Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH3:16])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=O)=[CH:9]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH2:1]([N:3]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH3:16])=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:34])[NH2:15])=[CH:9]2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(c1ccc(C)c2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CCN(c1ccc(C)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 40 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxamide (1.9 g), Lawesson's reagent (2.1 g) and tetrahydrofuran (100 ml) was stirred at 40° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from dichloromethane-toluene, and washed with toluene to give 7-[ethyl(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carbothioamide (2.0 g, yield quantitative) as pale-yellow crystals. A solution of the obtained crystals (2.0 g) and bromomalonaldehyde (2.4 g) in N,N-dimethylacetamide (50 ml) was stirred at 70° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from dichloromethane-toluene to give the title compound (1.6 g, yield 70%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27]3)[N:21]=[C:20]([C:33](O)=[O:34])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:37]([NH2:39])[CH3:38]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27]3)[N:21]=[C:20]([C:33]([NH:39][O:37][CH3:38])=[O:34])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(OCC4COC(C)(C)O4)n3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCC2COC(C)(C)O2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]pyrimidine-4-carboxylic acid (Example 314) and methoxylamine hydrochloride.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[F:22][C:23]([F:37])([F:36])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15](=[O:17])[NH:25][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:23]([F:37])([F:36])[F:22])=[N:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: O=C(O)/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2E)-3-[5-(Cyclopropylcarbamoyl)-4-(trifluoromethyl)pyridin-2-yl]acrylic acid (61 mg, 0.20 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (46 mg, 0.19 mmol) were initially charged in N,N-dimethylformamide and admixed with HBTU (72 mg, 0.19 mmol) and N-methylmorpholine (57 mg, 0.57 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed successively with a sodium hydrogencarbonate solution (10% Y) and a saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on a preparative HPLC with water/acetonitrile as the eluent (gradient=43 min from 10% acetonitrile in water to 100% acetonitrile).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>ClCCl.CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]4[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=4)=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)=[O:16])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(OC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Oc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 40.7 %

Procedure:
4-[4-(2-Aminoethyl)phenoxy]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.56 g, 1.5 mmol), was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.606 g, 1.5 mmol) according to Procedure G (eluant: 50:1 going to 20:1 dichloromethane-methanol) to give the title compound (0.47 g, 0.61 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7].C(N(CC)CC)C.[O:35]=[C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:45])[N:37]1[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH3:22])=[O:7])=[C:2]([NH:1][S:48]([CH2:47][CH2:46][N:37]2[C:36](=[O:35])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]2=[O:45])(=[O:49])=[O:50])[CH:26]=1
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.050 g, 0.13 mmol) in methylene chloride (1 mL) at ambient temperature was added triethylamine (0.027 mL, 0.19 mmol) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045 g, 0.17 mmol). The reaction was stirred overnight at ambient temperature. Additional triethylamine ((0.027 mL, 0.19 mmol) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045 g, 0.17 mmol) was added. The reaction was stirred one hour, then additional triethylamine (0.055 mL, 0.34 mmol) was added. The reaction was stirred and hour, then additional 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.090 g, 0.34 mmol) was added. After stirring an additional 1 hour, the reaction was treated with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via radial chromatography (2 mm plate) gave the title compound (0.030 g).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[C:12]1([CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(O)C>O>[C:12]1([CH2:18][CH2:19][NH:20][C:21]2[S:22][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[N:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)NCCc1ccccc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(CCNc2nc(-c3ccccn3)cs2)cc1
Yield: 67.6 %

Procedure:
A mixture of 2-bromo-1-pyridin-2-ylethanone hydrobromide (4.00 g), N-(2-phenylethyl)thiourea (3.60 g), sodium acetate (1.60 g) and ethanol (30 mL) was stirred with heating under reflux for 1 hr. After cooling, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (2.71 g, yield 48%) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:19]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[C:22]([O:24]C)[CH:23]=1)([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[C:20]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=1)([CH3:2])[CH3:3]
Reactant: COc1cc(-c2ccccc2)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cc(O)cc(-c2ccccc2)c1
Temperature: 190 °C
Yield: 85.5 %

