Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:46][C:47]1[CH:48]=[C:49](O)[CH:50]=[CH:51][CH:52]=1.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58]>C1C=CC=CC=1.CCOCC.C(O)C>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]/[C:57]([OH:59])=[O:58].[F:46][C:47]1[CH:52]=[C:51]([CH:50]=[CH:49][CH:48]=1)[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc(F)c1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CC[C@@H](Oc2cccc(F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added, over a 90 minute period and at 5° C. under a nitrogen atmosphere, to a mixture of 4.72 g of cis-1-methyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 3.08 g of 3-fluorophenol and 125 ml of dry benzene. After stirring 18 hours at room temperature, the solid is filtered off and washed well with hexane. The filtrate is concentrated in vacuo to an oil, which is stirred 18 hours with hexane. The resulting mixture is filtered, and the resultant gummy solid is washed well with hexane. The filtrate is concentrated in vacuo to an oil which is taken up in ether and extracted with 2 N HCl solution. The acid extracts are then extracted with dichloromethane. The dichloromethane extracts are washed with 10% by weight aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to afford an oil. This material is chromatographed on silica gel, using acetone as solvent. An oil is thus obtained, which is taken up in ether and treated dropwise with a solution of 1.55 g of fumaric acid in a mixture of 100 ml of ether and 50 ml of absolute ethanol. The solvent is removed in vacuo and the resulting gum is triturated to a solid with ether. The solid is filtered, washed with ether, and dried to afford a solid, mp s 160°, 161°-164° C. Recrystallization from ethyl acetate and then from a mixture of ethyl acetate and acetone affords trans-4-(3-fluorophenoxy)1-methyl-3-phenylpiperidine fumarate, mp s 155°, 156.5°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41][CH2:40]C(O)[CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)=[CH:18][CH:17]=1
Reactant: CN1CCC(O)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCN(C)CC4)cc3)c2cc1OC
Yield: 44.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-methyl-4-piperidinol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (33 mg, yield 37%).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:26][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(F)cc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(CCc2ccc(F)cc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 3.1 mL of methyl acetoacetate, 1.2 g of NaH 60% dispersion in oil, 18 mL of 1.6M n-butyl lithium in hexane, 6.0 g of 3-(4-fluorophenyl)propiophenone and 200 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 4 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 155°-157° C. ). 1H NMR (CDCl3) δ 2.23-2.29 (m, 2 H), 2.42-2.52 (m, 1 H), 2.67-2.78 (m, 1 H), 2.97 (dd, 2 H), 3.35 (dd, 2 H), 7.34-7.47 (m, 5 H), 6.91-7.07 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)[C:5]#[N:6].[CH2:18](OC(OCC)OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(Cl)Cl>[Br:17][C:13]1[CH:12]=[C:11]([N:10]2[C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=[CH:18]2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Nc2cccc(Br)c2)c(N)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
A mixture of compound D (1 g, 3.47 mmol), triethylorthoformate (660 mg, 4.5 mmol) and PTSA (200 mg, 1.16 mmol) in THF (10 mL) was stirred at 70° C. for 4 h. After cooling to RT, the reaction mixture was diluted with DCM, washed with sat. NaHCO3 solution to remove PTSA, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using 40% ethylacetate in hexane to afford compound 4 (1 g, 96%) as light brown solid, mp:168.5-174.4° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1C)=[CH2:2].[OH2:10]>>[C:3]1([OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:2]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1C
Reactant: O
Product: C=Cc1ccccc1
Product: Oc1ccccc1

