([CH:11]=2)[C:5]([OH:52])=[O:4])[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: COC(=O)c1cc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(F)c(C(=O)O)c1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C
Yield: 98.6 %

Procedure:
Add 2 N sodium hydroxide solution (2 mL) to a solution of (S)-5-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-2-fluoro-benzoic acid methyl ester (0.120 g, 0.167 mmol) in methanol (5 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (0.116 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 1.60-1.85 (m, 2H), 2.01-2.10 (m, 2H), 2.32 (s, 3H), 2.75-2.84 (m, 1H), 2.97-3.01 (m, 1H), 4.10-4.11 (m, 1H), 4.14 (s, 3H), 4.20-4.35 (m, 2H), 4.76-5.10 (m, 2H), 5.65-5.70 (m, 1H), 6.89 (s, 1H), 7.10-7.15 (m, 1H), 7.32-7.40 (m, 2H), 7.56-7.60 (m, 2H), 7.67 (s, 1H), 8.10(s, 1H); ESI MS m/z 705 [C31H26F10N6O2+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19](O)=[O:20])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([NH:24][CH3:22])=[O:20])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
A solution of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0155 mole) and 1,1'-carbonyldiimidazol (2.52 g, 0.0155 mole) in dry tetrahydrofuran (100 ml) was refluxed under nitrogen for two hours. The solution was cooled to room temperature and a stream of nitrogen was bubbled through it for thirty minutes. A solution of methylamine in tetrahydrofuran (36 ml of a 2.59M solution, 0.0932 mole) was added and the suspension was stirred at room temperature under nitrogen for three days. The solvents were evaporated under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, dried over magnesium sulfate, treated with charcoal and filtered while hot. The filtrate was reduced to one-half its original volume and isopropyl ether was added. Upon cooling to room temperature, solid precipitated, which was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at 60° C. to give 3.45 g (66% yield) of title compound, mp >250° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].CCO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([C:12](=[NH:13])[NH:18][OH:19])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Temperature: 60 °C

Procedure:
A 5 L round bottom flask equipped with an overhead stirrer, and 500 mL addition funnel was charged with 3-(t-butyloxycarbonylamino)benzonitrile (264.4 g, 1.21 mol), hydroxylamine hydrochloride (294.6 g, 4.24 mol) and 95% EtOH (1 L). The resulting suspension was treated with a solution of potassium carbonate (711.8 g, 5.15 mol) in water (1 L) and the suspension heated to 60° C. The reaction was followed by TLC and HPLC for starting material consumption to completion. The reaction mixture was then cooled to ambient temperature the organic layer was separated and concentrated to approximately 500 mL, then diluted with water (1 L). The resulting precipitate was collected by vacuum filtration and dried to yield the title compound as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:19]([NH:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc2c(c1F)CCC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C1CCc2c1ccc(NCc1ccccc1)c2F
Yield: 10.4 %

