Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([C:8]1[N:9]([CH2:21][CH2:22][CH2:23][C:24](=O)[CH3:25])[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH2:6][CH3:7]>CO>[CH3:3][O:2][N:4]=[C:24]([CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:8]1[CH2:5][CH2:6][CH3:7])[CH3:25]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(C)=O
Reactant: CON
Agent: Cl
Solvent: CO
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(C)=NOC
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
Methoxylamine hydrochloride (2.23 g, 26.7 mmol) was added to a solution of 5-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one (6.06 g of crude material prepared as described in Parts A and B of Example 22) in methanol (80 mL). The reaction mixture was stirred at room temperature for 48 hours and then concentrated under reduced pressure. The residue was dissolved dichloromethane (60 mL) and the pH was adjusted to 8 by the addition of saturated aqueous sodium bicarbonate (40 mL) and then solid sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (30 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to afford 6.33 g of 5-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one O-methyloxime a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1.IC1C=C2C(=CC=1)C(=O)[NH:36]C(=O)C2=COC.NCC1C=CC(C2C=CC=CN=2)=C(O)C=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:36]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Agent: NCc1ccc(-c2ccccn2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccn2)c(O)c1
Yield: 57 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (98 mg, 0.30 mmol) and 5-Aminomethyl-2-pyridin-2-yl-phenol (60 mg, 0.30 mmol) in 57% yield: MS (ESI): 498.1 (M+1)+1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][CH:38]=4)[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Diethyl azodicarboxylate (DEAD) (4.26 mL, 27.0 mmol) was added drop-wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (6.00 g, 18.0 mmol), 4-hydroxyquinoline (3.92 g, 27.0 mmol) and Ph3P (7.09 g, 27.0 mmol) in THF (90 mL) at room temperature. The mixture was stirred at room temperature for 1 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH, 95:5) to give the title compound (6.22 g, 75% yield) as a white solid: MS (ESI) m/z 460/462.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=O)=O.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([NH:20][CH2:6][CH2:7][CH2:8][C:9]#[C:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)OCCCC#Cc1cccs1
Product: CC(C)(C)NCCCC#Cc1cccs1
Reaction time: 96 h

Procedure:
A mixture of 210 mg of 2b and 5 ml of tert-butyl amine was stirred for 4 days. The reaction mixture was concentrated and the residue was treated with 20 ml of 1M K2CO3 and the product was extracted into ethyl acetate. The organic layer was washed once with water, dried and concentrated, to provide 250 mg of 2c as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2].[OH-].[Na+].CC(O)=O>CO.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([OH:32])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)CSC(CCc1ccccc1C(C)=O)c1cccc(COC2CCCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1CCC(SCC(C)C(=O)O)c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the ester of Step 7 (6.67 mmol) and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at r.t. for 24 hours. 25% Aq NH4OAc was then added and the mixture was acidified with HOAc. The title acid was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with acetone:toluene:HOAc.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH3:14].C(O)(C)C.C(=O)=O>C1(C)C=CC=CC=1>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH3:14]
Reactant: O=C1CCCCCN1
Reactant: CCCBr
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCN1CCCCCC1=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
In a 1 liter 3-neck flask equipped with a dry ice-isopropanol condenser, an addition funnel and a mechanical stirrer was placed 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M) and 150 ml of petroleum ether. The suspension was momentarily stirred and then sodium hydride was allowed to settle. Most of the petroleum ether was pipetted out and 200 ml of dry toluene was added. To this was added dropwise a solution of 20 g (0.177 M) of azacycloheptan-2-one in 100 ml of dry toluene. The mixture was refluxed for 1 hour and then cooled to room temperature. A solution of 30.75 g (0.25 M) of 1-bromopropane in 100 ml of dry toluene was added dropwise under stirring. Upon completion of the addition, the mixture was warmed to 80°-100° and the temperature was maintained there for 4 hours. Then the isopropanol-dry ice condenser was replaced with a water condenser and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled, filtered and the filtrate was concentrated to a yellow oil. Distillation afforded 22.2 g (81%) of colorless product; b.p. 83°-86°/0.25 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([C:31]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)N5CCCC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl-4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and (1H-indol-5-yl)(pyrrolidin-1-yl)methanone (intermediate-18).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl

