Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:27][C:28]1[N:33]=[C:32]([C:34]([C:36]2[N:37]=[CH:38][N:39]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:40]=2)=O)[CH:31]=[CH:30][CH:29]=1.CCOCC>C1COCC1>[CH3:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:34]([C:36]2[N:37]=[CH:38][N:39]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:40]=2)=[CH2:2])[N:33]=1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc(C)n1
Temperature: -50 °C
Yield: 50 %

Procedure:
Methyl triphenylphosphine bromide (commercially available from Aldrich) (2.2 g, 6.16, mmol) in THF(60 mL) at −70° C. was treated with nBuLi (2.44 mL, 2.5M in hexane). The reaction mixture warmed to −50° C. in 1 h. A solution of (6-methyl-pyridin-2-yl)-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate D3) (1.38 g, 3.2 mmol) in THF (25 mL) was added to the mixture via syringe at −50° C. The mixture was allowed to warm to rt for 1.5 h. The mixture was poured into ether (mL) and washed with water (2×10 mL). The organic solution was dried over MgSO4, filtered and evaporated to leave a residue. This was purified by chromatography on SiO2 with diethyl ether to give 2-methyl-6-[1-(1-trityl-1H-imidazol-4-yl)-vinyl]-pyridine (Intermediate D4) 0.68 g (50%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH3:21]>C(#N)C>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:35]
Reactant: CCN(CC)CCOCCC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCN(CC)CCOCCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 79 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[2-(diethylamino)ethoxy]ethyl]piperidine (b.p.0.4 mmHg 95°-99° C.) in a yield of 79% of theory. Colourless crystals, m.p. 134°-136° C. (acetonitrile).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)([CH:19]([CH3:21])[CH3:20])[CH2:10][CH2:11][CH2:12][N:13]([CH2:15][CH:16]([CH3:18])[OH:17])[CH3:14])#[N:8]>C1(C)C=CC=CC=1>[C:4]([O:17][CH:16]([CH3:18])[CH2:15][N:13]([CH2:12][CH2:11][CH2:10][C:9]([C:7]#[N:8])([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[CH:19]([CH3:20])[CH3:21])[CH3:14])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: COc1ccc(C(C#N)(CCCN(C)CC(C)O)C(C)C)cc1OC
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCN(C)CC(C)OC(=O)CC(C)=O)C(C)C)cc1OC
Temperature: 80 °C

Procedure:
2.7 ml of diketene was added, over 10 minutes, to a solution of 11.36 g of the compound prepared in Example 2 in 10 ml of toluene at 80° C. When the exothermic reaction was over, the reaction mixture was heated for 2 hours at 80° C. and, after cooling, it was evaporated to dryness in vacuo. The oily residue was then purified by silica gel column chromatography using ehtyl acetate containing decreasing amounts of petroleum ether as eluent. The unitary TLC fractions (chloroform:methanol 95:5 by volume) were evaporated to dryness in vacuo to give 11.61 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2)[CH:2]=[CH2:3].[Br:21][C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1>>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=1)[C:14]([CH3:19])=[CH:13]2)[CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCOc1ccc2[nH]c(C)cc2c1
Reactant: Fc1ccc(Br)cc1
Product: C=CCN(C)CCCCOc1ccc2c(c1)cc(C)n2-c1ccc(Br)cc1

Procedure:
In analogy to example 9.1, Allyl-methyl-[4-(2-methyl-1H-indol-5-yloxy)-butyl]-amine and 1-bromo-4-fluorbenzene were converted to yield Allyl-{4-[1-(4-bromo-phenyl)-2-methyl-1H-indol-5-yloxy]-butyl}-methyl-amine as orange viscous oil, MS: 426 (M, 1Br).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5]([C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=O.S(C)C>C1COCC1>[F:1][C:2]([F:23])([F:24])[CH2:3][NH:4][CH2:5][C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)NCC(F)(F)F
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CNCC(F)(F)F)CC1CCCCC1
Yield: 98.5 %

Procedure:
To a solution of tert-butyl (S)-1-(2,2,2-trifluoroethylcarbamoyl)-2-cyclohexylethyl-carbamate (1.8 g, 5.1 mmol) in anhydrous THF (30 mL) was added 2 M BH3.Me2S in THF (25 mL, 50 mmol) and the mixture was stirred at rt for 3 d. The reaction was quenched with MeOH (20 mL), the solvent was removed in vacuo and the residue was purified by silica chromatography to give crude tert-butyl (S)-1-(2,2,2-trifluoroethylamino)-3-cyclohexylpropan-2-ylcarbamate (1.7 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30](O)=[O:31])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[C:30]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:31])[CH2:27]2
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)C1C3CC4CC(C3)CC1C4)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.096 ml was added to a methylene chloride 5 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg and stirred at O@C for 30 min. 2-adamantane carboxylic acid 0.11 g and WSC 0.13 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 17 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(2-adamantylcarbonyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 24.0 mg and refluxed under heating for 2 hours. The-reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:36])[NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([O:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([O:25][S:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:36])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CCNCC1
Yield: 67.5 %

