Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)=[O:6].C(Br)(Br)(Br)Br.N1C(C)=CC=CC=1C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N:4]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]3)=[CH:11][CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2ccc(C(=O)NCCO)cc2)CC1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCc2ccc(C(=O)N3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Tert-butyl 4-[2-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate (280 mg), carbon tetrabromide (247 mg) and 2,6-lutidine (103 μl) were dissolved in dichloromethane (5.6 ml), and under ice cooling, triphenylphosphine (195 mg) was added thereto, followed by stirring at room temperature for 3 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=3:7 (v/v)) to obtain tert-butyl 4-{2-[4-(1-aziridinylcarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (136 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: Cc1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1C

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with 3,4-dimethylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a sticky oil (10.5 mg, 42%) having the following characteristics.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[S:21][CH2:20][CH2:19][C:18]2=[O:27].Cl>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[S:21][CH2:20][CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C:18]2=[O:27]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1cc2c(cc1OC)C(=O)CCS2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C(C(=O)C(F)(F)F)CS2
Temperature: 25 °C
Reaction time: 87.5 h
Yield: 64.9 %

Procedure:
Ethyl trifluoroacetate (0.84 g, 5.9 mmol) was dissolved in tetrahydrofuran (20 mL), and treated with 25% sodium methoxide (1.68 g, 7.8 mmol). To the stirred solution was added 6,7-dimethoxythiochroman-4-one from Step 2 (1.12 g, 5.0 mmol). The reaction was stirred at room temperature for 87.5 hours, treated with 3N HCl (25 mL) and filtered to give an orange solid (1.04 g, 65%): mp 148°-151° C.; 1H NMR (CDCl3) 300 MHz 16.05 (s, 1H), 7.48 (s, 1H) 6.78 (s, 1H) 3.94 (s, 3H) 3.92 (s, 3H) 3.83 (s, 2H); 19F NMR (CDCl3) 300 MHz -71.06 (s). Mass spectrum: M+H=321.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[NH:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3]1.O>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[NH:19][CH:20]([CH3:21])[CH3:22])[CH2:6][CH2:7]1
Reactant: CC(C)Nc1ccc([N+](=O)[O-])cc1C(=O)NN1CCN(C)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1ccc(N)cc1C(=O)NN1CCN(C)CC1

Procedure:
2.0 g (6.5 mmol) of N-(4-methylpiperazin-1-yl)-2-isopropylamino-5-nitrobenzamide were dissolved in 40 ml of glacier acetic acid and 6.8 g of zinc powder were added gradually at 45-50° C. For workup, 40 ml of water were added, the mixture was extracted once with ethyl acetate, the water phase was alkalized with NaOH, and the mixture was extracted repeatedly with methylene chloride. The residue remaining after drying and concentration (1.9 g) could be used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(-c2[nH]c3ccc(O)cc3c2C)cc(C)c1O
Product: Cc1cc(-c2[nH]c3ccc(OCc4ccccc4)cc3c2C)cc(C)c1O

Procedure:
5-Hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole and benzyl bromide were treated in the same way as in Example 35 to obtain 5-benzyloxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][O:22][C:23](=[O:31])[CH2:24][CH:25]1[CH2:29][CH2:28][C:27](=O)[CH2:26]1.[B][B][B][B][B][B][B][B][B][B]>>[CH3:21][O:22][C:23](=[O:31])[CH2:24][CH:25]1[CH2:29][CH2:28][CH:27]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@:4]3([CH3:12])[C:5]([CH3:10])([CH3:11])[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH2:1])=[N:3]3)[CH:18]=2)[CH2:26]1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: COC(=O)CC1CCC(=O)C1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: COC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and (3-oxo-cyclopentyl)-acetic acid methyl ester using decaborane yielded a mixture of isomers of the title compound as a white foam. MS (ESI): m/z=419.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[CH:12](=[O:16])/[CH:13]=[CH:14]/[CH3:15].C(OC(C)(C)C)(=O)C>>[CH3:8][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])=[CH:9][CH2:10][CH2:15][CH:14]=[CH:13][CH:12]=[O:16]
Reactant: C/C=C/C=O
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: CC(=O)OC(C)(C)C
Product: CC(C)=CCCC(C)=CCCC=CC=O
Yield: 78 %