Procedure:
To a 250 mL round bottom flask was added 1-(2,6-diisopropylphenyl)-2-(5-methoxy-[1,1′-biphenyl]-3-yl)-1H-imidazole (6.9 g, 16.81 mmol) and pyridine hydrochloride (15.85 g, 134 mmol). The reaction mixture was heated to 190° C. under a nitrogen atmosphere. After 4 hours the reaction mixture was cooled and water was added. A gray solid was filtered off and washed with water. The solid was dried under vacuum and 5.7 g of product was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[CH:36][C:31]([CH2:30][NH:29][S:26]([CH3:25])(=[O:27])=[O:28])=[CH:32][CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CS(=O)(=O)NCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(CNS(C)(=O)=O)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 16.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(methylsulfonamidomethyl)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give N-(4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzyl)methanesulfonamide (4.26 mg, 17%). 1H-NMR (MeOD): 2.06 (m, 1H), 2.22 (m, 1H), 2.76 (s, 3H), 3.04 (s, 3H), 4.17 (s, 2H), 5.80 (m, 1H), 6.92 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.32 (m, 4H), 7.37 (m, 2H), 7.39 (m, 2H), 7.41 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[CH3:37][N:38](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:37]([C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:23])([F:22])[F:24])[C:6]=2[CH:36]=1)#[N:38]
Reactant: CN(C)C=O
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(C#N)ccc32)cc1

Procedure:
A solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (1.0 g, 1.76 mmol), zinc cyanide (414 mg, 3.53 mmol) and tetrakis(triphenyl phosphine)palladium (102 mg, 0.088 mmol) in DMF (4.5 mL) was stirred at 100° C. for 3 hours. The temperature of the solution was brought to room temperature and the solution was diluted with ethyl acetate, which was washed sequentially with an aqueous citric acid solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (873 mg, 96%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ncco2)cc1
Reactant: OC1CCCNC1
Product: OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Yield: 44.8 %

Procedure:
1-(4-(Oxazol-2-yl)phenyl)piperidin-3-ol (245 mg, 1.00 mmol) was synthesized in 45% yield, as described in General Procedure B using 2-(4-bromophenyl)oxazole (500 mg, 2.232 mmol) and piperidin-3-ol (451 mg, 4.46 mmol). Anal. Calcd. for C14H16N2O2 m/z 244.2, found: 245.0 (M+H)+.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Br.[CH2:7]([O:9][C:10]([C:12]([NH2:14])=[NH:13])=[O:11])[CH3:8].C(N(CC)CC)C>C(O)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:14]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[N:13]=1
Reactant: CCOC(=O)C(=N)N
Reactant: C=C(Cl)C#N
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 2-chloroacrylonitrile (437 mg) and 1-ethoxycarbonylformamidine hydrobromide (985 mg) in ethanol (5 ml) was added dropwise triethylamine (1.01 g) at 0° C. The reaction mixture was stirred for 4 hours at ambient temperature and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water, and extracted with ethyl acetate three times. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give ethyl 4-aminopyrimidine-2-carboxylate (480 mg), which was recrystallized from a mixture of ethyl acetate and benzene, mp. 101°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:19][NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.[Cl:33][C:34]1[C:42]([O:43][CH2:44][CH2:45][Br:46])=[C:41]([O:47][CH3:48])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[Cl:33][C:34]1[C:42]([O:43][CH2:44][CH2:45][Br:46])=[C:41]([O:47][CH3:48])[CH:40]=[CH:39][C:35]=1[C:36]([N:20]([CH2:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:37]
Reactant: COc1ccccc1Cc1c(CNCCC(C)C)nc2ccccn12
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCBr)c2Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.4 %

Procedure:
To a solution of ({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl) (3-methylbutyl) amine (1.4 g, 4.2 mmol) in dichloromethane (15 ml) is added triethylamine (0.7 ml, 5 mmol) followed by 2-chloro-3-bromoethoxy-4-methoxybenzoic acid chloride (1.5 g, 4.5 mmol). The reaction mixture is stirred at ambient temperature for 65 h. Aqueous 1 N sodium hydroxide (20 ml) is added and the resulting mixture is extracted with dichloromethane (3×20 ml). The combined organic layers are dried over magnesium sulfate, filtered, and evaporated at reduced pressure. Chromatography on silica gel with ethyl acetate provides 1.7 g (65%)of (2-chloro-3-bromoethoxy-4-methoxyphenyl)-N-({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)} methyl)-N-(3- methylbutyl)carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:24]#[N:25])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C#N)cc1-2
Temperature: 175 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (120 mg, 0.31 mmol) was dissolved in DMF (1.6 mL) in a 10-mL microwave vial. Purged with N2 and added zinc cyanide (36 mg, 0.31 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol). Sealed the vial and evacuated and recycled twice with N2. The vessel was subjected to microwave irradiation with stirring for 10 min at 175° C. The vessel was then cooled to r.t. and the reaction mixture was diluted with dichloromethane and water. The phases were separated and the organic layer was washed once with water, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by ISCO chromatography (40 g column, 0-10% MeOH/DCM) to provide 76 mg (73% yield) of 136. LC/MS (ESI+): m/z 338 (M+H)
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[C:11]([F:21])[CH:10]=1)=[O:7].[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:28][Si:25]([CH3:26])([CH3:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:30])[CH3:29])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[C:11]([F:21])[CH:10]=1)=[O:7]
Reactant: [H][H]
Reactant: C/C(=C\c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F)C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F)C(=O)O
Yield: 94 %

