Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2]
Reactant: CCOC(=O)CCc1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(CCC(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a stirred solution of ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)propanoate (0.28 g, 0.72 mmol) in dioxane (6 ml) was added lithium hydroxide monohydrate (0.18 g, 4.3 mmol) and water (3 ml). The mixture was stirred at room temperature for 8 hr. It was concentrated under reduced pressure, neutralized with 5% HCl, extracted with EtOAc, and dried over MgSO4. The solvent concentrated and purified by silica gel flash column chromatography dichloromethane/methanol (8:2) to give the product (0.09 g, 35%). 1H NMR (300 MHz, CDCl3) δ 7.77 (br, NH)), 7.19 (d, 1H), 6.91 (d, 1H), 4.04 (m, 2H), 3.68 (m, 2H), 3.16 (m, 1H), 3.06 (t, 2H), 2.85 (m, 1H), 2.74 (m, 3H), 2.18 (m, 1H), 1.98 (m, 3H), 1.35 (d, 6H), 0.94 (t, 3H); ESI (+) MS m/e=360 (MH+), ESI (−) MS m/e=358 (MH−).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(CC)C2CCN(CC3C=CC=CC=3)C2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH2:85]2)(=[O:82])=[O:81])(=[O:73])=[O:72])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)[CH2:85]2)(=[O:81])=[O:82])(=[O:73])=[O:72])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccc(C)cc1OCCCOc1cccc2c1C(=O)NC2=O
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccc(C)cc1OCCCONC(=N)N
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Yield: 83 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 83% yield from N-{3-[5-methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 11.15 (br s, 2H), 8.18 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (br s, 4H), 7.38 (m, 5H), 6.74 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 4.66 (br s, 1H), 4.04 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.50 (m, 2H), 2.75-3.20 (m, 5H), 2.21 (s, 3H), 2.13 (m, 2H), 2.01 (pentet, J=6.2 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C30H39N5O7S2: 646.2 (M+H). Found: 646.0.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH:33][CH2:32][CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(C(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCCC1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(C(=O)NCCC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid and 2-(tetrahydro-2H-pyran-4-yl)ethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[CH:7]=[N:8][CH:9]=1)(=[O:3])[NH2:2].Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH:40]1[CH2:42][CH2:41]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[C:6]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[C:27]3[CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:7]=[N:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(N)=O)c1
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3CC3CC3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: NC(=O)c1cncc(-c2ccc3[nH]cc(C[C@H]4CCCN4CC4CC4)c3c2)c1

Procedure:
5-Carbamoyl-3-pyridyltri-n-butylstannane (see Preparation 43) and 5-bromo-3-(1-cyclopropylmethylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 56) were reacted together in the presence of palladium (II) acetate, tri-o-tolylphosphine and triethylamine using a procedure similar to that described in Example 1. This yielded the title compound. Found: C,71.56; H,7.13; N,13.72. C23H26N4O.3/16CH2Cl2 requires: C,71.33; H,6.,81; N,14.35%.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:7][CH2:1][CH:2]2[CH2:3][CH2:4][CH2:5][O:6]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: NCC1CCCO1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCC1CCCO1)c1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
1.70 ml of commercially available tetrahydrofurfurylamine are dissolved in 45 ml of dry dichloromethane. A solution of 3.83 g of 4-bromo-benzenesulfonyl chloride in 20 ml of dichloromethane are slowly added at room temperature. Subsequently, 5.14 ml of Hünig's base are added and stirring is continued for 1.5 hours. For extraction, the reaction mixture is diluted with 150 ml of dichloromethane and 50 ml of water. The organic layer is dried using Na2SO4, filtered with suction, and concentrated in vacuo. Purification by chromatography on flash silica gel (eluent: dichloromethane/0-5 vol. % ethanol) affords 4.33 g of the title compound as an light yellow oil. ESI-MS: 320.3/322.1 (MH+, 100%:98%). TLC: Rf=0.65 (dichloromethane/ethanol 20:1 parts by volume).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: NC1CC1
Reactant: O=Cc1cc(Cl)cc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Clc1cc(Br)cc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 4:1 (v/v) MeOH:THF solution (0.06 M) of 3-bromo-5-chlorobenzaldehyde (1 eq.) and cyclopropylamine (1.1 eq.) was added sodium cyanoborohydride (1.5 eq.) portionwise followed by neat acetic acid (3 eq.). The resulting mixture was stirred at RT for 20 h. The volatiles were then removed in vacuo. The resulting residue was taken up in ether and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH:22](OCC)OCC)=[S:19])=[CH:13][CH:12]=1)([O:8]CC)=[O:7]>O>[C:6]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH:22]=[CH:21][NH:20][C:18]2=[S:19])=[CH:15][CH:16]=1)([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(NC(=S)NCC(OCC)OCC)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(-n2cc[nH]c2=S)cc1
Temperature: 25 °C

