Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](=[N:11]/[O:12][C:13]([C:16]([NH:18][C:19]([NH2:21])=[O:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22]1(N=C=NC2CCCCC2)CCCCC1.C[CH:38]([S:65][C:66]1[NH:70][N:69]=[N:68][N:67]=1)[C:39]1[CH2:40][S:41][C@@H:42]2[C@H:62]([NH2:63])[C:61](=[O:64])[N:43]2[C:44]=1[C:45]([O:47][CH:48]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>ClCCl.CN(C)C=O>[CH3:22][N:70]1[C:66]([S:65][CH2:38][C:39]2[CH2:40][S:41][C@@H:42]3[C@H:62]([NH:63][C:8](=[O:10])/[C:7](/[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11]\[O:12][C:13]([C:16]([NH:18][C:19]([NH2:21])=[O:20])=[O:17])([CH3:15])[CH3:14])[C:61](=[O:64])[N:43]3[C:44]=2[C:45]([O:47][CH:48]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46])=[N:67][N:68]=[N:69]1
Reactant: CC(C)(O/N=C(\C(=O)O)c1ccccc1)C(=O)NC(N)=O
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NC(N)=O)c3ccccc3)[C@H]2SC1
Reaction time: 20 h

Procedure:
A solution of Z-2-phenyl-2-(2-ureidocarbonylprop-2-yloxyimino)acetic acid (460 mg) in dichloromethane (6 ml) and dimethylformamide (2 ml) was added slowly to a stirred solution of dicyclohexylcarbodiimide (370 mg) and diphenylmethyl (6R,7R)-3-(1-methyltetrazol-5-ylthiomethyl)-7-aminoceph-3-em-4-carboxylate (790 mg) in dichloromethane (10 ml) and dimethylformamide (3 ml) and the mixture was stirred for 20 hr. The solution was filtered, the filtrate was evaporated, and the residue was dissolved in ethyl acetate (50 ml). The filtered solution was washed with 2N- hydrochloric acid (2×15 ml) and saturated sodium hydrogen carbonate solution (2×15 ml), dried (Na2SO4) and evaporated. The residue was purified on silica gel plates in light petroleum-ethyl acetate (1:1 v/v) to give the ester, 580 mg, λmax (Nujol) 3400, 3280 (NH, NH2), 1788 (β-lactam), 1720, 1710 (--CO2R), 1685, 1670 cm-1 (--CONHCONH2, --CONH--), τ(DMSO d6) 0.60 (--CONHCO--), 8.59 (--C(Me)2 --), 2.0-2.9 (Phenyls), --0.06 (--CONH--), 3.87 (7 H), 4.62 (6H), 5.9, 6.5 (2--CH2 --), 5.59, 5.79 (3--CH2 --), 6.09 (--N--Me), 3.0 (--CH Ph2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]([O:16][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)OCC(=O)c1ccc(F)cc1
Yield: 99.5 %

Procedure:
The title compound (3.2 g) was prepared from (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (2.02 g) and 2-bromo-4′-fluoroacetophenone (1.91 g) according to the method of description 36.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:40][CH3:41])=[C:26]([C:28]2[N:36]3[C:31]([CH:32]=[N:33][C:34](S(C)=O)=[N:35]3)=[CH:30][CH:29]=2)[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:40][CH3:41])=[C:26]([C:28]2[N:36]3[C:31]([CH:32]=[N:33][C:34]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:35]3)=[CH:30][CH:29]=2)[CH:27]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1ccc(Cl)cc1-c1ccc2cnc(-n3cnc4cnccc43)nn12

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 67.32 mg of 1-[7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=377.6. 1H NMR (400 MHz, DMSO, d6) δ 9.38 (s, 1H), 9.17 (s, 1H), 8.50 (m, 1H), 8.21 (m, 1H), 8.07 (m, 1H), 7.41 (m, 1H), 7.36 (m, 1H), 7.32 (m, 3H), 3.85 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].CN(C)C=O>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3ccccc23)CC1

