Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)[C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC#N>[CH2:10]([N:9]([CH2:12][CH3:13])[C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([CH:2]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc3cccnc23)cc1
Reactant: C1CNCCN1
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1

Procedure:
The crude product compound III (˜6.6 mmol) and piperazine (2.3 g, 26 mmol) was dissolved in dry MeCN (50 mL) and heated at reflux 12 h. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 and washed with water and the organic phase dried (K2CO3) and evaporated in vacuo. After chromatography on silica (0-20% MeOH in CH2Cl2, 1% NH4OH), a total of 1.8 g (68%, 2 steps) compound 1 was obtained. Further purification could be achieved by reverse phase chromatograpy (LiChroprep RP-18, 10-50% MeCN in water, 0.1% TFA) to give 1.2 g colorless product. The dihydrochloride salt was made by treatment with 2 eq. HCl in ether.
Reaction SMILES: [C:1]1([C:7]([CH3:11])=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18]([C:21]#[N:22])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(OCCCC)(OCCCC)OCCCC>>[C:12]1([S:18]([C:21]2[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=[CH:9][N:22]=2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=CC=O)c1ccccc1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Product: O=S(=O)(c1ccccc1)c1cc(-c2ccccc2)ccn1
Temperature: 112 °C
Yield: 68.7 %

Procedure:
First, 0.93 g (6.36 mmol) of 3-phenyl-2-butenal and 0.99 g (5.91 mmol) of benzenesulfonyl cyanide were introduced to a 3-necked flask (25 ml volume) equipped with a thermometer, a magnetic stirrer, a Dean-Stark water type distilling receiver, and a condenser tube. Toluene (5 ml) as the solvent and butanol (0.5 ml) were added, and 0.14 g (0.59 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 2 hours while agitating at an internal temperature of 112° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=¼) to give 1.20 g of 2-benzenesulfonyl-4-phenylpyridine with the following properties as colorless crystals (purity of 99%, yield of 71% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[N:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1.[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[N:10]=[N:11][C:12]([O:15][CH3:23])=[CH:13][CH:14]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)N=C(Oc2ccc(O)nn2)c2cc(C#N)ccc2O1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(OC2=NC(C)(C)Oc3ccc(C#N)cc32)nn1
Reaction time: 3 h

Procedure:
A mixture of 296 mg of 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-2H-1,3-benzoxazine, 1 g of K2CO3,0.65 ml of dimethyl sulfate and 16 ml of DMF is boiled for 3 hours and subjected to customary work-up. 2,2-Dimethyl-4-(6-methoxy-3-pyridazinyloxy)-6-cyano-2H-1,3-benzoxazine is obtained.
Reaction SMILES: C([O:5]O)(C)(C)C.C([Li])CCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]([CH:26]2[CH2:27][O:5]2)=[O:28])[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OO
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CO2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.9 %

Procedure:
A solution of anhydrous t-butyl hydroperoxide (5.5M in nonane, 2.07 ml, 11.38 mmol, 1.5 eq) was added to anhydrous THF (50 mL), at −78° C. under argon. To the resulting solution at −78° C. was added butyl lithium (2.3M in n-hexane, 3.36 ml, 8.4 mmol, 1.1 eq) was added and the solution is stirred for a further 5 min at this temperature. A solution of the 4-Acryloyl-piperazine-1-carboxylic acid tert butyl ester (1.96 g, 7.64 mmol, 1 eq) in anhydrous THF (20 ml) was then added dropwise at −78° C. The resulting mixture was then allowed to warm slowly to room temperature and stirred for a further 16 hr. To the mixture was then added sodium sulfite (1.5 g, 12 mmol, 1.55 eq) and this was then stirred for 15 min. The mixture was then diluted with diethylether (50 ml), filtered through celite and the filtrate evaporated. The residue was purified by chromatography (ethyl acetate/n-hexane 4/1) to give the product (0.39 g, 19%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(#N)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: ClCCl
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Temperature: 70 °C
Yield: 57.8 %

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated to at 70° C. for 1 hour. The mixture was reduced in vacuo and the remaining black residue was taken up in dichloromethane (250 ml) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The layers were separated and the organic dried over sodium sulfate and reduced in vacuo. The mixture was chromatographed using an ethyl acetate:hexanes (0-100%) gradient on an isco flash chromatography system. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow oil (3 g, 57.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH:62]([CH3:74])[C@@H:63]([O:70][N+:71]([O-:73])=[O:72])[C@H:64]([O:66][N+:67]([O-:69])=[O:68])[CH3:65])=[O:58])([CH3:55])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].CO>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][C:53]([O:56][C:57]([O:59][CH2:60][CH2:61][CH:62]([CH3:74])[C@@H:63]([O:70][N+:71]([O-:73])=[O:72])[C@H:64]([O:66][N+:67]([O-:69])=[O:68])[CH3:65])=[O:58])([CH3:54])[CH3:55])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[({[(4R,5R)-3-Methyl-4,5-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]-1-methylethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (1.77 g, 1.76 mmol) was dissolved in CH2Cl2 (5 mL) and MeOH was added (30 mL). After stirring at room temperature for 72 hrs, the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, CH2Cl2/MeOH 98:2) affording the tile compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:34])([CH3:33])N1CCOC1=O.[Br:35]N1C(=O)CCC1=O>ClCCl>[Br:35][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:34])([CH3:33])[CH3:25])=[O:9]
Reactant: C[Si](C)(C)N1CCOC1=O
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 48 %

