Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([OH:23])=O)=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12.O1C=C[N:26]=C1Cl>O1CCCC1.CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([NH2:26])=[O:23])=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12
Reactant: CSc1sc(C(=O)O)c2c1-c1sc(-c3ccccc3)cc1CC2
Reactant: Clc1ncco1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSc1sc(C(N)=O)c2c1-c1sc(-c3ccccc3)cc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
4,5-Dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxylic acid (0.50 g) was dissolved in tetrahydrofuran (10 ml); oxazolyl chloride (0.15 ml) and then N,N-dimethylformamide (one drop) were added. After the mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml); concentrated aqueous ammonia (5 ml) was added. After the reaction mixture was stirred at room temperature for one hour, it was poured over water and extracted with chloroform-methanol. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxamide (0.28 g, 56%), which was recrystallized from ethanol. Melting point 192-193° C.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[O:16]1[CH2:27][CH:17]1[CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]1[O:26][CH2:25]1>CO>[CH2:1]([N:5]([CH2:25][CH:24]([OH:26])[CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH:17]([OH:16])[CH2:27][N:5]([CH:6]1[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][C:10]([CH3:12])([CH3:13])[CH2:11]1)[CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]1[CH2:7][C:8]([CH3:14])([CH3:15])[NH:9][C:10]([CH3:13])([CH3:12])[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: C(COCC1CO1)OCC1CO1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CCCCN(CC(O)COCCOCC(O)CN(CCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h

Procedure:
A mixture of 6.4 g of 4-butylamino-2,2,6,6-tetramethylpiperidine and 2.6 g of ethylene glycol bis(2,3-epoxypropyl)ether in 50 ml of methanol was refluxed, with stirring for 5 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and then the residue was recrystallized from n-hexane, giving the desired compound in the form of white crystals melting at 81°-83° C. and boiling at 258°-262° C. at 0.06 mmHg.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22]3)[C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:25]1([C:16]2[C:17]3[C:23]([CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:24][C:15]=2[C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: NS(=O)(=O)c1ccc(-c2cc3cccccc-3c2-c2ccccc2)cc1
Yield: 129.5 %

Procedure:
Methyl 3-bromo-2-(4-t-butylaminosulfonylphenyl) azulene-1-carboxylate: To a solution of 2-(4-t - butylaminosulfonylphenyl) -1-phenylazulene (0.50 g) in CCl4 (20.0 ml) was added N-bromosuccinimide (0.25 g) and α,α'-azobis (isobutyronitrile) (0.01 g), and the reaction mixture was heated under reflux for 1 hr. The reaction mixture was filtered, and concentrated. The crude product was purified by SiO2 column chromatography (benzene/EtOAc, 20:1) to give the title compound (0.56 g) as violet crystals; mp 171°-172° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([CH2:15][CH3:16])[CH:8]=1>CN(C=O)C.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[C:9]([CH2:15][CH3:16])[CH:8]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: c1cn[nH]c1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1Cn1cccn1
Temperature: 80 °C
Reaction time: 13 h
Yield: 79.6 %

