Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)[CH2:48][CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:43][C:41]1[CH:42]=[C:37]([CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=1)[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH2:47][CH2:48][CH3:49])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CCCc1nc(C(=O)O)cs1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.25 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.16 g), 2-propylthiazole-4-carboxylic acid (example 56, step c) (0.09 g) and triethylamine (0.29 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the mixture evaporated to give the subtitled compound as a clear gum. Yield 0.14 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([Cl:10])[CH:3]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a magnetically stirring solution of (4-bromo-2-chloro-phenyl)-methanol (2.80 g, 12.67 mmol) from step 1 above in CH2Cl2 (60.0 mL) under argon at 0° C., was added carbon tetrabromide (4.41 g, 13.30 mmol) followed by triphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture was stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (10% EtOAc in Hexanes) to yield the intermediate bromide as a clear oil (3.59 g, 100%). 1H NMR (400 MHz, CDCl3): δ 4.53 (s, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.39 (dd, J=8.2, 1.9 Hz, 1H), 7.56 (d, J=1.9 Hz, 1H).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.CO>C(Cl)(Cl)Cl>[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:5]3[S:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Reactant: OB(O)c1cc2ccccc2s1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1ccc2sc(-c3ccc(OCCN4CCCC4)nc3)cc2c1
Yield: 68 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 5-bromopyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 68% yield as an oil following flash chromatography (SiO2; gradient of 0-4% MeOH in CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11](C2C=CC=CC=2)(C2C=CC=CC=2)[PH2]=O)[CH:7]=1)=[O:5])[CH3:2].[Li]CCCC.[CH2:31]([C:35]1[C:39]([CH:40]=O)=[C:38]([CH3:42])[O:37][N:36]=1)[CH2:32][CH2:33][CH3:34]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:40]/[C:39]2[C:35]([CH2:31][CH2:32][CH2:33][CH3:34])=[N:36][O:37][C:38]=2[CH3:42])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCCc1noc(C)c1C=O
Reactant: CCOC(=O)c1cc(C([PH2]=O)(c2ccccc2)c2ccccc2)no1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1/C=C/c1cc(C(=O)OCC)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
To a solution of 3-(diphenyl-phosphinoylmethyl)-isoxazole-5-carboxylic acid ethyl ester (410 mg, 1.2 mmol) in THF (10 mL) at −78° C. was added BuLi (1.6 M in hexanes, 0.79 mL, 1.3 mmol) and the mixture warmed up to 0° C. over 1 h and a solution of 3-butyl-5-methyl-isoxazole-4-carbaldehyde (193 mg, 1.2 mmol) in THF (5 mL) added and stirred for 2 h. The mixture was extracted with ethyl acetate and the combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 7:3) afforded the title compound (75 mg, 21%) as a colourless oil. MS: m/e=305.2 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>>[CH3:29][C:30]([CH3:35])([CH3:34])[C:31]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:28])[CH:7]=1)[CH2:26][CH3:27])=[O:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C(C)(C)C

Procedure:
(2′-{[(2,2-Dimethyl-propionyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-245) was prepared using the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and trimethylacetyl chloride.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[NH2:16][C@H:17]([C:19]([NH:21][C@H:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[CH3:18]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][CH:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[CH3:18])=[O:15])([CH3:2])[CH3:3]
Reactant: C[C@H](N)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N[C@@H](C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure (5-A1) using 2,6-diisopropylphenyl isocyanate and (S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 539 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=4)=[S:28])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2nc3cc(Cl)ccc3s2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4cc(Cl)ccc4s3)cc2)ccc1Cl
Yield: 0 %

Procedure:
2-(4-aminophenylthio)-5-chlorobenzothiazole (5.5 moles, 1.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (5.5 moles, 1.3 g) were reacted according to procedure C to yield the title compound 0.7 g, 24%. Mass Spec (FD 529. Calculated for C21H12C12F3N3S3 : C, 47.55; H, 2.28; N, 7.92. Found: C, 47.55; H, 3.32; N, 7.87.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:27])[NH:9][C:10]2[S:14][N:13]=[C:12]([S:15]CC3C=CC(OC)=CC=3)[C:11]=2[C:25]#[N:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]1([O:7][C:8](=[O:27])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:25]#[N:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CSc2nsc(NC(=O)Oc3ccccc3)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1c(S)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 101 %

