Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15](N)[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:2].[BrH:22].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.CC#N>[Br:22][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH:4]([N:5]3[CH:9]=[CH:8][N:7]=[CH:6]3)[CH:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[CH:19]=[CH:18][C:13]=2[N:14]=1
Reactant: CCC(CC)C(c1ccc2nc(N)sc2c1)n1ccnc1
Reactant: Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (260 mg, 0.866 mmol) and water (4 mL) at 0° C. was added aqueous HBr (0.98 mL, 8.66 mmol) and the mixture was cooled to −10° C. A cold (−10° C.) solution of sodium nitrite (75 mg, 1.08 mmol) in water (1 mL) was added to the reaction mixture over a period of 5 min while maintaining the temperature below −5° C. and the reaction was stirred at −10° C. for 15 min. To a cold (−10° C.) solution of CuBr2 (253 mg, 1.08 mmol) in water (4 mL) was added the reaction mixture and stirred for 10 min at 0° C. MeCN was added to the reaction mixture and then the reaction mixture was stirred for 2.5 h while warming to RT. The reaction was basified with sat. aq. NaHCO3 (pH 7) and then 10 N NaOH (pH 8) followed by celite filtration. The aqueous phase was extracted three times with DCM and the organic extracts were combined and dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as eluent to afford to 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole as white solid. MS (ES+): m/z 364 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].Cl[C:11]1[C:12]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:13][C:14]2[N:15]([C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][N:19]=2)[N:16]=1.[H-].[Na+]>CN(C=O)C.O>[CH3:30][C:27]([C:12]1[C:11]([O:9][CH2:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][N:6]=2)=[N:16][N:15]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][N:19]=[C:14]2[CH:13]=1)([CH3:28])[CH3:29]
Reactant: CCn1ncnc1CO
Reactant: CC(C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of (2-ethyl-2H-1,2,4-triazol-3-yl)methanol (0.094 g, 0.74 mmol) and 6-chloro-7-(1,1-dimethylethyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (0.15 g. 0.49 mmol) in DMF (10 ml) was added sodium hydride (0.024 g of a 60% dispersion in oil, 1.1 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was diluted with water (80 ml) and the solid that precipitated was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from ethyl acetate/hexane to give pure title compound (0.085 g, 44%). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.40-1.47 (12H, m), 4.14 (2H, t, J=7.3 Hz), 5.26 (2H, s), 7.26-7.38 (2H, m), 7.53-7.58 (1H, m), 7.86-7.90 (1H, m), 7.93 (1H, s), 7.99 (1H, s); MS (ES+) m/e 396 [MH]+. Anal. Found C, 61.02; H, 5.45; N, 24.75%. C20H22FN7O requires C, 60.75; H, 5.61; N, 24.79%.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1.Br[CH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[S:23][C:22]=1[C:34]([O:36][CH3:37])=[O:35]>CO.C(Cl)Cl>[C:26]([C:25]1[C:21]([CH2:20][N:10]2[C:9](=[O:8])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11]2)=[C:22]([C:34]([O:36][CH3:37])=[O:35])[S:23][C:24]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)#[N:27]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1CBr
Reactant: Oc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Cn1cnc2ccccc2c1=O
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
Under N2 atmosphere Sodium hydride (23.0 mg, 0.910 mmol) was suspended in anhydrous N,N-Dimethylformamide (3.0 mL, 39 mmol), cooled with ice bath and stirred for 10 min. 4-hydroxyquinazoline (0.120 g, 0.821 mmol) was added and the clear solution was stirred at r.t. for 10 min, cooled with ice bath. Methyl 3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate (0.203 g, 0.588 mmol) was added and the reddish-brown solution was stirred with cooling for 40 min. The mixture was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc. The EtOAc solution was washed with water (3×) then brine, dried over Na2SO4, filtered, rotavaped to give a crude solid. Chromatograph in a silica gel column using MeOH/DCM (0/100 to 5/95) afforded a solid product (0.211 g, yield 87.4%). LC/MS: (FA) ES+ 411. 1H NMR (400 MHz, d-chloroform) δ 8.30 (m, 1H), 8.26 (s, 1H), 7.68-7.76 (m, 2H), 7.45-7.49 (m, 1H), 5.43 (s, 2H), 3.83-3.85 (m, 4H), 3.82 (s, 3H), 3.59-3.62 (m, 4H).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:20])([C:16]([F:19])([F:18])[F:17])[C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[O:4]=[C:1]1[NH:5][C:8]([C:7]([F:6])([F:20])[C:16]([F:18])([F:17])[F:19])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: C=CC(N)=O