Procedure:
110 parts of geraniol, 50 parts of crotonaldehyde and 3.2 parts of t-butyl acetate are heated for six hours at 30 atmospheres pressure and at 150° C in an agitated autoclave having a capacity of 250 parts by volume. Working up gives 85 parts of 7.11-dimethyldodeca-2,6,10-trien-1-al having a boiling point of 93° to 96° C at 0.2 mm. The yield is 78% of theory at a conversion of 74% (based on crotonaldehyde).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1([F:30])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:20]=2[O:19]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:25]2[CH:24]=[CH:23][C:21]3[O:22][C:18]([F:30])([F:17])[O:19][C:20]=3[CH:26]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc3c(c1)OC(F)(F)O3)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2,2-difluoro-benzo[1,3]dioxol-5-carboxylic acid
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[C@@H:41]([CH2:45]O)[CH:42]([CH3:44])[CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[CH:41]([CH2:45][I:1])[CH:42]([CH3:44])[CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[C@H](CO)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(CI)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
Iodine (42 g), triphenylphosphine (47 g) and imidazole (12 g) were added to a solution of 4-(R)-benzyl-3-(2-(R)-hydroxymethyl-3-methylbutanoyl)oxazolidin-2-one (45 g) in toluene (400 ml) and the mixture was heated to 80° C. for 1 h, then cooled and washed with water and saturated brine. The solvent was dried (Na2SO4) and evaporated and the residue filtered through silica (200 g) eluting with diethyl ether-hexane 1:1 to give the title compound as a yellow viscous oil (56.4 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)(=O)C.C(OC1C=CC(C(CCNC2C=C(OC)C(OC)=CC=2[C@@H]2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)(=O)C>>[CH2:1]([N:3]([C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([OH:34])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: COc1cc(NCCC(=O)c2ccc(OC(C)=O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Product: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-acetoxybenzoic acid according to an analogous synthetic method to Preparation Example 154, pivalic acid (R)-6-{2-[(4-acetoxybenzoyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (471 mg) was used according to an analogous synthetic method to Preparation Example 155 to provide the title compound (311 mg).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:2]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(C)ccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin in 80 ml. of chloroform are heated under reflux for 20 hours with 38.4 g. of 1-carbethoxy-piperazine. The mixture is poured on to ice-water and extracted with chloroform. The organic phase is dried over magnesium sulfate, evaporated under reduced pressure, and there is obtained crude, oily 1-carbethoxy-4-[8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl]-piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([CH3:33])([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClC(Cl)C.CCOCC>[CH2:1]([O:3][C:4](=[O:34])[C:5]([CH3:33])([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc2ncccc2c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc2ncccc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a LDA solution (42 mL, 1.5 M solution in THF) in 65 mL of dry THF at −78° C., a solution of 2-(quinolin-6-yloxy)-propionic acid ethyl ester (8.61 g, 0.035 mol) in 65 mL of dry THF was cannulated in. The resulting solution is allowed to stand at −78° C. for 3 min. Solid 4-benzyloxybenzaldehyde (6.71 g, 0.032 mol) was added and resulting mixture was allowed to stand at −78° C. for 5 min until all solid dissovled in the solution. Reaction was then quenched with AcOH (6.03 mL, 0.105 mol) in 60 mL of THF at −78° C. The mixture was then diluted with Et2O and washed with sat'NH4Cl, water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography to give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester in 86% yield. A of solution of 2.75 g of give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (6.01 mmol), trifluoroacetic acid (2.8 mL, 36.1 mmol), triethylsilane (5.8 mL, 36.1 mmol) in 80 mL of dichloroethane was heated to reflux for 50 h. The mixture was cooled to r.t. and diluted with Et2O and washed with sat′ NaHCO3, water and brine. Organic layer was dried over Mg SO4, filtered and concentrated. Residue was purified by chromatography (5% MeOH in CH2Cl2) to give 86% of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ 8.78 (dd, 1H, J=4.4, 1.6 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.98 (d, 1H, J=8.8 Hz), 7.45-7.32 (m, 7H), 7.19 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 6.93 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.23 (q, 2H, J=7.1 Hz), 3.38, 3.18 (ABq, 2H, J=13.8 Hz), 1.53 (s, 3H), 1.19 (t, 3H, J=7.1 Hz). MS (ES+) m/z mass calcd for C28H28NO4 (m+1) 442, found 442.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[CH3:20][N:21](C)[CH:22]=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([N:21]([CH3:22])[CH3:20])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(I)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(I)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Iodo-2-nitrobenzoic acid (15.5 g) was dissolved in chloroform (30 mL). Oxalyl chloride (13.4 g) was added thereto at 0° C., and then DMF (dimethylformamide) (0.1 mL) was further added. The mixture was stirred at room temperature for 2 hours, and then concentrated. After addition of toluene to the residue, the mixture was further concentrated. A solution of the concentrated residue in ethyl acetate (60 mL) was added dropwise to a mixed solution of 50% (w/w) aqueous dimethylamine (7.5 mL) saturated aqueous sodium bicarbonate (60 mL), and toluene (60 mL) under stirring and ice-cooling. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, and concentrated to give the title compound (15.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(C)c1ccc(/C=C/CBr)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(OC/C=C/c2ccc(C(C)C)cc2)c(C)c(C)c1NC=O
Yield: 59 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-isopropylbenzene, the title compound was synthesized according to Reference Example 17a. Yield: 59%. Melting point: 165-167° C. (Ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:5])=[O:4])[CH3:2].[ClH:24].O.[H][H]>C(O)C.[Pd]>[ClH:24].[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:5])=[O:4])[CH3:2]
Reactant: [H][H]
Reactant: CCS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution of the product of stage (i) (280 mg) in a mixture of ethanol (40 ml), 2N hydrochloric acid (0.7 ml) and water (5 ml; added to dissolve some precipitated hydrochloride of the starting material) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on carbon (50% w/w with H2O, 330 mg) as the catalyst. After 1 h; when 22 ml (0.92 mmol) of hydrogen had been absorbed, the reaction was stopped. The mixture was filtered and the filtrate was evaporated to give a foam (302 mg). The foam was crystallised from ethanol (ca. 3 ml) to give the title compound (196 mg) as a powder, with m.p. 229°-232°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:15]([CH2:14][C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:24]4[CH:25]=[CH:26][S:22][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:16]1
Reactant: OB(O)c1cccs1
Reactant: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccsc2)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Temperature: 120 °C
Yield: 87.3 %