Procedure:
To a mixture of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl)-carbamic acid phenyl ester (1.0 g, 2.5 mmol), trifluoracetic acid (26 mL) and anisole (2.7 g, 25 mmol) at 0° C. was added mercuric acetate (0.80 g, 2.5 mmol). The mixture was allowed to warm to room temperature overnight. After concentration in vacuo, the mixture was diluted with 100 mL of water and 100 mL of ethyl acetate. Hydrogen sulfide was bubbled in slowly until precipitation of the mercury salts was complete. The mixture was diluted with brine, extracted 3× with 200 mL of ethyl acetate, and the combined organic layers were filtered through celite, dried over Na2SO4, filtered and concentrated in vacuo, affording 0.70 g (100%) of (4-cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester as a colorless solid. 1H NMR (400 MHz, acetone-d6) δ 7.47 (t, 2H, J=7.6 Hz), 7.35-7.30 (m, 3H) ppm; MS (APCI, m/z): 276 [M−H]−.
Reaction SMILES: [CH:1]([Li])([CH3:3])[CH3:2].[CH:5]([O:8][B:9](OC(C)C)[O:10][CH:11]([CH3:13])[CH3:12])([CH3:7])[CH3:6]>>[CH:1]([B:9]([O:10][CH:11]([CH3:13])[CH3:12])[O:8][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: [Li]C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: CC(C)OB(OC(C)C)C(C)C
Temperature: 80 °C

Procedure:
The title compound was prepared following the procedure of Example 1, from isopropyllithium (177 mL, 101 mmol) and triisopropoxyborane (19.0 g, 101 mmol). Solvent was removed at 0° C. and 15 mm Hg. The oil bath was heated to 80° C. Yield: 16.3 g (94.2 mmol, 93%), bp 138° C. (749 mm Hg); n20D 1.3853; proton NMR (CDCl3) δ4.40 (septet, J=18 Hz, 2H); 1.13 (d, J=18 Hz, 12H), 0.93 (bs, 7H); boron NMR (neat) δ+30.5 ppm (s). Anal. Calcd. for C9H21BO2 : C, 62.80; H, 12.22; B, 6.29. Found: C, 62.59; H, 12.59; B, 5.93.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.CC(C)=O.CCOCC>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)=[O:9])[CH:4]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(CBr)on1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1cc(CN2CCN(c3ccccc3)CC2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 115.6 %

Procedure:
A solution of 3.7 g of (5-bromomethylisoxazol-3-yl)-4-fluorophenylmethanone in 100 ml of Et2O was added dropwise to a solution of 5.2 g of N-phenylpiperazine in 400 ml of 20% acetone/Et2O. The resulting mixture was stirred at room temperature for 24 hours. This mixture was filtered and the solution was washed with water (2×200 ml) and saturated NaCl, and dried over MgSO4. Concentration of the product gave 5.5 g of a solid which was dissolved in 100 ml of CH2Cl2 and stirred with 5 g of SiO2. This mixture was filtered, the silica washed with CH2Cl2, and the organics were evaporated to give 3.7 g of a solid. The amine was recrystallized from 135 ml of 8% toluene/hexane to yield 2.5 g (53%) of needles, m.p. 94°-95°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[O:25][CH2:24]4)[C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([CH2:4][O:5][C:6]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[O:25][CH2:24]4)[C:7]=2[O:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(=O)O)c1OCC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a stirring solution of ethyl 2-(2-(cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetate (300 mg, 0.726 mmol) in tetrahydrofuran (15 mL) was added lithium hydroxide (152 mg, 3.631 mmol) in water (5 mL) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with water, dried over sodium sulphate and concentrated under reduced pressure to afford the 2-(2-(Cyclopropylmethoxy)-3-methoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)acetic acid as a solid (200 mg, 71.5%).
Reaction SMILES: CCN=C=N[CH2:6][CH2:7][CH2:8][N:9]([CH3:11])C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:23]2[CH:24]=[CH:25]C=[CH:27][C:22]=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH:9]1[C:8]2[C:23](=[CH:22][CH:27]=[CH:6][CH:7]=2)[CH2:24][CH:25]=[CH:11]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C1=CNc2ccccc2C1