Procedure:
400 ml of 30% sulfuric acid was added to 80 g of N-(4-carboethoxyphenyl)-N'-(2,2-diethoxyethyl)thiourea, and the mixture was refluxed for 1 hour using an oil bath. The reaction mixture was cooled to room temperature, then 600 ml of water was added thereto, followed by cooling in an ice bath. Crystals precipitated were collected by filtration, then washed successively with 200 ml of water, 100 ml of isopropyl alcohol, and 100 ml of hexane. Yield: 48 g (92.8 mol%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14].O.[NH2:16]N>>[Cl:1][C:2]1[C:7]([NH:8][NH2:16])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: NN
Solvent: O
Product: NNc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
Process of claim 1 wherein pentachlorophenylhydrazine is prepared by reacting pentachloronitrobenzene with hydrazine hydrate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:9]([NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccccc1Cl
Reactant: CCCCCCN
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCCCCCNc1ccccc1C
Temperature: 85 °C
Yield: 90.5 %

Procedure:
Following general procedure D, a mixture of 2-chlorotoluene (1.17 mL, 10 mmol), hexylamine (1.82 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap; 0-50% EtOAc/hexanes) to provide the title compound as a clear oil (1.732 g, 91%). 1H NMR (300 MHz, CDCl3) δ: 7.33 (t, J=7.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.83 (m, 2H), 3.61 (s, 1H), 3.33 (t, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.85 (septet, J=7.0 Hz, 2H), 1.58 (m, 6H), 1.14 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 146.8, 130.4, 127.6, 122.0, 117.0, 110.0, 44.4, 32.2, 30.0, 27.4, 23.2, 17.9, 14.5 ppm. IR (neat, cm−1): 3430, 2956, 2924, 2856, 1607, 1514, 1473, 1317, 1260, 745. Anal. Calcd. for C13H21N: C, 81.61; H, 11.06. Found: C, 81.81; H, 11.02.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:3]=1.[F-:18].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:3]=[C:2]2[F:18]
Reactant: [F-]
Reactant: COCCOc1cc2c(Cl)cccc2c(Cl)n1
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCOc1cc2c(Cl)cccc2c(F)n1
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-(2-methoxyethoxy)isoquinoline (578 mg, 2.124 mmol) in DMSO (5 mL) was added CsF (323 mg, 2.124 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude product purified via biotage (90 g column, 5-50% EtAOc:Hex) to give the product 5-chloro-1-fluoro-3-(2-methoxyethoxy)isoquinoline (250 mg, 46% yield) as a light yellow solid. MS: MS m/z 256.15(M++1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>C1(C)C=CC=CC=1.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:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3ccccn3)n2Cc2ccccc2)n1
Temperature: 110 °C
Reaction time: 6 h
Yield: 40.3 %

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 2-(tributylstannyl)pyridine (0.11 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was stirred at 110° C. for 6 hours. Solvent was removed in vacuo and the residue was dissolved in MeCN, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded desired product (40 mg, 40%).
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][CH2:20][C:11]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:11]12([CH2:20][CH2:21][CH2:22][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12]2
Reactant: c1ccc(CN2CCCC3(CC2)OCc2ccccc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ccc2c(c1)COC21CCCNCC1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of (RS)-1-benzyl-3′H-spiro[azepane-4,1′-[2]benzofuran] (4.00 g, 13.6 mmol) in methanol (50 ml) in an autoclave was purged with argon. After addition of the palladium catalyst (10% Pd on activated charcoal, 1 g) the autoclave was pressurized with 5 bar of hydrogen gas. The mixture was stirred over night at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium hydroxide solution (pH 14). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound as white solid (2.5 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:37]([O:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)[CH2:36][CH:35]=[CH2:34]
Reactant: COC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: C=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Yield: 40.1 %

Procedure:
To a solution of methyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (100 mg, 0.223 mmol) in DMF (2 mL) was added 4-bromobut-1-ene (90 mg, 0.668 mmol) and Potassium Carbonate (154 mg, 1.113 mmol). The mixture was heated to 65° C. for 16 h. After cooling to rt, the mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give methyl 4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (45 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](B1OB(C=C)OB(C=C)O1)=[CH2:12].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)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>[CH:11]([C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)=[CH2:12]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC#N
Product: C=Cc1ccc(C(C)=O)cn1
Temperature: 115 °C