Procedure:
Compound 14 (214 mg) was dissolved in tetrahydrofuran (4.0 ml) and methanol (4.0 ml), and a 10% palladium carbon catalyst (70.0 mg) was added thereto. The obtained mixture was stirred at room temperature in a hydrogen atmosphere for 6 hours. The catalyst was removed by Cerite filtration, and the solvent was distilled off from the filtrate under reduced pressure. As a result, Compound 16 (202 mg, 94%) was obtained as an opalescent solid.
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][CH:7]=[N:8][OH:9])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[CH:18]1([C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:20][CH2:19]1.[O-]CC.[Na+]>CN(C)C=O.O1CCCC1>[CH:18]1([C:22]2[O:9][N:8]=[C:7]([CH2:6][O:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CC(=O)C1CCC1
Reactant: CC(C)(C)OCC=NO
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(COC(C)(C)C)noc1C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (1,1-dimethylethyl)oxyethanal oxime (1.71 g, 13.0 mmol) in N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.74 g, 13.0 mmol) while the flask was in a water bath. After approximately 10 minutes the flask was removed from the water bath and the solution was stirred for approximately 1 hour. The solution, containing the crude imidoyl chloride, was then poured into ether and washed twice with water followed by brine, and then was dried over magnesium sulfate and concentrated. Then to a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.66 g, 15.6 mmol) in tetrahydrofuran (8 mL) at 0° C. was added sodium ethoxide (21 wt % solution in ethanol, 5.82 mL, 15.6 mmol). The above imidoyl chloride was diluted with tetrahydrofuran (6 mL) then added to the solution containing the ketoester. A solid was seen to precipitate. After the addition the solution was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured into ether and washed twice with water followed by brine, dried over magnesium sulfate and concentrated to afford ethyl 5-cyclobutyl-3-{[(1,1-dimethylethyl)oxy]methyl}-4-isoxazolecarboxylate (3.13 g, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 4.53 (s, 2H), 4.22 (q, J=7 Hz, 2H), 4.17-4.05 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.03 (m, 1H), 1.95-1.86 (m, 1H), 1.26 (t, J=7 Hz, 3H), 1.17 (s, 9H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]2[N:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])=[N:11]2)[CH2:7][N:6]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:4].[Li+].[OH-]>CO>[C:26]([O:25][C:23]([N:6]1[CH2:7][C@@H:8]([N:10]2[N:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])=[N:11]2)[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CC(n2nnc(-c3ccc(F)cc3F)n2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](n2nnc(-c3ccc(F)cc3F)n2)C[C@H]1C(=O)O
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.14 g, 0.34 mmol) in MeOH (25 ml) cooled to 0 degree was added LiOH (0.06 g, 1.36 mmol), and the mixture was stirred overnight. After removal of MeOH, the residue was acidified with 2M HCl. The aqueous layer was extracted with EA, the organic solution was dried and concentrated to give title product as yellow oil (0.1 g, 0.25 mmol). MS m/e=396.3 [M+H]+.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH:28]([CH3:33])[CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.[K+].[Br-]>>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH:28]([CH3:33])[CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(c2ccnc3cc4c(cc23)OCO4)C(C)CN(C)C)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COc1cc2c(=O)n(C(C)CN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 30.4 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(N,N-dimethylamino)-1-methylethyl)-2-iodo-4,5-dimethoxybenzamide; (30.4% yield); reaction time 30 min; mp 186-187° C.; IR (KBr) 1649; 1H NMR (CDCl3); δ 1.95-1.98 (m, 9H), 2.77 (dd, 1H, J=12.0, 8.0), 3.21 (dd, 1H, J=12.0, 8.0), 4.06 (s, 3H), 4.13 (s, 3H), 4.84-4.92 (m, 1H), 6.17 (s, 2H), 7.46 (s, 1H), 7.66 (s, 1H), 7.77 (s, 1H), 7.87 (s, 1H), 9.35 (s, 1H); 13C NMR (CDCl3) δ 19.7,45.5, 56.2, 56.3, 59.5, 63.1, 100.9, 101.9, 102.1, 107.0, 108.7, 112.4, 115.2, 120.5, 127.3, 142.6, 143.3, 147.0, 147.3, 149.9, 150.1, 154.0, 164.9; HRMS calcd for C24H25N3O5H: 436.1794; found 436.1863.