Procedure:
A mixture consisting of 753 mg (2.16 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide, 785 mg (4.94 mmoles) of N-trimethylsilyl-2-oxazolidinone and 70 ml of dichloromethane was refluxed for 2 hours, after which a clear, almost colorless solution was obtained. This was cooled in an ice-bath and bromination was carried out in half an hour using 624.5 mg (3.51 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 48% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13]O)=[CH:4][C:3]=1[F:21].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].S(Cl)([Cl:36])=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13][Cl:36])=[CH:4][C:3]=1[F:21]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cn(CCO)c2cc(Cl)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(CCCl)c2cc(Cl)c(F)cc2c1=O
Yield: 80 %

Procedure:
27 g of the foregoing ester product were added, portionwise, to an agitated and cooled solution of pyridine (8.1 cm3) in thionyl chloride (54 cm3). The addition was carried out at such a rate that the temperature of the mixture remained between 0° and 5° C. After returning to room temperature, the solution was heated for 1 hour under reflux and the excess of reagent was then removed by distillation under reduced pressure. The residue was added, with agitation, to 100 cm3 of iced water. The suspension obtained was neutralised by the addition of 10% aqueous Na2CO3. The precipitate obtained was filtered off, washed with water and recrystallised from ethanol (480 cm3). 22.4 g of 7-chloro-1-(2-chloroethyl)-3-ethoxycarbonyl-6-fluoro-4-oxo-1,4-dihydro-quinoline, m.p. 222° C., were obtained; yield 80%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.C(O)C>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 94 °C
Yield: 72 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and ethanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was slowly heated to reflux (94° C.) under a nitrogen atmosphere and kept at this temperature overnight. The reaction mixture was cooled to below 50° C. and water (10 mL, 2 vol) was added to precipitate out the solid, which was isolated by filtration. The light yellow solid was washed twice with water (5 mL) and dried to furnish pure olanzapine in 72% yield (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.C(O)(=[O:27])C.[CH:29]([NH2:31])=[NH:30]>C(N)=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:31]=[CH:29][N:30]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:27])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Solvent: NC=O
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 1.0 g (9.6 mmol) of formamidine acetate and 20 ml of formamide was heated on a steam bath for 6 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized with the addition of a mixture of ether and methylene chloride to give off-white crystals, mp 186°-188° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[C:9](=[O:27])[N:10]3[CH2:26][CH2:25][CH2:24][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.[OH-:39].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:8]2[C:9](=[O:27])[N:10]3[CH2:26][CH2:25][CH2:24][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:36])=[O:39]
Reactant: [OH-]
Reactant: CSc1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC(C)(C)C)ncn1-2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2cccc1S(C)(=O)=O

Procedure:
4 g (10.83 mmol) of t-butyl (S)-11,12,13,13a-tetrahydro-8-methylthio-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are dissolved in 50 ml of methylene chloride and treated portionwise at room temperature with 4.0 g (about 20.8 mmol) of about 90 percent m-chloroperbenzoic acid. Subsequently, the mixture is warmed to boiling under reflux for 2.5 hours, then poured into 2 N sodium hydroxide and the methylene chloride solution is separated. The organic phase is dried over magnesium sulphate and evaporated. After recrystallization from chloroform/hexane, there is obtained t-butyl (S)-11,12,13,13a-tetrahydro-8-methylsulphonyl-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 244°.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:42]1[CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[N:42]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4[CH2:21][C:20](=[O:22])[NH:19][C:18]5[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=5[N:16]=4)[CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:5][N:4]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: C1CNC1
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2cccc(-c3ccnc(CN4CCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with azetidine in DMF according to the general procedure of example 288. Obtained as an off-white solid (153 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]([F:40])([F:39])[C:36]([O-:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(Br)ccnc32)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
A mixture of Example 220C (8 g, 15.02 mmol) and trifluoroacetic acid (11.58 mL, 150 mmol) in dichloromethane (100 mL) was stirred at 20° C. for 12 hours. The mixture was concentrated to give the title compound as a trifluoroacetate salt. MS (CI) m/z 432 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([C:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[CH:10].C(NC(C)C)(C)C.C1(C)C=CC=CC=1>C1COCC1.[Pt]=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:10][CH2:9][C:11]2([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: C#CC1(N)CCCCC1
Reactant: Fc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=[Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: NC1(CCc2ccc(F)cc2)CCCCC1