Procedure:
A mixture of 3-(1-piperazinyl)-1H-indazole (4.0 g, 20 mmol), K2CO3 (3.0 g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90° C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield, 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone, m.p.=155-157° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:42](=[O:43])[CH2:41][N:38]1[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: O=C(O)CN1CCOCC1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCOCC4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 2-morpholinoacetic acid were combined to give 14 as previously described. LCMS (+ESI) 627 (M+). 1H-NMR (CDCl3, δ): 8.58 (dd, J=0.8, 4.8 Hz, 1H), 7.88 (bt, 1H), 7.58 (td, J=1.6, 8.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.67 (d, J=3.2 Hz, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.87 (dd, J=5.2, 17.6 Hz, 1H), 3.77 (m, 4H), 3.54 (dd, J=4.4, 17.6 Hz, 1H), 3.25 (s, 3H), 2.55 (m, 4H). Calcd. for C30H32Cl2N6O5: C, 57.42; H, 5.14; N, 13.39. Found: C, 57.23; H, 5.22; N, 13.23.
Reaction SMILES: [CH:1](=[N:3]O)[CH3:2].ClCl.[CH3:7][SH:8].[OH-:9].[Na+:10]>O>[CH3:7][S-:8].[Na+:10].[OH:9][CH2:2][C:1](=[NH:3])[S:8][CH3:7]
Reactant: [OH-]
Reactant: CC=NO
Reactant: CS
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: CSC(=N)CO
Product: C[S-]
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 83 %

Procedure:
Acetaldoxime (30 g., 0.5 mole) was dissolved in 200 g. of water and the solution cooled to -5 to -10° C. Over a period of 20 to 30 minutes, 30 g. of chlorine was introduced into the solution with agitation. During the chlorine addition, the reaction temperature was maintained at -5° to -10° C. An additional 6 grams of chlorine was added in 10 minutes. The mixture was stirred for 10-15 minutes at -10° C. A sodium methyl mercaptide solution was prepared by dissolving methyl mercaptan (25 g, 0.52 mole) in a caustic solution containing 40 g. of sodium hydroxide in 100 g. of water. The mercaptide solution was fed directly into the reaction mixture over a 15 to 20 minute time period while maintaining the temperature at -10° C. The reaction mixture was stirred for an additional 15 minutes and then neutralized to a pH 7.5 by addition of 50% sodium hydroxide solution. Crystaline methyl hydroxythioacetimidate was recovered at -10° C. by filtration. The product was re-slurried in hexane, filtered and dried to obtain 43 grams (83% yield) of methyl hydroxythioacetimidate, mp 87°-88° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[S:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].S(Cl)(Cl)=O.[NH2:24][C:25]1[S:26][C:27]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:31]=[C:30]([O:40][CH3:41])[C:28]=2[N:29]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:24][C:25]2[S:26][C:27]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:31]=[C:30]([O:40][CH3:41])[C:28]=3[N:29]=2)=[O:14])=[CH:15][CH:16]=1)(=[O:6])=[O:7])[CH2:18][CH3:19]
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Nc2nc3c(OC)ccc(-c4ccccc4)c3s2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a suspension of 4-dipropylsulfamoyl-benzoic acid (185 mg, 0.65 mmol) in toluene (10 ml) was added thionylchloride (600 mg, 5 mmol) and the mixture heated to 80° C. for 17 h. After cooling the solvent was evaporated and the resudue was taken up in THF (20 ml), 2-amino-4-methoxy-7-phenyl-benzothiazole (128 mg, 0.5 mmol), triethylamine (105 μl, 0.75 mmol), and DMAP (6 mg, 0.05 mmol) were then added and the mixture was stirred for 1 hour at r.t. followed by 1 hour at 60° C. After cooling to r.t. the reaction mixture was quenched by addition of 10% aq. Na2CO3 solution (30 ml) and EtOAc (30 ml) and vigorous stirring. After separation of the phases the aqueous phase was extracted with EtOAc (30 ml) and the combined orgainc phases were washed with 10% aq. Na2CO3, dried with Na2SO4, filtered and evaporated. The residue was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with a gradient of cyclohexane/EtOAc from (1:4) to 100% EtOAc. After pooling and evaporation of the product fractions the title compound was obtained as a white solid (240 mg, 92% yield), MS: m/e=524.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12])[CH3:2].[C:14](Cl)(=[O:16])[CH3:15]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccc(F)cc1NC(C)=O
Reaction time: 1 h