Reactant: CCOC(=O)CC(=O)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: CCOC(=O)C1=C(C(F)(F)C(F)(F)F)NC(=O)CC1
Temperature: 120 °C
Yield: 4.2 %

Procedure:
A suspension of acrylamide (4.11 g), ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (16.5 g) and p-toluenesulphonic acid (0.120 g) in chlorobenzene (40 mL) was sonicated for 30 minutes then heated by microwave irradiation (150 W, 120° C.) for 3 h. The reaction mixture was concentrated in vacuo and subjected to flash column chromatography (eluent 1:3 ethyl acetate/isohexane) to yield a colourless solid (0.697 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](/C=C/c1ccc(Br)cc1)CO
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a solution of [(E)-(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-allyl]-carbamic acid tert-butyl ester (14.7 g) in methanol (150 ml) was added 10% Pt/C (1.68 g) and the resulting mixture was stirred under a H2 balloon at room temperature for 3 hours (whereby the reaction progress was checked continuously by 1H NMR). The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford [(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-propyl]-carbamic acid tert-butyl ester as a yellow solid (11.5 g, 78%). MS (ISP): 346.0 ([{81Br}M+H]+), 344.0 ([{79Br} M+H]+), 289.9 ([{81Br}M+H—C4H8]+), 288.0 ([{79Br} M+H—C4H8]+), 246.1 ([{81Br}M+H—C4H8—CO2]+), 244.1 ([{79Br} M+H—C4H8—CO2]+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[BH4-].[Na+]>C(O)C.[OH-].[Na+]>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCC(=O)CCC1CCC(=O)C1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)CCC1CCC(O)C1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
A solution of the crude 7-[2-oxo-5-(3-oxo-1-octyl)cyclopentyl]heptanoic acid (0.8 g.) in ethanol (20 ml.) was neutralised by addition of 1N sodium hydroxide (2.40 ml.). The resulting solution was then treated with a solution of sodium borohydride (0.25g.) in 0.2 N sodium hydroxide (2.5 ml.) and stirred at ambient temperature for 1 day. The ethanol was then evaporated in vacuo, water added and any non-acidic material removed by extraction with diethyl ether. The aqueous phase was covered with a layer of diethyl ether and acidified by dropwise addition of hydrochloric acid. The ether layer was separated and the aqueous phase extracted again with diethyl ether. The combined ether extracts were dried over sodium sulphate and evaporated to give 7-[2-hydroxy-5-(3-hydroxy-1-octyl)cyclopentyl]heptanoic acid (0.6 g.).
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].C(N(CC)CC)C>C(O)CCC>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][S:1]([C:3]2[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=2)(=[O:10])=[O:2])[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: NCCCN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Nc1ccc(S(=O)(=O)NCCCN2CCCC2=O)cc1

Procedure:
Sulphanilyl fluoride (6.5 g, 37.1 mmol), 3-(pyrrolidin-2-on-1-yl)propylamine (5.79 g, 40.8 mmol) and triethylamine (5.69 ml, 40.8 mmol) in n-butanol (15 ml) was heated at reflux for 10 hours. The mixture was allowed to cool, silica was added and the volatiles were evaporated. The residue was purified by chromatography eluting with DCM/MeOH (100:0) increasing in polarity to (90:10) to give the title compound m/z: 297.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:23])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].[C:24](Cl)(=[O:27])[CH2:25][CH3:26].[K+].[Br-]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:27])[CH2:25][CH3:26])=[C:3]([C:12](=[O:23])[C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[N+:20]([O-:22])=[O:21])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12
Reactant: CCC(=O)Cl
Agent: [Br-]
Agent: [K+]
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccc2[N+](=O)[O-])[nH]c2cc(Cl)ccc12

Procedure:
The title compound were prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(5-chloro-2-nitrobenzoyl)indole (step 2) and propionyl chloride. m.p.: 245-246° C. IR (KBr) ν: 3078, 1665, 1628, 1580, 1526, 1497, 1340, 1313, 1238, 1022, 843 cm−1 1H-NMR (DMSO-d6) δ: 12.09 (1 H, br s), 9.26 (1 H, br s), 8.29 (1 H, d, J=8.7 Hz), 7.87 (1 H, dd, J=2.3, 8.7 Hz), 7.66 (1 H, d, J=2.0 Hz), 7.49 (1 H, d, J=8.6 Hz), 7.46 (1 H, d, J=2.0 Hz), 7.11 (1 H, dd, J=1.8, 8.7 Hz), 1.89 (2 H, q, J=7.9 Hz), 0.84 (3 H, t, J=7.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[N:24]([CH3:30])[C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CNN(c2cc(Cl)c(Oc3ccc(S(C)(=O)=O)cc3)c(Cl)c2)C1=O