Procedure:
A solution of 4-[6-(4-fluorobenzenesulfonyloxy)benzothiazol-2-ylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (intermediate 3) (100 mg, 0.187 mmol) and of TFA (0.5 ml) in dichloromethane (4.5 ml) is stirred at room temperature for 1 hour. The reaction medium is evaporated to dryness. The residue is taken up in a minimum amount of water, neutralized by addition of aqueous 10% Na2CO3 solution and extracted with ethyl acetate to give 55 mg of 4-fluorobenzenesulfonic 2-[(piperidine-4-carbonyl)amino]benzo-thiazol-6-yl ester (white solid).
Reaction SMILES: [Na].[CH2:2]([SH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([C:15]1[CH:16]=[C:17]([CH:37]=[C:38]([CH3:41])[C:39]=1[OH:40])[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=[C:21](Cl)[N:20]=1)([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([C:15]1[CH:16]=[C:17]([CH:37]=[C:38]([CH3:41])[C:39]=1[OH:40])[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:31][C:30]([CH3:32])([CH3:33])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=[C:21]([S:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:20]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1cc(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCS
Agent: [Na]
Solvent: CO
Product: CCCCCCCCSc1nc(Nc2cc(C)c(O)c(C(C)(C)C)c2)nc(NC2CC(C)(C)NC(C)(C)C2)n1
Temperature: 0 °C

Procedure:
1.15 g of sodium were dissolved in 150 ml of methanol and 7.3 g of n-octylmercaptan were added. A solution of 10.8 g of 2-(3-tert.-butyl-5-methyl-4-hydroxyanilino)-4-[(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-6-chloro-1,3,5-triazine in 200 ml of methanol was added to the resulting sodium n-octylmercaptide, whilst stirring. The reaction mixture was kept under reflux for 16 hours and then poured into 400 ml of ice water, a slightly brownish precipitate, which was filtered off, being formed. Recrystallization from ethyl acetate/hexane gives 13.9 g of almost colourless 2-(3-tert.-butyl-5-methyl-4-hydroxyanilino)-4-[(2,2,6,6-tetramethyl-piperidin-4-yl)-amino]-6-(n-octylthio)-1,3,5-triazine having a melting point of 133° C. (stabiliser 2).
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=1[F:23].[C-]#N.[Na+]>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([C@H:19]2[O:20][CH:13]=[N:12][C@@H:11]2[S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:17][C:16]=1[F:23]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(Cl)c(F)c2)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.30 g, 1.52 mmol), 4-chloro-3-fluorobenzaldehyde (0.25 g, 1.60 mmol) and NaCN (10 mg, 0.20 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 373.5 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42](=[O:44])[CH3:43])=[CH:39][CH:40]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)Oc1ccc(CN(c2ccc(I)cc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccc(OC(C)=O)cc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 66 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (45.6 mg) was reacted with (4-iodophenyl)-(4-acetoxybenzyl)pyrimidin-2-ylamine (67.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-acetoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (61.7 mg). Column chromatography (silica gel, eluent: ethyl acetate/hexane=1/3→3/1) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=1/5) were used for purification. (2) To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-acetoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (61.7 mg) in THF (3.0 ml), 0.1N aqueous sodium hydroxide solution (3.0 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-hydroxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (43 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][CH3:24])[CH2:37][CH2:36]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CSc1ccccc1N1CCNCC1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 71.4 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: CN(C)C([S:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([S:13]C(=O)N(C)C)[CH:12]=1)[NH2:9])=O.[OH-].[Na+]>>[SH:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([SH:13])[CH:12]=1)[NH2:9]
Reactant: CN(C)C(=O)Sc1cc(N)cc(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(S)cc(S)c1

Procedure:
3,5-Bis(dimethylcarbamoylthio)aniline was subjected to hydrolysis with aqueous sodium hydroxide according to the ordinary procedure, giving 3,5-dimercaptoaniline.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-6-nitro-benzoic acid (5.6 g, 30.9 mmol, 1.0 eq, Aldrich) and acetone (100 mL) was added crushed K2CO3 (21.4 g, 154.6 mmol, 5 eq) and MeI (9.6 mL, 154.6 mmol, 5.0 eq). The reaction was heated to reflux for 15 h then cooled to RT, filtered and concentrated in vacuo. The filtrate was dissolved in EtOAc, washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a reddish-brown oil which upon standing at RT crystallized to tan needles
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH:14]=[CH:21][N:24]([CH3:26])[CH3:25])[C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c([N+](=O)[O-])ccc(C=CN(C)C)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 57.7 %