Procedure:
A solution of pyrazole (616 mg, 9.1 mmol) in anhydrous DMF (30 mL) was treated with naH (60%, 362 mg). 4-Bromo-1-bromomethyl-2-ethyl-benzene (2.5 g, 9.1 mmol) was added and the resulting solution was stirred at 80° C. for 13 hours before it was cooled down to room temperature. The mixture was diluted with H2O, extracted with Et2O. The combined organic extracts were washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product (1.92 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ 1.15 (t, J=7.5 Hz, 3 H), 2.59-2.66 (m, 2 H), 5.30 (s, 2 H), 6.26-6.28 (m, 1 H), 6.86-6.88 (m, 1 H), 7.29-7.32 (m, 2 H), 7.37-7.38 (m, 1 H), 7.54-7.55 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[C@@H:18]4[CH2:19][C@@H:15]([CH2:16][CH2:17]4)[N:14]3[C:20](=[O:31])[C@@H:21]([NH:26][C:27](=[O:30])[O:28][CH3:29])[C@H:22]([O:24][CH3:25])[CH3:23])=[N:10][CH:9]=2)=[C:4]([F:32])[CH:3]=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([NH:65][C:66](=[O:69])[O:67][CH3:68])[C:36](=[O:64])[N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]1[NH:46][C:45]2[C:47]3[C:52]([CH:53]=[CH:54][C:44]=2[N:43]=1)=[CH:51][C:50](B1OC(C)(C)C(C)(C)O1)=[CH:49][CH:48]=3.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:68][O:67][C:66]([NH:65][C@@H:35]([CH:34]([CH3:70])[CH3:33])[C:36]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C:42]1[NH:46][C:45]2[C:47]3[C:52]([CH:53]=[CH:54][C:44]=2[N:43]=1)=[CH:51][C:50]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]4[C@@H:18]5[CH2:19][C@@H:15]([CH2:16][CH2:17]5)[N:14]4[C:20](=[O:31])[C@@H:21]([NH:26][C:27](=[O:30])[O:28][CH3:29])[C@H:22]([O:24][CH3:25])[CH3:23])=[N:10][CH:9]=2)=[C:4]([F:32])[CH:3]=1)=[CH:49][CH:48]=3)=[O:64])=[O:69]
Reactant: COC(=O)N[C@H](C(=O)N1C(c2ncc(-c3ccc(Br)cc3F)[nH]2)[C@H]2CC[C@@H]1C2)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
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: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc(C6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)c(F)c4)ccc3c2[nH]1)C(C)C
Yield: 47.8 %

Procedure:
Methyl (2S,3R)-1-((1R,4S)-3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate (162 mg, 0.318 mmol), methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (199 mg, 0.382 mmol), Pd(PPh3)4 (37 mg, 0.0318 mmol) and K2CO3 (2M in H2O, 0.4 mL, 0.8 mmol) were suspended in DME (3 mL). The reaction mixture was degassed with N2 for 11 min then heated to reflux for 2.5 h. Upon completion, the reaction mixture was diluted with MeOH, filtered over a thiol SPE column and concentrated. The crude residue was purified by silica column chromatography (0% to 50% MeOH/EtOAc) to afford the title compound (125 mg, 48%). (ESI) m/z 823 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: CCc1ccccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1ccccc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a reactor were charged 8.77 g (71 mmol) of 2-ethylphenol, 10.00 g (79 mmol) of benzyl chloride, 8.06 g (144 mmol) of KOH, and 30 g of DMF, and the mixture was stirred at 65° C. to 85° C. for 3 hours. To this mixture, 55 g of hydrochloric acid and 50 g of toluene were added, the organic layer was washed with water, and the solvent was evaporated. The residue was purified by column chromatography (n-hexane) to yield the desired product, 1-benzyloxy-2-ethylbenzene, as colorless liquid (9.23 g, Yield: 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].CO[C:21](OC)(OC)[CH2:22][Cl:23]>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:21]([CH2:22][Cl:23])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Reactant: COC(CCl)(OC)OC
Product: CCCC(CCC)NC(=O)c1ccc2oc(CCl)nc2c1
Yield: 65 %

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 41a) and trimethyl chloro-orthoacetate. Yield: 65%. mp 108.5-109° C. MS (M+H, 309.05).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-])=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([NH:27][CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30])=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([NH:13][C:29](=[O:30])[CH:28]([NH:27][C:25](=[O:26])[CH2:24][C:19]2[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([F:16])[CH:18]=2)[CH2:32][CH2:33][CH3:34])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cn(Cc2ccccc2)cn1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(Cc2ccccc2)cn1