Procedure:
Following Example 91, to a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate in tetrahydrofuran and water was added lithium hydroxide, monohydrate to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid, which was coupled with methylamine, HBTU, and DIEA in dichloromethane to give 8-bromo-N-(2-chloro-4-(methylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([NH:23][C:24]([C:26]3([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[C:20]([NH2:22])=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C@H:19]([NH:23][C:24]([C:26]3([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[C:20]#[N:22])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(OS(C)(=O)=O)cc3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(OS(C)(=O)=O)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.9 %

Procedure:
(S)-4′-(3-Amino-2-(4-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxamido)-3-oxopropyl)biphenyl-4-yl methanesulfonate (Example 6, step (i), 234 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (199 mg) and the mixture was stirred at room temperature for 18 h. It was partially evaporated and then purified by chromatography on silica using diethyl ether and then 1:1 ethyl acetate/isohexane as eluent to a afford the sub-titled compound as a white solid (267 mg).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)([Cl:27])=O>>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]([Cl:27])=[O:17])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1

Procedure:
A mixture of 1.9 g of 6-[(2-biphenylcarbonyl)amino]pyridine-3-carboxylic acid and 9 ml of thionyl chloride is refluxed for 1 hour and then concentrated to dryness under vacuum. Toluene (15 ml) is added (twice) to the residue and the solvent removed under vacuum to give 2.1 g of a light brown oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[Cl:36]>O1CCCC1>[Cl:33][C:32]1[CH:31]=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([Cl:36])[C:27]=1[CH2:26][CH:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[C:12]1=[O:16]
Reactant: O=C1CCCN1C1CCC2(CC1)OCCO2
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CC2CCN(C3CCC4(CC3)OCCO4)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in THF (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS m+1 414.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][C:8]([N:10]([CH2:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=1)[C:21]([O:23]CC[Si](C)(C)C)=[O:22])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][C:8]([N:10]([CH2:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=1)[C:21]([OH:23])=[O:22])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CCCC(=O)N(Cc1cccc(C(=O)OCC[Si](C)(C)C)c1)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)CCCC(=O)N(Cc1cccc(C(=O)O)c1)c1cccnc1
Yield: 54.2 %

Procedure:
By using 375 mg of 2-(trimethylsilyl)ethyl 3-{[(5-ethoxy-5-oxopentanoyl)(pyridin-3-yl)amino]methyl}benzoate and 1.0 mL of 1.0 M TBAF (THF solution), 160 mg of 3-{[(5-ethoxy-5-oxopentanoyl)(pyridin-3-yl)amino]methyl}benzoic acid was obtained by the method similar to Preparation Example 22.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1>CCOC(C)=O.CCO.CCCCCC.CCOC(C)=O.[Pd]>[C:18]1([N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1ccc2c(ccn2-c2ccccc2)c1
Yield: 62.1 %

Procedure:
3.8 g (10 mmol) 5-Benzyloxy-1-(4-bromo-phenyl)-1H-indole in 30 ml EtOAc and 10 ml EtOH were hydrogenated in the presence of 5% Pd/C. Column chromatography on silica gel in hexane/EtOAc 5:1 yielded 1.3 g (62%) 1-Phenyl-1H-indol-5-ol as colorless viscous oil, MS: 209 (M).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.BrC1C=C2C(C=CN2)=CC=1.[C:34]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[C:37]([O:36][C:34]([N:41]1[CH2:46][CH2:45][N:44]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:8]3[CH2:11][CH3:12])=[CH:4][CH:3]=2)[CH2:43][CH2:42]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(Br)cc3n2CC)cc1
Agent: [Pd]
Agent: Brc1ccc2cc[nH]c2c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2c(C#N)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3n2CC)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 86.4 %