Procedure:
2.5 g (11.3 mmol) 1-fluoro-4-iodo-benzene, 1.5 g (11.9 mmol) 1-ethynyl-cyclohexylamine, 793 mg (1.13 mmol) PdCl2(PPh3)2, 67 mg (0.35 mmol) copper iodide and 50 mL diisopropylamine are stirred for 2 hours at 70° C. Then the base is distilled off and the residue is combined with ethyl acetate. The insoluble constituents are filtered off and the filtrate is evaporated down. The alkyne thus prepared is dissolved in 35 mL THF and 35 mL toluene and hydrogenated with platinum oxide as catalyst at normal pressure. The catalyst is separated off and the filtrate is freed from the solvent. The crude product is dissolved in ethyl acetate and combined with 10% hydrochloric acid in ethyl acetate. The precipitated solid is filtered off and washed with ethyl acetate. Yield: 1.3 g (45%; hydrochloride); mass spectroscopy: [M+H]+=222.
Reaction SMILES: O.O.C(O)(=O)C(O)=O.[CH2:9]([O:11][C:12](=[O:37])[CH:13]([O:34][CH2:35][CH3:36])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][C:17]=1[O:30][CH:31]([CH3:33])[CH3:32])O)[CH3:10]>C(O)(C)C.[Pd]>[CH2:9]([O:11][C:12](=[O:37])[CH:13]([O:34][CH2:35][CH3:36])[CH2:14][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[O:30][CH:31]([CH3:32])[CH3:33])[CH3:10]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1OC(C)C
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C(Cc1ccc(O)cc1OC(C)C)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.80 g of Pd/C (10%) and 6.0 g of oxalic acid dihydrate were added under argon to 3.20 g (7.95 mmol) of [rac]-3-(4-benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester [mixture of diastereomers] dissolved in 60 ml of isopropanol. This solution was stirred for 24 hours at room temperature and 50 bar H2. Filtration over dicalite and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9:1 to 1:1) left 0.69 g (29% of theory) of [rac]-2-ethoxy-3-(4-hydroxy-2-isopropoxy-phenyl)-propionic acid ethyl ester as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19](SC)=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:28][S:29]([O-:31])=O.[K+].O1CCC[CH2:34]1>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:29]([CH3:34])(=[O:31])=[O:28])=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N+:24]([O-:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
2-(Benzyloxy)-4-[4-(methylthio)phenoxy]-1-nitrobenzene (10.3 g) was dissolved in a mixed solvent of tetrahydrofuran (200 mL)-methanol (100 mL)-water (50 mL), Oxone (trade mark) (42.0 g) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtered to remove a white solid, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with a diethyl ether-hexane mixed solvent to give the title compound (11.0 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]4)[CH:22]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 84.7 %

Procedure:
Following general procedure F, {6-Bromo-4-[1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-ylamino]quinolin-3-yl}(cyclopropyl)methanone (53 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.165 mmol) to afford the desired product (50 mg, 84%) as a green-yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.06 (s, 1H), 8.23 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.7, 2.1 Hz, 1H), 7.93-7.85 (m, 2H), 7.50 (s, 2H), 7.43 (s, 1H), 4.22-4.12 (m, 1H), 2.94 (d, J=11.4 Hz, 2H), 2.88-2.79 (m, 1H), 2.39 (s, 3H), 2.27-2.20 (m, 2H), 2.02-1.89 (m, 4H), 1.02-0.91 (m, 4H); ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.6% (AUC), tR=10.40 min.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.CCOC(C)=O>O1CCOCC1>[CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([O:25][CH2:35][CH:37]4[CH2:38][O:39]4)=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC1CCCCC1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(I)c(Oc2cc(I)c(OCC3CO3)c(I)c2)c(I)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 4.8 %

Procedure:
Compound 4 (2.0 g, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous dioxane (30 mL), then anhydrous Cs2CO3 (684 mg, 2.1 mmol, 1.0 eq.) was added and then epibromohydrin (1.8 mL, 21.0 mmol, 10.0 eq.) was added dropwise. The reaction medium was then slowly heated to reflux. The mixture was stirred during 12 hours upon reflux then cooled to room temperature. EtOAc (10 mL) was then poured and the precipitate was filtered. EtOH (20 mL) was then added to the solution and the precipitate was filtered off. The remaining solution was analyzed by TLC. The first precipitate was washed thoroughly with EtOAc (30 mL). The organic solution was then evaporated and purified by column chromatography using silica gel (DCM/hexanes 80/20). The product was further recrystallized to give N-cyclohexyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetamide (93 mg, 0.1 mmol) as a powder. The second filtrate and the remaining solution were revealed by TLC to be the starting material which did not react.