Procedure:
As presented in the following reaction formula, a mixture of 5-amino-4-fluoro-2,3-dihydro-1H-inden-1-one (2.3 g, 14 mmol), cesium carbonate (Cs2CO3; 12 g, 28 mmol) and benzyl bromide (0.17 g, 72 mmol) in acetonitrile (CH3CN; 20 mL) was stirred under reflux for 48 hours. The mixture was concentrated to obtain the residue, which was dissolved in water (20 mL). The resulting solution was extracted three times with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine (50 mL), and dried and concentrated with anhydrous sodium sulfate to thereby give a crude product, which was purified by pre-TLC to give 5-(benzylamino)-4-fluoro-2,3-dihydro-1H-inden-1-one (370 mg, yield: 10%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[N:30]1([CH2:36][CH2:37][C:38]#[C:39][C:40](O)=[O:41])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl.ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:40](=[O:41])[C:39]#[C:38][CH2:37][CH2:36][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCNC4)ccc1OCc1ccccn1
Reactant: O=C(O)C#CCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(C#CCCN1CCCCC1)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a suspension of [3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)amine (0.051 g, 0.00028 mol), 5-Piperidin-1-yl-pent-2-ynoic acid (0.100 g, 0.00023 mol), O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.091 g, 0.00028 mol) in mixture of dichloromethane/tetrahydrofuran (1.2/1.2 ml) was added diisopropylethylamine (0.123 ml, 0.001 mol) slowly over 15 min. The mixture stirred at room temperature for 3 hours. Reaction was judged complete by TLC (Eluent: 10% MeOH/DCM). The reaction mixture was concentrated to dryness under vacuum, dissolved in MeOH (1.5 ml), filtered and subjected to reverse phase HPLC purification to give the desired product (0.087 g, 62.81%)of the desired product. 1H-NMR (CD2Cl2) δ 8.60 (d, 1H), 8.45 (s, 1H), 7.80 (m, 2H), 7.63 (d, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 7.04 (m, 2H), 5.25 (s, 2H), 4.98 (d, 2H), 4.05 (dd, 2H), 3.10 (d, 2H), 2.60 (m, 4H), 2.40 (m, 4H), 1.62 (m, 4H), 1.45 (m, 2H); LCMS RT=2.37 min; [M+H]+=587.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH:6]=O.[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:19]2[CH2:18][CH2:17][N:16]([C:22]3[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=3)[CH2:21][CH2:20]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)Oc1ccc(C=O)cc1OC
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)Oc1ccc(CN2CCN(c3ccc(C(C)=O)cc3)CC2)cc1OC

Procedure:
To a solution of 3-methoxy-4-(methylaminocarbonyloxy)benzaldehyde (1.0 g) in 1,2-dichloroethane (20 ml) was added 4′-piperazinoacetophenone (0.98 g), followed by sodium triacetoxyborohydride (1.53 g), with stirring. The reaction mixture was stirred overnight at ambient temperature, poured into saturated sodium carbonate solution (75 ml) and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel and dichloromethane), eluting with the same solvent system, followed by 1% methanol:dichloromethane. The appropriate fractions were combined and concentrated. The residue was recrystallized from ethyl acetate to give product, mp 120-123° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14](Br)=[C:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:12]=1)=[O:10].[CH:29]1([CH2:32][O-:33])[CH2:31][CH2:30]1.[Li+]>O1CCCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[C:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:12]=1)=[O:10]
Reactant: [O-]CC1CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.048 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide was added 1 ml of a 0.25 M solution of lithium cyclopropylmethoxide in tetrahydrofuran and the mixture was stirred at room temperature for 30 min. The orange reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine. After evaporation the crystalline residue was triturated under methanol to yield 0.028 g of the title compound as white crystals. MS (M−H) at 468.2.
Reaction SMILES: F[C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=C[C:20]([C:21]#N)=[CH:19]N=1.C1(O)CCCC1>>[CH:3]1([O:4][C:5]2[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:21][CH2:20][CH2:19][CH2:2]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: OC1CCCC1
Product: CC(N)c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and cyclopentanol.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17].O>C1CCCCC1>[Cl:14][C:15]1[C:16]([OH:17])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:21]=1[CH3:23]
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of 30.0 g (0.18 mole) trichloroacetamidine, 25.2 g (0.18 mole) potassium carbonate, 30.3 g (0.18 mole) ethyl 2-chloroacetoacetate, and 300 ml water was stirred 18 hours. The aqueous solution was decanted from heavier tars and acidified with hydrochloric acid. The precipitate that was formed was filtered, washed, and dried to give 14.7 g (31% yield; mp 130°-145° C.) of crude product. An analytical sample was prepared by recrystallization from cyclohexane (mp 156°-157° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=CC(C2CCC3C(=CC=C(OC4N=CC(N)=CC=4)C=3)O2)=CC=1>C(OCC)(=O)C.CCCCCCC>[F:29][C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
N-{6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl] methane sulfonamide in Example 46 starting from 442 mg of 6-[2-(4-fluorophenyl)-chroman-6-yloxy]-pyridin-3-ylamine (Example 76). The product was passed through silica gel using ethyl acetate-heptane (10:3) as an eluant and then crystallised from diethyl ether. 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, 1H, J 2.8 Hz), 7.72 (dd, 1H, J 8.9, 2.8 Hz), 7.40 (m, 2H), 7.08 (m, 2H), 6.92-6.87 (m, 4H), 6.74 (s, 1H), 5.03 (dd, 1H, J 10.4, 2.3 Hz), 3.01 (m, 1H), 3.00 (s, 3H), 2.80 (m, 1H), 2.19 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:9]=O)(=[O:4])=[O:3].[I-].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](/[CH:33]=[CH:9]/[C:8]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=2)=[N:25]1
Reactant: CS(=O)(=O)Nc1cc(C=O)ccc1OCCN1CCOCC1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(/C=C/c2n[nH]c3ccccc23)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of 3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehyde obtained in Step 4 (0.27 g, 0.83 mmol) in DMF (5.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium iodide obtained in Step 4 of Example 1 (0.40 g, 0.77 mmol) and potassium carbonate (0.23 g, 1.66 mmol), followed by stirring at room temperature for 2 hours, and further stirring at 60° C. for 11 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, the crude product was purified by silica gel chromatography [amino-modified chemically bound silica gel Chromatorex (registered trademark) NH, Fuji Silysia Chemical Ltd.; ethyl acetate, then methanol/ethyl acetate=1/19], was crystallized from ethyl acetate to obtain Compound 7 (0.05 g, 14%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([CH3:41])[C:12]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:30])[C:15]=3[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])=[CH:13][C:5]1=2)[CH:2]=[CH2:3].[CH2:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O)[CH2:43][CH:44]=[CH2:45].C([O-])([O-])=O.[Na+].[Na+].N#N>CN(C=O)C.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>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[C:11]([CH3:41])[C:12]([C:14]3[N:19]4[N:20]=[C:21]([C:23]5[CH:24]=[C:25]([C:47]6[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=6[CH2:42][CH2:43][CH:44]=[CH2:45])[CH:26]=[CH:27][CH:28]=5)[CH:22]=[C:18]4[N:17]=[C:16]([CH3:30])[C:15]=3[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])=[CH:13][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCOc2cc(C)c(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)cc21
Reactant: C=CCCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4cc5c(cc4C)OCCN5CC=C)n3n2)c1
Temperature: 90 °C