Procedure:
6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-indole-3-carbonitrile (0.37 g, 1.0 mmol), prepared from 6-bromoindole using the procedure described in example 1Gb, is mixed with NaO t-Bu (0.13 g, 1.4 mmol), Pd2(dba)3 (0.009 g, 0.01 mmol), BINAP (0.019 g, 0.03 mmol), 1-Boc-piperazine (0.22 g, 1.2 mmol) and dry toluene (3.0 mL). The mixture is stirred at 80° C. for 6 h. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, DCM/EtOAc, 9.5/0.5) to provide 4-[3-cyano-2-(4-ethoxyphenyl)-1-ethylindol-6-yl]piperazine-1-carboxylic acid tert-butyl ester (0.41 g, 86%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11](N1C=CN=C1)([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:12]>O1CCCC1>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCN1CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCCN1CCCC1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a flask under nitrogen, 4-Pyrrolidin-1-yl-butylamine (1.3 equiv, 10.1 g) was taken up in tetrahydrofuran (105 mL, 5 volumes). The mixture was cooled to 0° C. and 1,1′-carbonyldiimidazole (1.3 equiv, 11.6 g) was added. The mixture stirred at 0° C. for 20 minutes, then warmed to 20° C. over 10 minutes and held at 20° C. for 30 minutes.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20]>>[C:1]([O:6][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=C(C)C(=O)OC(C)OCC
Reaction time: 4 h
Yield: 20 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, nitrogen inlet and a magnetic stirrer was added 300 mL of ethyl vinyl ether and 25.0 g (0.29 mol) of methacrylic acid. The mixture was cooled in an ice bath and 0.2 g (0.001 mol) of p-toluenesulfonic acid monohydrate was added. The flask was removed from the ice bath and stirred for 4 hours at which time the mixture was filtered through a bed of sodium carbonate and the ethyl vinyl ether removed on a rotary evaporator. The resulting oil was distilled twice from sodium carbonate at reduced pressure to yield 8.9 g (20%) of the title compound as a clear, colorless oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[CH2:1]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCc1ccc(Oc2cccc(C=C3SC(=S)NC3=O)c2)cc1
Yield: 61.9 %

Procedure:
The 3-(4-n-pentylphenoxy)benzaldehyde was coupled with rhodanine in acetic acid and sodium acetate essentially as described previously to yield 1.3 grams (61.9%) of the title product. mp 125°-127° C. NMR. FDMS (M+) 383.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([C:21]1[N:22]=[N:23][C:24](Cl)=[C:25]([C:40]([F:43])([F:42])[F:41])[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)[CH2:18][CH2:19][CH3:20]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:24]2[N:23]=[N:22][C:21]([CH2:17][CH2:18][CH2:19][CH3:20])=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]4)=[CH:29][CH:28]=3)[C:25]=2[C:40]([F:43])([F:42])[F:41])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCCCc1nnc(Cl)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 20.3 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.45 mmol, 0.29 g) in anhydrous DMF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (4.36 mmol, 0.175 g) and continued stirring for 10 min. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-5-trifluoromethyl-pyridazine (72.5 mmol, 25.0 g) in anhydrous DMF (1 mL). After 30 minutes, no starting material was remaining as indicated by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 24 g SiO2 cartridge using an ethyl acetate/hexanes gradient to give 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-4-trifluoromethyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.17 g).
Reaction SMILES: BrC1N=C(NC2C=CC(C3C(=O)N(C)CCN3C(OC(C)(C)C)=O)=CC=2)C(=O)N(C)C=1.Br[C:33]1[C:34](=[O:41])[N:35]([CH3:40])[CH:36]=[C:37]([Br:39])[CH:38]=1.[CH2:42]([N:44]1[CH:48]=[CH:47][C:46]([NH2:49])=[N:45]1)[CH3:43]>>[Br:39][C:37]1[CH:38]=[C:33]([NH:49][C:46]2[CH:47]=[CH:48][N:44]([CH2:42][CH3:43])[N:45]=2)[C:34](=[O:41])[N:35]([CH3:40])[CH:36]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCn1ccc(N)n1
Agent: CN1CCN(C(=O)OC(C)(C)C)C(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Product: CCn1ccc(Nc2cc(Br)cn(C)c2=O)n1

Procedure:
Following the same general procedure as described for 102k, reaction of 3,5-dibromo-1-methylpyridin-2(1H)-one (1.20 g, 4.50 mmol) with 1-ethyl-3-amino-1H-pyrazole 111b (500 mg, 4.50 mmol) gave a 23% (300 mg) yield of 106a as a white solid: mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.00 (d, 1H, J=2.7 Hz), 7.54 (d, 1H, J=2.4 Hz), 7.37 (d, 1H, J=2.4 Hz), 6.05 (d, 1H, J=2.4 Hz), 4.03 (t, 2H, J=7.2 Hz), 3.49 (s, 3H), 1.36 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 298.1 (M+H).