Procedure:
a water soluble product produced by condensing 1 mol of phenol with 1 to 3 mols of styrene or vinyltoluene and reacting the condensation product with 8 to 50 mols of ethylene oxide or propylene oxide, the weight ratio of (a) to (b) ranging from 1:1-20.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][O:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:13]=2[OH:22])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:40])[CH3:39])[C:32]=1[O:41][C:42](=[O:44])[CH3:43]>CN(C)C=O>[C:3]1([CH2:9][O:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:40])[CH3:39])[C:32]=3[O:41][C:42](=[O:44])[CH3:43])=[C:14]([CH2:19][CH2:20][CH3:21])[C:13]=2[OH:22])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Oc1cccc(CCCCCCBr)c1OC(C)=O
Reactant: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCc2cccc(OC(C)=O)c2OC(C)=O)ccc(C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
To a suspension of 0.14 g (3.5 mmol, 60% on oil) of sodium hydride in 10 mL of anhydrous dimethylformamide stirred at room temperature was added 0.88 g (3.1 mmol) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester. The reaction mixture was stirred for 2 hours and then 1.09 g (3.1 mmol) of 1-(6-bromohexyl)-2,3-bis(acetyloxy)benzene in 10 mL of dimethylformamide was added dropwise. Stirring at 50° was continued for 16 hours and then the solvent was removed on the oil pump. The crude product was purified by HPLC using 25% ethyl acetate-hexane to give 0.55 g (28% yield) of 4-[6-[2,3-bis(acetyloxy)phenyl]hexyloxy]-2-hydroxy-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C[Si]([C:38]#[N:39])(C)C.Cl([O-])(=O)(=O)=O.[Li+]>O1CCCC1.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:38]#[N:39])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: NCc1ccccn1
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: N#CC(NCc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzaldehyde (0.30 g), 2-aminomethylpyridine (0.09 g) and trimethylsilylcyanide (0.08 g) in tetrahydrofuran (5 mL), lithium perchlorate (0.8 g) was added, and the mixture was then stirred for one hour at room temperature. After the reaction mixture was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to obtain {4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}[(pyridin-2-ylmethyl)amino]acetonitrile (0.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CN
Reactant: C=Cc1ccccc1
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: COc1ccccc1CNc1ccc2cc(CCc3ccccc3)ccc2n1

Procedure:
The title compound, MS: m/e=369.1 (M+H+), was prepared in accordance with the general method of examples 2 and 3 from 6-bromo-2-chloroquinoline, 2-methoxybenzylamine and styrene.
Reaction SMILES: [O:1]=[C:2]1[CH:7](C#N)[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[CH:5](C#N)[C:4](=[O:19])N1.S(=O)(=O)(O)O.[OH-:25].[Na+].C[OH:28]>O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]([CH3:10])([CH2:7][C:2]([OH:1])=[O:28])[CH2:5][C:4]([OH:19])=[O:25]
Reactant: [OH-]
Reactant: CO
Reactant: CC1(c2ccccn2)C(C#N)C(=O)NC(=O)C1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(CC(=O)O)(CC(=O)O)c1ccccn1
Temperature: 25 °C

Procedure:
To a mixture of D75 (6 g, 23.6 mmol) in water (3 ml) stirred at r.t., sulfuric acid (3 ml) was carefully added. The resulting mixture was heated at 170° C. for 24 h. After cooling, NaOH (50% aqueous solution) was added dropwise (to afford pH 5-6). Then, MeOH was added to the aqueous mixture. The precipitate thus obtained was filtered and dried in vacuo to yield intermediate D76 (3.5 g, 66.4%) as a green dark oil
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:6]
Reactant: O=C(O)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cn(-c2ccnc3cc(C(F)(F)F)ccc23)c2ccccc12

Procedure:
5 cm3 of thionyl chloride are added to 0.5 g (1.4 mmol) of 3-carboxy-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.58 g of 3-chlorocarbonyl-1-(7-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].C([O-])(=O)C.[Na+].[F:13][C:14]1[C:19]([C:20](=O)[CH3:21])=[CH:18][CH:17]=[C:16]([F:23])[N:15]=1.O>C1COCC1.C(OCC)(=O)C>[F:13][C:14]1[C:19]([C:20](=[N:6][OH:7])[CH3:21])=[CH:18][CH:17]=[C:16]([F:23])[N:15]=1
Reactant: CC(=O)c1ccc(F)nc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=NO)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Hydroxylamine sulfate (13.1 g) and sodium acetate (10.9 g) were added to a solution of 1-(2,6-difluoropyridin-3-yl)ethanone (4.18 g) in aqueous THF (50%, 200 mL), and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 2.44 g of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:24]#[C:23][C:20]3[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=3)=[CH:4][CH:3]=2)=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: C#Cc1ccc(CCCC)cc1
Product: CCCCc1ccc(C#Cc2ccc(C#Cc3ccc(CCCC)cc3)c3ccccc23)cc1