Procedure:
1 g of 2-[3,5-dichloro-4-(4-methylsulfonylphenoxy)phenyl]hexahydro-1,2,4-triazine-3,5-dione was dissolved in 10 ml of dimethylformamide and, with exclusion of moisture, about 250 mg of a suspension of sodium hydride were added. After the evolution of gases was complete, 1 ml of methyl iodide was added, with stirring, and then the mixture was stirred at room temperature for a further 5 h. The reaction solution was poured onto water, and the precipitate was filtered off with suction and recrystallized from isopropanol, melting point 217° C.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH2:17])[C:5]=2[N:6]=[CH:7][N:8]=1.O>COCCOC>[NH2:1][C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH2:17])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C=C[C@@H](CCn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Reactant: N
Solvent: O
Solvent: COCCOC
Product: C=C[C@@H](CCn1cc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 8 h

Procedure:
28% aqueous ammonia (17.5 ml) was added to a solution of (R)-tert-butyl (5-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)pent-1-en-3-yl)carbamate (3.49 g) obtained in Step 4 in DME (17.5 ml), and the mixture was stirred in an autoclave at an internal temperature of 105° C. for 8 hours. After cooling the reaction mixture, water (70 ml) was added thereto, and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with water, and dried to obtain the title compound as a light-yellow solid (3.20 g).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.N([O-])=O.[Na+].[NH4+].[OH-].[BrH:18]>O>[Br:18][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Br
Reactant: Nc1cccc2cnccc12
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Brc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The procedure described by Osborn AR, et al, J Chem Soc 1956:4191 was used. 5-Aminoisoquinoline (43.6 g, 0.302 mol) was dissolved in 300 ml 48% HBr and 200 mL water and cooled in an ice bath. NaNO2 (21.21 g, 0.307 mol) in 130 mL of water was added dropwise to the HBr solution and the reaction stirred for 1 hour. CuBr (52 g, 0.363 mol) in 500 mL of 48% HBr was heated to 85° C., the diazonium solution added dropwise from an ice-cooled jacketed-addition funnel, and the reaction stirred overnight at 50° C. The reaction mixture was cooled in an ice bath and the acid neutralized by dropwise addition of concentrated NH4OH solution. The solid precipitates were filtered off, washed with concentrated NH4OH until colorless, and then water. The solid was dissolved in ethyl acetate, washed with brine (2×), and dried over magnesium sulfate, filtered, and evaporated. The reside was chromatographed on silica gel (30% ethyl acetate in hexane as eluant) to give 53.7 g (86%) of the product as an off-white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)=[O:12]>C(OCC)(=O)C.O1CCCC1.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=1)=[O:12]
Reactant: O=C(C#CCOC1CCCCO1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCCOC1CCCCO1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
4-(Tetrahydro-2H-pyran-2-yloxy)-1-(1-trityl-1H-imidazol-4-yl)-2-butyn-1-one (29.63 g) was dissolved in a mixture of ethyl acetate (200 ml) and tetrahydrofuran (800 ml). 10% Palladium carbon (2.6 g) was added and the mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. 10% Palladium carbon was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to give the title compound (28.53 g) as a brown solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)=[CH2:22].C(N(C(C)C)C(C)C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1/[CH:21]=[CH:22]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: C=Cc1cnccn1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2cnccn2)c2ccc(C=O)cc21