Procedure:
A solution of (2S)-methyl 2-(7-(4-allyl-7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.028 g, 0.045 mmol), (2-(but-3-en-1-yl)phenyl)boronic acid (0.016 g, 0.090 mmol) and 2.0 M aq. Na2CO3 (0.056 ml, 0.113 mmol) in dry DMF (2.5 ml) was sparged with N2 for 15 min, then treated with Pd(Ph3P)4 (3.7 mg, 3.2 μmol), sparged for another 5 min, then heated (90° C.) for 16 h. The reaction was cooled, filtered (0.45 μm syringe tip filter), and purified by prep-HPLC to afford the desired product. 1H NMR (500 MHz, CDCl3) δ 7.88 (dt, J=7.9, 1.3 Hz, 1H), 7.83 (t, J=1.5 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.32-7.36 (m, 2H), 7.29-7.31 (m, 1H), 7.26-7.28 (m, 2H), 6.88 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 5.65-5.85 (m, 2H), 5.21 (dd, J=17.2, 1.6 Hz, 1H), 5.10-5.15 (m, 2H), 4.85-4.94 (m, 2H), 4.33-4.38 (m, 2H), 3.78-3.86 (m, 1H), 3.68-3.76 (m, 1H), 3.67 (s, 3H), 3.23-3.40 (m, 2H), 2.78 (s, 3H), 2.66-2.74 (m, 2H), 2.26 (td, J=7.9, 6.7 Hz, 2H), 1.92 (s, 3H), 1.20 (s, 9H). LCMS (M+H)=671.5.