Procedure:
A mixture of 3-methyl-2,6-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water and the precipitate was collected via filtration and washed with water to give 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester (25 g, 58%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])[CH3:32]>CN1C(=O)CCC1>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)N1CCN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Trifluoro-methane sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml) and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at 120° C. for 3 hours. After cooling to room temperature, purification was carried out by HPLC to obtain the target compound (white powder, 12.8 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:5]=[C:6]([O:13][CH2:14][CH3:15])[C:7]=1[O:8]S(C)(=O)=O.F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:5]=[C:6]([O:13][CH2:14][CH3:15])[C:7]=1[O:8][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OS(C)(=O)=O)c(OCC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c(OCC)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of the product of step b (0.20 g), 1-fluoro-4-nitrobenzene (53 μL) and cesium carbonate (0.22 g) was dissolved in dimethyl sulfoxide (1 mL) and stirred at 80° C. for 16 h. Dichloromethane was added and the reaction mixture was washed with a solution of 1% hydrochloric acid in water and with saturated brine. The organic phase was concentrated and the title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:28])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]=2[CH3:27])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:30]([O:32][NH2:33])[CH3:31]>>[CH2:23]([S:22][CH2:21][C:15]1[C:14]([CH3:27])=[C:13]([CH:9]2[CH2:10][C:11](=[O:12])[C:6]([C:1](=[N:33][O:32][CH2:30][CH3:31])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:28])[CH2:8]2)[C:18]([CH3:19])=[CH:17][C:16]=1[CH3:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCSCc1c(C)cc(C)c(C2CC(=O)C(C(=O)CCC)=C(O)C2)c1C
Reactant: CCON
Agent: Cl
Product: CCCCSCc1c(C)cc(C)c(C2CC(=O)C(C(CCC)=NOCC)=C(O)C2)c1C

Procedure:
5-[3-(n-Butylthiomethyl)-2,4,6-trimethylphenyl]-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one (59) was prepared from 2-butyryl-5-[3-(n-butylthiomethyl)-2,4,6-trimethylphenyl]-3-hydroxycyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC([O-])(C)C.[K+].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:45][CH3:46])=[C:27]([C:29]([CH3:44])([CH3:43])[CH2:30]/[C:31](=[N:36]/S(C(C)(C)C)=O)/[C:32]([F:35])([F:34])[F:33])[CH:28]=1>C(OCC)C.C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:45][CH3:46])=[C:27]([C:29]([CH3:43])([CH3:44])[CH2:30][C:31]([NH2:36])([CH2:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:32]([F:35])([F:34])[F:33])[CH:28]=1
Reactant: COc1ccc(F)cc1C(C)(C)C/C(=N/S(=O)C(C)(C)C)C(F)(F)F
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1cc2ccccc2[nH]1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
To a chilled (−78 C.) solution of 40 mg (0.30 mmol) of 2-methylindole in 3 mL of diethyl ether was added 0.56 mL (0.91 mmol) of a 1.6 M solution of n-BuLi in hexanes. The resulting orange solution was stirred for 5 min and treated with 0.60 mL (0.60 mmol) of a solution of 1 M solution of KOt-Bu in THF. The reaction was slowly warmed until a bright yellow precipitate formed. After 5 min, the reaction mixture was cooled to −78° C. and treated with 138 mg (0.362 mmol) of a solution of 2-methyl-propane-2-sulfinic acid [3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amide in 0.5 mL of diethyl ether. Next, the mixture was warmed to room temperature, quenched with aqueous ammonium chloride and extracted with EtOAc (3×). The combined organic layers were dried over (MgSO4), filtered and concentrated. The residue was dissolved in 2 mL of methanol, 3 drops of concentrated HCl were added and the reaction warmed at 75° C. in a sealed tube. After 1 h, the reaction was cooled to room temperature, concentrated in vacuo, neutralized with aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and concentrated to leave an oil. The residue was purified by preparative thin layer chromatography eluting with toluene to afford an oil that had to be further purified by preparative thin layer chromatography eluting with hexanes-EtOAc (9:1) to afford 40 mg (33%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: OC1CCN(c2nncc3cc(Br)ccc23)C1
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: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCC(O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(6-bromophthalazin-1-yl)pyrrolidin-3-ol (0.11 g, 0.37 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.11 g, 0.37 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol) and 2M potassium carbonate (0.6 mL, 1.2 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) eluting with 2% 2M ammonia in MeOH/DCM (0.13 g) to afford the title compound as a yellow solid. Found MS (ES+): 389(M+H)+.