Procedure:
A total of 3.84 g of 2-amino-4-fluoro-benzoic acid ethyl ester obtained in Production Example II-7-a was dissolved in 50 ml of pyridine, 1.64 ml of acetyl chloride was added under ice-cooling, and the mixture was stirred for 1 hours. The reaction mixture was diluted with water and was extracted with diethyl ether. The resulting organic layer was washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate, and then evaporated, to give 4.0 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH:12]1([CH2:18][N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([NH2:27])=[S:26])[CH2:20]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCOC(C)=O>CC#N>[ClH:1].[CH:12]1([CH2:18][N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]3[S:26][CH:2]=[C:3](/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:27]=3)[CH2:20]2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)/C=C/C(=O)CCl
Reactant: NC(=S)N[C@@H]1CCN(CC2CCCCC2)C1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1csc(N[C@@H]2CCN(CC3CCCCC3)C2)n1
Product: Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
The mixture of ethyl (2E)-5-chloro-4-oxo-2-pentenoate (0.8 g) and 1-[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]thiourea (1.09 g) in CH3CN (16 mL) was stirred at 70° C. for 2 hrs. To the reaction mixture was added an AcOEt (32 mL) and isolated precipitate was collected by filtration to give ethyl (2E)-3-(2-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}thiazol-4-yl)acrylate hydrochloride (1.10 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2cnccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)COc1cccc2cnccc12