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 43.3 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol), 2-vinylpyrazine (27 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(o-MeC6H4)3 (16 mg, 0.052 mmol) in anh MeCN (2.5 mL) was heated with stirring in a sealed tube under microwave irradiation at 120° C. for 40 min. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 2:1 hexanes/EtOAc) to provide the title compound as a colorless solid (28 mg, 43%): 1H NMR (400 MHz, CDCl3) δ ppm 10.18 (s, 1H), 8.73 (s, 1H), 8.60 (br. s., 1H), 8.47 (d, J=2.26 Hz, 1H), 8.14-8.18 (m, 2H), 8.07 (d, J=16.06 Hz, 1H), 7.84 (d, J=8.53 Hz, 1H), 7.61 (d, J=16.31 Hz, 1H), 5.85 (s, 2H), 3.61 (t, J=8.28 Hz, 2H), 0.94 (t, J=8.53 Hz, 2H), −0.05 (s, 9H); MS ESI 381.2 [M+H]+, calcd for [C20H24N4O2Si+H]+ 381.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][C:19]=2[F:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19]=2[F:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(OCCCN2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C(=O)O)cc2F)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 4-[3-(4-ethoxycarbonyl-2-fluoro-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E39.1 (1.7 g, 4.1 mmol) in dioxan (25 ml) was treated with 2N NaOH (3 ml) and the mixture stirred at 50° C. for 18 h. A further aliquot of 2N NaOH was added (2 ml), and stirring continued at 50° C. for 3 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel (eluant; 1% acetic acid:9% methanol:90% chloroform) to yield the title compound (1.45 g, 92%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:9]=1.O=S(Cl)Cl>C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][C:13]([N:14]3[C:1](=[O:7])[CH2:2][CH2:3][C:4]3=[O:6])=[CH:8][CH:9]=2)=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CCC(=O)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of succinic anhydride (250 mg, 2.50 mmol) and 4-amino-4′-chloro diphenylether (500 mg, 2.27 mml) in toluene is heated to 110° C. for 14 h. and cooled down to room temperature. SOCl2 (1.5 mL) is added into the mixture and stirred at room temperature for 8 h. After the solvent is removed under vacuum, the residue is treated with saturated NaHCO3 aqueous solution (20 mL) and extracted with CHCl3 (3×50 mL). The combined organic layer is washed with brine and dried (MgSO4). After filtering the drying agent, the filtrate is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 30%˜80%) to provide 1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidine-2,5-dione as white solid (570 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>CO>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[NH2:1]
Reactant: COc1cc(N)ccc1S
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)ccc1SCc1cccnc1
Yield: 63 %

Procedure:
4-amino-2-methoxybenzenethiol (1.0 g) was dissolved in methanol (20 ml), and to this solution was added 3N aqueous solution of sodium hydroxide (6.4 ml) and then, 3-(chloromethyl)pyridine hydrochloride (1.27 g), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]aniline (1.0 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:11]1[CH:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:12]1>C1COCC1>[C:4]1([CH2:3][O:10][CH2:12][CH:13]([OH:11])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(OCC2CO2)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)COc1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
Sodium hydride (80% dispersion in oil, 0.045 g) was added to a mixture of benzyl alcohol (4 ml) and THF (3 ml) and warmed gently until effervescence ceased. To the cooled solution was added 1,2-epoxy-3-[3-(trifluoromethyl)phenoxy]propane (2.12 g). After stirring for 3 h the mixture was poured into ER (50 ml) and washed with brine. The dried extracts were evporated and the residue distilled (b.p. 140°-144°/0.03 mm) to yield the title compound as an oil (2.25 g). I.r. (Neat) 3420 cm-1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[NH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[N:16]([CH3:24])[CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CI
Solvent: CC#N
Product: Cc1noc2c1-c1ccn(C)c(=O)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepin-7(8H)-one (0.070 g, 0.215 mmol) in acetonitrile (2 mL) were added cesium carbonate (0.210 g, 0.645 mmol) and iodomethane (16.09 μl, 0.258 mmol) at room temperature. The reaction was stirred at room temperature for 2 h before it was diluted with CH2Cl2 and filtered. The filtrate was concentrated to dryness under vacuum, and the residue was purified by flash chromatography (hexane/EtOAc 9:1 to 3:7) to give 6-(4-chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one as an off-white solid (0.064 g) and 6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine as side product. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=7.10 Hz, 1H), 7.34 (d, J=2.06 Hz, 4H), 6.67 (d, J=7.10 Hz, 1H), 5.20 (d, J=13.05 Hz, 1H), 4.06 (d, J=13.05 Hz, 1H), 3.43 (s, 3H), 2.51 (s, 3H); LC/MS m/z 340 [M+H]+.