Procedure:
In Step A, a substituted benzaldehyde is condensed with a substituted acetophenone or 1-pyridin-3-yl-ethanone (V), in the presence of an inorganic base such as NaOH, in a polar protic solvent such as MeOH, to give the corresponding α,β-unsaturated ketone of formula (VI). This product can be reduced to the corresponding saturated ketone by hydrogenation in presence of a catalyst, such as platinum (IV) oxide, in a mixture of polar solvents, such as ethanol and EtOAc, as described in Step B. When R1 or R2 are chloro, this moiety can simultaneously be reduced using palladium on carbon as a catalyst instead of platinum (IV) oxide. In step C, the aniline (VII) can be acylated by heating at reflux in the presence of an acyl chloride such as methyl oxalyl chloride in an apolar solvent such as toluene. The amide (VIII) can cyclize by heating at reflux in a polar protic solvent, such as methanol, in the presence of an inorganic base, such as potassium carbonate, as described in Step D to afford the corresponding 1,4-dihydroquinoline. When R1 is a carboxylic ester moiety in the coupling Step A, both the ester and corresponding carboxylic acid can be formed by hydrolysis; the acid can then be coupled with an amine NHR9R10 in the presence of coupling agents such as EDCI and BOP and an organic base such as diisopropylethylamine in a polar solvent such as tetrahydrofuran. The amide of generic formula (IX) can undergo the same Steps described above from B to D to give the corresponding 1,4-dihydroquinoline.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1>C(O)C>[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)[NH:12][C:11]1=[O:15]
Reactant: O=C1Cc2ccc(-c3cccs3)cc2N1
Reactant: O=Cc1ccccc1O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3cccs3)ccc2C1=Cc1ccccc1O
Yield: 50.1 %

Procedure:
A mixture of 6-thiophen-2-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hydroxybenzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was stirred at reflux overnight. The reaction mixture was concentrated and column chromatographed (eluant—isopropanol/dichloromethane) to give 80 mg (50%) of 3-(2-hydroxybenzylidene)-6-thiophen-2-yl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C[C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.[CH2:27](Cl)Cl>>[CH2:9]([NH:8][C:7]1[CH:2]=[C:3]([OH:21])[CH:4]=[CH:5][C:6]=1[CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: ClCCl
Reactant: CCCCCCCCCCCCNc1cccc(OC)c1C
Agent: BrB(Br)Br
Product: CCCCCCCCCCCCNc1cc(O)ccc1C
Temperature: 0 °C
Yield: 70 %