Procedure:
In 10 ml of acetonitrile, 1.0 g of 5-hydroxyisoquinoline and 1.52 ml of ethyl bromoacetate were added in the presence of 2.07 ml of DBU and the resultant mixture was refluxed for 8 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in 1N-HCl, washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (chloroform) to give 1.46 g of ethyl 5-isoquinolyl-oxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 6.5 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and the precipitated crystals were filtered, washed with water and dried to give 0.68 g of the title compound.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:10]([NH:12]CC)[CH3:11].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][NH:12][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: CCNCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Cyclohexanecarboxaldehyde (38 g), diethylamine hydrochloride (55 g) and acetic acid (29 ml) are dissolved in methylene chloride (500 ml) and thereto is added triacetoxy sodium borohydride (71.8 g) at room temperature and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution and methylene chloride, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and the mixture is concentrated under reduced pressure to give cyclohexylmethyl-ethyl-amine (40.1 g) as a crude product. MS (m/z): 142 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:14]=1)=[O:12])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[Cl:46].O>O1CCCC1>[Cl:46][C:37]1[CH:38]=[C:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:40]=[CH:41][C:36]=1[CH2:35][O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([Si:22]([CH:23]([CH3:24])[CH3:25])([CH:29]([CH3:30])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:14]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOc1c(O)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(OCc2ccc(S(C)(=O)=O)cc2Cl)cccc1C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2-ethoxy-3-hydroxy-phenyl)-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (665, 40 mg, 0.064 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (3.32 mg, 0.083 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 40 minutes, then 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (21.72 mg, 0.077 mmol) was added to the reaction mixture. It was stirred at room temperature overnight. The mixture was then poured into water and was extracted with ethyl acetate. The organic layer was collected and washed with brine, dried over magnesium sulfate. After removal of the solvent, a crude compound as light yellow oil was obtained (666, 84 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[K+].[K+]>ClCCl>[C:26]1([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.1 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenylisocyanate (0.143 g, 1.2 mmol) in dichloromethane (20 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and stirred at RT for 18 h. The reaction mixture was stirred with 10% K2CO3 for 1 h and then partitioned after diluting with additional dichloromethane (200 mL). The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (100 mg, 22%) as a white solid after trituration with diethyl ether. MS (APCI 10V) AP+ 454.28; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.29 (s, 3H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.37 (s, 1H) 6.89 (t, J=8.60 Hz, 1H) 7.03 (m, 2H) 7.12 (d, J=7.60 Hz, 1H) 7.19-7.22 (m, 3H) 7.38 (d, J=7.8 Hz, 1H) 7.41 (d, J=8.77 Hz, 2H) 8.20 (dd, J=8.8 Hz, 2.8 Hz, 1H) 8.50 (s, 1H) 8.55 (s, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19].C1N2CCN(CC2)C1.CC1C=CC(S(O[CH2:41][C:42]2[C:47]3[CH2:48][CH2:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:46]=3[CH:45]=[CH:44][CH:43]=2)(=O)=O)=CC=1>O.CCCCCCC.C(#N)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:41][C:42]2[C:47]3[CH2:48][CH2:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:46]=3[CH:45]=[CH:44][CH:43]=2)=[O:13])[CH:7]=[CH:6][C:5]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Cc1ccc(S(=O)(=O)OCc2cccc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(=O)O
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)c(Cl)c1)C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
A solution of potassium hydroxide (1.03 grams, 0.016 mole) in water (6.0 ml) was added to a stirred mixture of 2-(2-chloro-α,α,α-trifluoro-p-toluidino)-3-methylbutyric acid (4.62 grams, 0.016 mole, prepared by the method of C. A. Henrick, et al., Pest. Sci. 11, 224-41 (1980) in n-heptane (75.0 ml). The mixture was stirred until all the acid dissolved, at which time the water was distilled from the mixture. Additional n-heptane (50.0 ml) was added, followed by a solution of 1,4-diazobicyclo[2.2.2]octane (0.12 gram, 0.00097 mole) and (6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-yl)methyl p-methylphenylsulfonate in acetonitrile (40.0 ml). After complete addition, the mixture was stirred and heated at reflux for approximately 18 hours. The mixture was cooled, then evaporated to dryness under reduced pressure to leave a residue. The residue was partitioned between diethyl ether (250 ml) and water (150 ml) and the phases separated. The organic phase was washed in succession with aqueous 2% hydrochloric acid (two 50 ml portions), water (two 25 ml portions), aqueous 10% sodium carbonate (two 25 ml portions), and saturated aqueous sodium chloride (25 ml). The washed organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to leave an oil. The oil was purified by column chromatography on silica gel (250 grams), n-heptane:toluene (30:70) as the eluant, to yield (6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-yl)methyl 2-(2-chloro-α,α,α-trifluoro-p-toluidino)-3-methylbutyrate (4.95 grams) as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cncnc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 9% yield: LCMS (ESI) m/z 360 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:25]([OH:27])[CH3:26].C(N(CC)C(C)C)(C)C.C(OC(N[C@@H]1CCN(CCO)C[C@@H]1C(OC)=O)=O)C1C=CC=CC=1>ClCCl.CO>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:14][CH2:13][N:12]([CH2:26][CH2:25][OH:27])[CH2:11][C@H:10]1[O:15][CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(O)Br
Reactant: CO[C@@H]1CNCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CO[C@@H]1CN(CCO)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Yield: 66.7 %

Procedure:
A mixture of cis(±)N,N-dibenzyl-3-methoxypiperidin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (0.5 mL, 7.1 mmol), and N,N-diisopropylethylamine (1.4 mL, 8.3 mmol) were reacted as described for Intermediate 37, but heating for one hour at 70° C. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 1.3 g (68%) of product as a colorless solid.