Procedure:
1-Benzyl-4-nitro-1H-imidazole was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 470 m/z (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[C@H:11]([CH2:12][CH2:13][CH3:14])[N:10]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:9]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S(=O)(=O)(O)[O-:26].[Na+]>O1CCOCC1.CCOCC>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][NH:10][C@@H:11]([CH2:12][CH2:13][CH3:14])[C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([OH:22])=[O:26]
Reactant: CCC[C@H]1[C@@H](CC2CCCCC2)C(=O)N1OC1CCCCO1
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC[C@H](NOC1CCCCO1)[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
(3R,4S)-3-Cyclohexylmethyl-4-propyl-1-(2-tetrahydropyranyloxy)azetidin-2-one (2.25 g, 7.27 mmol) is dissolved in 10 mL of 1,4-dioxane. 2.5 N Aqueous sodium hydroxide solution (8.73 mL, 21.8 mmol) is added and the reaction stirred for 18 h at 25° C. The solution is diluted with 50 mL of ether and shaken. The organic phase is discarded and the aqueous layer is acidified with solid sodium bisulfate and then extracted with two 25-mL portions of ether. The combined organic phases are dried over sodium sulfate and concentrated in vacuo giving (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid as an oil (2.02 g, 85% yield).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](Cl)(=[O:29])[CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:27](=[O:29])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in dichloromethane, 1.1 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine would be added. The reaction would be stirred at room temperature under nitrogen overnight. The reaction would be diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C-:25]#[N:26].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@H:10]([C:25]#[N:26])[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (4R)-1-(tert-butyloxycarbonyl)-4-(methane-sulfonyloxy)-L-proline tert-butyl ester (680 mg, 1.86 mmol) and sodium cyanide (912 mg, 18.6 mmol) in N,N-dimethylformamide (14 mL) was stirred for 16 hours at 80° C. under a nitrogen atmosphere. The cooled reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting with 20% ethyl acetate/hexane. Fractions containing the TLC less-mobile isomer were combined and evaporated to afford the desired title compound; yield 275 mg (50%). 400 MHz 1H NMR (CDCl3): δ1.42-1.48 (4s, 18H); 2.24 (m, 1H); 2.67 (m, 1H); 3.08 (m, 1H); 3.64 (m, 1H); 3.81-3.96 (m, 1H); 4.17-4.28 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23].[H-].[Na+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH3:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To 82 mg (0.28 mmol) of 1-benzyloxycarbonyl-4-(methoxycarbonylamino)piperidine from Step A and 0.045 mL (0.56 mmol) of ethyl iodide in 4 mL of DMF under nitrogen was added 22 mg (0.56 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 1 h and was then poured into water containing 1 mL of 2N hydrochloric acid and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 50% ethyl acetate/hexanes to afford 87 mg of title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.2 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (63 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.COCCOC>C(O)C>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]2[CH:13]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccn2cc(CCl)nc2c1
Reaction time: 2.5 h
Yield: 1.8 %