Procedure:
As a general methyl group de-protection procedure, 4 methyl-3-dodecylamino-1-methoxy benzene 120 was suspended in dry CH2Cl2, cooled to 0° C. and 5 equivalents of a solution of BBr3 (1M CH2Cl2, Aldrich Chem. Co.) were added and the reaction maintained at 0° C. for 16 hours. The reaction was quenched at 0° C. by slow addition of MeOH and then careful addition of solid NaHCO3 (10 Equiv.) until foaming stops. The mixture was filtered, the filtrate was concentrated to an oil, and the product was isolated by normal phase chromatography eluting with methanol/CH2Cl2. The solvent was removed from the pure fractions to give 3-dodecylamino-1-hydroxy-4 methylbenzene 120 (R═H, R′═R′″═H, R″═Me) as a waxy solid in 70-80% yield (1HNMR (CDCl3) δ 6.91 (d, 1H), 6.17 (d, 1H), 6.14 (dd, 1H) 4.62 (bs, OH), 3.53 (bs, NH), 3.14 (t, 2H), 2.09 (s, 3H), 1.70 (p, 2H), 1.46 (m, 18H), 0.93 (t, 3H))
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:8])[C:5]([OH:7])=O.[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].N1C=CC=CC=1>C(Cl)Cl>[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:5](=[O:7])[C:4]([O:3][CH3:2])=[O:8])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(=O)O
Reactant: Nc1cccc(OCCCBr)c1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(OCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 ml of oxalic acid monomethyl ester chloride in 10 ml of methylene chloride is added dropwise to a solution of 3.5 g of 3-(3-bromopropoxy)-aniline and 1.3 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 2 hours, the mixture is poured onto water and extracted with methylene chloride. The combined extracts are evaporated and the residue is chromatographed on silica gel with methylene chloride/ethyl acetate (10:1). The eluate is evaporated and the residue is crystallised from ether/hexane. Methyl N-[3-(3-bromopropoxy)-phenyl]-oxamate of melting point 90°-91° is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:22][CH:23]=[CH2:24].C(#N)C>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH2:24][CH:23]=[CH2:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C=CCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]-piperazine (International Publication 88/08424, 2.78 g), 3-bromopropene (1.87 g), anhydrous potassium carbonate (3.3 g) and acetonitrile (100 ml) is refluxed for 36 hr. The mixture is cooled and then diluted with dichloromethane and aqueous potassium carbonate solution. The phases are separated and the organic phase is washed with saline and than concentrated in vacuo. Purification by flash column chromatography (2% methanol/chloroform) provided of the title compound. Capillary GC analysis (HP1 column, initial temperature at 100° for 1 min, then programmed to rise 20° per minute to 250°) gave a peak at 6.06 (96%) minutes.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4].C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>C(Cl)Cl>[C:25]([NH:1][CH2:2][CH:3]([C:5]1[N:9]=[C:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][N:6]=1)[CH3:4])(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CC(CN)c1nsc(NC(=O)OC(C)(C)C)n1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC(C)c1nsc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [3-(2-amino-1-methylethyl)-1,2,4-thiadiazol-5-yl]carbamate (0.27 mmol) was dissolved in DCM (5 mL) and triethylamine (1.4 eq) was added followed by n-butyric acid chloride (1.1 eq). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Purification, using preparative LCMS (30–70% MeCN over 10 min followed by 100% MeCN for 5 min), afforded tert-butyl [3-(2-butyrylamino-1-methyl-ethyl)-[1,2,4]thiadiazol-5-yl]-carbamate. Deprotection was carried out in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 1.5 h at room temperature. The solvent was removed under reduced pressure affording the crude product which was converted to the sulfonamide using method C without any further purifications.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH:42]([NH2:44])[CH3:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([NH:44][CH:42]([CH3:43])[CH2:41][C:39]2[O:40][C:36]([C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=3)=[CH:37][CH:38]=2)=[O:12])[NH:8][N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(N)Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1)NC(=O)c1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
5-Tert-butyl-2H-pyrazole-3-carboxylic acid (94 mg; 0.55 mmol) was dissolved in DCM:DMF (4:1, 5 ml). DCC (172 mg; 0.83 mmol) was added. 1-(5-(3,4-dichlorophenyl)furan-2-yl)propan-2-amine (149 mg; 0.55 mmol) was dissolved in 2 ml of DCM and TEA (77 μl, 0.55 mmol) and the resulting solution was added to the reaction mixture. The reaction mixture was stirred overnight at RT. Then DCM (50 ml) was added and organic phase was washed with water (2×30 ml). The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, 1st column silica, eluent: 7.5-100% EtOAc/heptane; 2nd column silica, eluent: 0-5% MeOH/DCM) to give 35 mg (15%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 1.27 (s, 9H), 2.88 (dd, 1H), 2.98 (dd, 1H), 4.33 (quintet, 1H), 6.29 (d, 1H), 6.33 (s, 1H), 7.00 (d, 1H), 7.60 (m, 2H), 7.83 (d, 1H), 7.89 (d, 1H), 12.84 (s, 1H).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:7])[NH:5][CH:6]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.CCN(CC)CC>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:5]2[CH:6]=[C:2]([I:1])[N:3]=[C:4]2[CH3:7])=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1nc(I)c[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(I)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
4-Iodo-2-methyl-1H-imidazole (200 mg, 1.0 mmol), 4-fluorophenylboronic acid (215 mg, 1.6 mmol), copper(II)acetate (210 mg, 1.2 mmol) and Et3N (0.16 ml, 1.2 mmol) were suspended in 10 ml THF and oxygen was bubbled through the reaction mixture for 40 min. The reaction mixture was stirred for 48 hours at RT and then filtrated over dicalit. The filtrate was concentrated and then purified by flash chromatography to yield 1-(4-fluoro-phenyl)-4-iodo-2-methyl-1H-imidazole (120 mg, 0.40 mmol, 41%).