Procedure:
5-bromo-3-[(1,1-dioxidotetrahydro-3-thienyl)methyl]-1H-indole-7-carboxamide (40 mg, 0.108 mmol), 2-thienylboronic acid (20.68 mg, 0.162 mmol, 1.5 eq), PdCl2(dppf) (7.88 mg, 10.77 μmol, 0.1 eq), potassium carbonate (44.7 mg, 0.323 mmol, 3 eq) were diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL), in a 2-5 mL biotage microwave reaction tube. The mixture was degassed by bubbling nitrogen through for 5 minutes and was then heated in a microwave at high absorption for 15 minutes at 120° C. The reaction was filtered through a thiol SPE cartridge (polymer labs) and was concentrated and purified by Gilson HPLC with trifluoroacetic acid buffer. The desired product fractions were combined and concentrated in an EZ2 Genevac evaporator, giving 35.3 mg (82%) of the title compound.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N+:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.BrCC(C1C=CC(F)=CC=1)=O.CC1C=C2C([CH:39]=[CH:40][CH:41]=[N:42]2)=CC=1>>[C:41]([C:40]1[CH:39]=[C:10]([C:9](=[O:22])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[CH:14]=[CH:13][C:12]=12)#[N:42]
Reactant: Cc1ccc2cccnc2c1
Reactant: Cc1ccc2ccc[n+](CC(=O)c3ccc(F)cc3)c2c1
Agent: O=C(CBr)c1ccc(F)cc1
Agent: [Br-]
Product: Cc1ccc2ccc3c(C#N)cc(C(=O)c4ccc(F)cc4)n3c2c1

Procedure:
1-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-7-methyl-quinolinium bromide: The title compound was prepared from 2-bromo-(4-fluoro-phenyl) ethanone (0.352 g, 2.46 mmol) and 7-methyl-quinoline (0.71 g, 3.27 mmol), by a method similar to that described for the preparation of Example 1a, and yielded 0.741 g (84%). 1H NMR (DMSO-d6): 9.42 (dd, J=16.2, 5.7 Hz, 2H), 8.44 (d, J=8.4 Hz, 1H), 8.35 (s, 1H), 8.24 (m, 3H), 7.92 (d, J=8.4 Hz, 1H), 7.56 (m, 2H), 6.95 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][NH:29][CH:30]([CH3:32])[CH3:31])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][N:29]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=1)[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1cccc(Cl)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200.0 mg, 0.70 mmol), 3-chloro-N′-isopropylbenzohydrazide (223.3 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (40% EtOAc) for refinement and dried so that white ((E)-tert-butyl 3-(3-(2-(3-chlorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (166.0 mg, 49.2%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:19])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(Cl)Cl>[Br:42][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[N:15]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([CH3:19])=[N:8]2)=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (14.96 g, 58.1 mmol) and TEA (12.15 mL, 87 mmol) in DCM (100 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (13.18 mL, 57.4 mmol) dropwise. After the addition, the reaction mixture was stirred at RT for 3 h. It was cooled with an ice bath and quenched with 50 mL of saturated NaHCO3. The layers were separated. The aq. layer was extracted with DCM (2×50 mL). The combined DCM extracts were dried over Na2SO4 and concentrated. The remaining light brown oil was dissolved in THF (100 mL) and H2O (10 mL), cooled with an ice bath, and treated with NBS (10.35 g, 58.1 mmol) in a single portion. The resulting mixture was stirred at 0° C. for 2 h, quenched with 50 mL of saturated NaHCO3, and extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with 20 mL of brine, dried over MgSO4 and concentrated. The resulting yellow solid was treated with 100 mL of MeOH and stirred for 10 min. The yellow solid was filtered, rinsed with MeOH (2×5 mL), collected and dried in a vacuum oven at RT for 18 h to give 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (15.5 g, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (1H, dd, J=8.0, 1.6 Hz), 7.75 (1H, dd, J=7.3, 1.5 Hz), 7.41 (1H, t, J=7.6 Hz), 6.18 (1H, s), 5.15 (2H, s), 2.58 (3H, s), 1.52 (9H, s). m/z (ESI, +ve) 336/338 (M+H)+.