Procedure:
The title compound is prepared analogously to Example 3 from 1,4-dibromonaphthalene and two equivalents of 4-n-butylphenylacetylene.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH:23]=[C:24]1[C:29](=[O:30])[O:28][C:27]([CH3:32])([CH3:31])[O:26][C:25]1=[O:33])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37]1([Mg]Br)[CH2:39][CH2:38]1.Cl.O>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]([CH:37]2[CH2:39][CH2:38]2)[CH:24]2[C:25](=[O:33])[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29]2=[O:30])[CH:34]=[CH:35][CH:36]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]C1CC1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(c2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.39 g) in THF (85 mL) was added dropwise a 0.70 M solution of cyclopropylmagnesium bromide in THF (54.7 mL) at 0° C. over 15 min, and the mixture was stirred at 0° C. for 5.5 hr. 0.50N Hydrochloric acid (300 mL) was added dropwise at 0° C., and water was further added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.05 g) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:10]=[N:11][C:12]([NH2:22])=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:32]>>[ClH:32].[NH2:22][C:12]1[N:11]=[CH:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:23])=[O:5])=[CH:14][C:13]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)C=Cc1cnc(N)c(CN2CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Nc1ncc(/C=C/C(=O)O)cc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-(6-amino-5-piperidin-1-ylmethyl-pyridin-3-yl)acrylic acid tert-butyl ester (250 mg, 0.79 mmol) in CH2Cl2 (3 mL) was treated with TFA (2 mL). After stirring at room temperature under N2 for 45 min, the solution was concentrated. The resulting oil was treated with anhydrous HCl in dioxane (10 mL, 4.0 M) and then sonicated until the oil was converted to a fine off-white solid. After stirring under N2 for 20 min, the solid was isolated by filtration, washed with Et2O, and dried under vacuum for several hours to give the title compound (282 mg, quantitative) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (br s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.39-8.28 (m, 3H), 7.53 (d, J=15.0 Hz, 1H), 6.46 (d, J=15.0 Hz, 1H), 4.33 (s, 2H), 3.43-3.35 (m, 2H), 2.97 (s, 2H), 1.79-1.69 (m, 5H), 1.35 (s, 1H).
Reaction SMILES: N1C=CC([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:22]=3)[C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14]2)=CC=1.C([Sn](CCCC)(CCCC)[C:38]1[S:42][CH:41]=[N:40][CH:39]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:19]1[CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:38]2[S:42][CH:41]=[N:40][CH:39]=2)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=[O:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCCC(c2ccccc2-c2cncs2)N1Cc1cccc(-c2nccs2)c1
Temperature: 75 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (preparation described in example 450; 50 mg; 0.11 mmol), commercially available 5-(tributylstannyl)thiazole (51 mg; 0.13 mmol), and PdCl2(PPh3)2 (8 mg; 0.011 mmol) in THF (1 ml) was heated to 75° C., under nitrogen, for 17 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.80 min.; [M+H]+: 446.11 g/mol.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[C:25]([C:26]([N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH:38]5[CH2:40][CH2:39]5)[CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][C:13]=2[Cl:41])=[CH:6][C:5]=1[Cl:42].C1COCC1.[OH-].[Li+].Cl>O.CO>[Cl:42][C:5]1[CH:6]=[C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]3[C:25]([C:26]([N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([CH:38]5[CH2:40][CH2:39]5)[CH2:30][CH2:29]4)=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:14][C:13]=2[Cl:41])[CH:8]=[CH:9][C:4]=1[C:3]([OH:43])=[O:2]
Reactant: COC(=O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C#Cc2cc(Cl)c(Oc3ncccc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1Cl
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of 2-chloro-4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-phenylethynyl}-benzoic acid methyl ester (150 mg, 0.24 mmol, 1.0 equiv; Example 167) in a 2:2:1 mixture of THF, methanol and water (2 mL) was added lithium hydroxide (11.4 mg, 0.47 mmol, 2.0 equiv; [CAS RN 1310-65-2]) and the reaction mixture stirred at rt over night. The crude reaction product was taken up in water (50 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol to give 110 mg (75%) of the title compound as a light brown solid. MS (ISN): 616.1 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][F:42])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate (165 mg, 0.55 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (202 mg, 0.66 mmol) in 2 mL of NMP was added Cs2CO3 (179 mg, 0.55 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (3×50 mL) and dried over MgSO4. After solvent removal, the residue was chromatographed (hexane/EtOAc) to afford tert-butyl 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ylcarbamate as a white solid (130 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83-7.79 (m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.86 (dd, J=8.4, 2.0 Hz, 1H), 6.83 (dd, J=8.8, 2.4 Hz, 1H), 6.63 (s, 1H), 4.64 (m, 1H), 4.51 (m, 1H), 4.21 (m, 2H), 3.91 (m, 2H), 3.81-3.71 (m, 6H), 1.55 (s, 9H); MS (ESI) m/z 433 (M+H+).