Procedure:
The reaction mixture of 1-(6-bromopyridin-3-yl)ethanone (0.68 g, 3.41 mmol), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane:pyridine (1:1) (0.57 g, 2.39 mmol), potassium carbonate (0.85 g, 6.14 mmol), and Pd(Ph3P)4 (0.16 g, 0.14 mmol) in acetonitrile (10 mL) was degassed with argon for 5 minutes. Then it was heated in the microwave for 30 min at 115° C. The organic phase was removed using a pipette, dried (MgSO4), filtered and concentrated and purified by flash chromatography (SiO2; heptane/EtOAc, gradient 20-80%). Yield: 0.36 g (72%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:4]1[C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=[C:2]([CH3:1])[C:3]=1[OH:11]
Reactant: Cc1cc2ncsc2cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2ncsc2c(Br)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-methylbenzo[d]thiazol-6-ol (5C) (140 mg, 0.84 mmol) in acetic acid (5 ml), was added bromine (40 μL) slowly. The reaction mixture was stirred at room temperature for 1 h. The precipitate was collected, washed with acetic acid, water and dried under high vacuum. LCMS-ESI+: calc'd for C8H6BrNOS: 244.0 (M+H+). Found: 244.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:31][CH2:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=CCO)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C=CCCl)cc1
Yield: 42.7 %

Procedure:
Compound 102-1 (2.50 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (4.86 g) and N-chlorosuccinimide (2.84 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. Triphenylphosphine (4.86 g) and N-chlorosuccinimide (2.84 g) were further added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (1.20 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([OH:14])=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:10][CH2:11][C:12]([Cl:17])=[O:14])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)COc1nc(Cl)c(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)COc1nc(Cl)c(Cl)cc1Cl
Temperature: 70 °C
Yield: 98 %

Procedure:
3,5,6-Trichloro-2-pyridyloxyacetic acid (20 g, 0.078 mole was stirred with toluene (46.5 ml). Thionyl chloride (26 ml) was added dropwise to the well-stirred mixture over 15 minutes. The mixture was then heated under reflux (70° C.) for 3 hours. The effluent gases (SO2 +HCl) were absorbed into aqueous 5N sodium hydroxide. The cooled reaction mixture was filtered and evaporated to yield the title compound (20.9 g, 98 percent) as a thick dark brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][Br:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][Br:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCBr)c(OC)cc23)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCBr)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.25 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (352 mg, 2.50 mmol) and 1,2-dibromoethane (0.129 μL, 1.25 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (278 mg, 2.50 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 μL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-bromo-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (80 mg, 100% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]>CCOCC.N1C=CC=CC=1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:21][CH:16]=1
Reactant: COc1ccccc1I
Reactant: c1ccc2occc2c1
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
A solution of 46.0 g (0.39 mole) of benzofuran in 100 mL of Et2O was treated with 0.40 mol (1.6 M in hexanes) of n-BuLi at such a rate as to keep the reaction temperature below 25° C. The mixture was stirred for 15 min and was added to a 10° C. solution of 57.2 g (0.40 mole) of CuBr in 100 mL of Et2O at a rate so as to keep the reaction temperature below 10° C. The mixture was allowed to reach room temperature over 0.5 h and was treated with a solution of 93.6 g of iodoanisole in 300 mL of pyridine. The mixture was heated to 110° C. for 3 h, allowing the Et2O to boil off. The reaction mixture was concentrated in vacuo and the residue was dissolved in 3 L of EtOAc. The organic layer was washed several times with 2 N aqueous HCl and once with H2O, dried over MgSO4, and filtered. Concentration in vacuo afforded a residue which was recrystallized from MeOH to afford 44.5 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=O.[NH2:20][CH2:21][CH2:22][SH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:19][C:17]1[CH:16]=[C:4]([C:5]23[S:23][CH2:22][CH2:21][N:20]2[C:9](=[O:11])[C:8]2[C:7]3=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:18]=1
Reactant: Cc1cc(C)cc(C(=O)c2ccccc2C(=O)O)c1
Reactant: NCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(C)cc(C23SCCN2C(=O)c2ccccc23)c1
Yield: 53 %

Procedure:
10 mmol 2-(3,5-dimethylbenzoyl)-benzoic acid were dissolved in 100 ml of xylene and, after addition of 20 mmol cysteamine, as well as a catalytic amount of p-toluenesulphonic acid, heated for 2 h under reflux on a water separator. The solvent was then removed in a vacuum and the residue recrystallised from ethanol. Yield 53%, m.p. 163° C.