Procedure:
A mixture of 2-amino-4-picoline (Aldrich; 500 g), 1,3-dichloroacetone (Aldrich; 5.89 g), and 1,2-dimethoxyethane (Aldrich; 44 mL) is stirred for 25 min at 53° C., at which time ethanol (47.5 mL) is added. After stirring for 2.5 h at reflux, the mixture is concentrated under reduced pressure and the residue is partitioned between dichloromethane and saturated sodium bicarbonate and brine. The organic layers are dried over MgSO4 and concentrated under reduced pressure. The crude material is chromatographed on silica gel using methanol/dichloromethane (1/99 to 2/98) to give, after crystallization from dichloromethane/hexane, 3.06 g of product. A portion of this material is dissolved in dichloromethane and refluxed with activated charcoal for 30 min. The activated charcoal is removed by filtration through a pad of diatomaceous earth and the filtrate is atmospherically concentrated, at which time hexane is added. The resulting solids are filtered, washed with hexane, and vacuum dried to give 0.15 g of 2-(chloromethyl)-7-methylimidazo[1,2-a]pyridine; mp 250° C. (decomp); ms m/z 180, 182; IR (mineral oil) 774, 1649, 1504, 1252, 701 cm-1 ; 1H NMR (CDCl3) δ 2.39, 4.75, 6.63, 7.32, 7.53, 7.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]#[CH:14])[CH3:10]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:14]#[C:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[CH:3]=1
Reactant: C#CC(OCC)OCC
Reactant: Clc1cccc(I)c1
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cccc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 1-chloro-3-iodobenzene (4 g, 16.8 mmol), propargylaldehyde diethyl acetal (2.66 mL, 18.5 mmol), bis(trifenilphosphine)palladium(II)dichloride (295 mg, 0.42 mmol), cuprous iodide (160 mg, 0.84 mmol) and triethylamine (60 mL) was stirred at r.t. for 3 h. After 4 h, the reaction mixture was quenched with H2O, extracted with EtOAc, which was washed with brine, dried over Na2SO4, and evaporated to dryness in vacuo. The residue was purified by automated flash chromatography (Horizon®TM-Biotage; Petroleum Ether-EtOAc 97:3) to give 4 g of the title compound as a fluid yellowish oil. Yield: 100%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:30][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH2:26][CH3:27])[C:20]([CH2:28][CH3:29])=[N:19]4)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH:35]=[C:34]([C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)[CH2:33][CH2:32]1>CS(C)=O.C(OCC)(=O)C>[CH2:26]([C:21]1[C:20]([CH2:28][CH3:29])=[N:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:31]4[CH2:32][CH:33]=[C:34]([C:37]5[C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[NH:39][CH:38]=5)[CH2:35][CH2:36]4)[O:30][C:17]3=2)[N:22]=1)[CH3:27]
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1nc2ccc3c(c2nc1CC)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO3
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1nc2ccc3c(c2nc1CC)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of (2R)-8,9-diethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.300 g, 0.700 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.555 g, 2.800 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.184 g (58%) of the (S)-enantiomer of the title compound as a yellow crystalline solid. Rf=0.41 (silica, methanol:ethyl acetate 1:9); mp>120° C. dec.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[F:25][C:26]1[C:31]([F:32])=[C:30](F)[CH:29]=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35]>C(OCC)(=O)C>[F:32][C:31]1[C:26]([F:25])=[C:27]([N+:34]([O-:36])=[O:35])[CH:28]=[CH:29][C:30]=1[O:11][C:8]1[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(F)c2F)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
112 mg of 6-methanesulfonyl-pyridin-3-ol and 100 mg of potassium carbonate were added to an N-methylpyrrolidinone (3 ml) solution of 135 mg of 2,3,4-trifluoro-nitrobenzene, and the reaction liquid was stirred at 50° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=O)[NH:10]2.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:5]=2[O:4][C:3]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:2]=2[F:1])[N:10]=1
Reactant: COc1ccc2[nH]c(=O)ccc2c1Oc1ccc(F)cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)ccc2c1Oc1ccc(F)cc1F
Yield: 87.5 %

Procedure:
A solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-1H-quinolin-2-one derivative (0.3 g) in 10 mL of POCl3 was refluxed for 1.5 hours. POCl3 was removed under vacuum, the residue was stirred with saturated aqueous sodium bicarbonate solution, the product was extracted with methylene chloride, and the organic layer was dried (MgSO4). Solvent removal gave 0.28 g (87.5%) of 2-chloro-5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline as pure white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1>>[CH:18]1([N:13]2[C:12]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: c1cc(-c2c3c(nn2C2CC2)CCNCC3)cs1
Yield: 109.9 %

Procedure:
The title compound (134 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 84 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C14H17N3S, 259.11; found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.64-7.63 (m, 2H), 7.31-7.29 (m, 1H), 4.65 (br s, 1H), 3.70-3.60 (br s, 1H), 3.57-3.52 (m, 1H), 3.40-3.38 (m, 1H), 3.19 (br s, 1H), 3.13-3.11 (m, 1H), 2.99-2.96 (m, 1H), 2.91-2.89 (m, 1H), 0.93-0.88 (m, 4H).