Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([Cl:24])[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:16][C:17]1[N:18]=[C:19]([Cl:24])[N:20]=[C:21]([NH:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH3:14])[CH:4]=[C:3]3[N:2]([CH3:15])[CH3:1])[N:22]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cc(N(C)C)c2cc(N)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)c2cc(Nc3nc(Cl)nc(Cl)n3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution containing 3 g of 4-dimethylamino-2-methylquinolin-6-amine, 2.75 g of 2,4,6-trichloro-s-triazine and 4 g of potassium carbonate in 300 ml of tetrahydrofuran is stirred overnight at room temperature, in a 1 l three-necked flask. The reaction medium is filtered, and then the filtrate is concentrated under reduced pressure; 5.1 g (98%) of 4,6-dichloro-2-(4-dimethylamino-2-methylquinolin-6-yl)amino-[1,3,5]triazine are thus obtained in the form of a brown solid whose characteristics are the following:
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]2[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=2[OH:20])=[O:19])=[CH:12][C:13]=1[CH3:18]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(C)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(C)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 76 %

Procedure:
3-[(4-Fluoro-3-methylbenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 64-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as white crystals (76% yield); mp 160–164° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, s, CH3), 3.10 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 6.97 (1H, m, aromatic), 7.12 (2H, m, aromatics). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.41; H, 5.61; N, 8.90.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31](=[O:34])[CH2:32]Br)([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31](=[O:34])[CH2:32][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 29 %

Procedure:
(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (3.00 g, 9.87 mmol) was dissolved in DMF (50 mL). To the solution was added potassium carbonate (6.0 g, 39 mmol) and bromoacetic acid tert-butyl ester (6.0 mL, 39 mmol). The solution was heated to 70° C. for 3 h. The reaction was quenched with EtOAc and saturated NaHCO3. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude oil was further purified on a Biotage 40M (loaded in CH2Cl2, eluted in 30% EtOAc/hexanes) to afford a white powder (1.2 g, 35%). MS (ESI), (M+H)+ 446.3; 1H NMR (CDCl3) δ 7.76 (d, 2H, J=8.0), 7.52 (d, 2H, J=8.0), 6.61 (br s, 1H) 5.45 (s, 1H), 4.15-4.18 (m, 1H), 3.09-3.24 (m, 2H), 2.50-2.58 (m, 4H), 2.31-2.39 (m, 2H), 1.92-1.99 (m, 1H), 1.15-1.59 (m, 8H), 1.00-1.04 (m, 7H), 0.71-0.74 (m, 6H).
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][O:54][CH2:55][CH2:56][NH2:57].[BH3-]C#N.[Na+]>>[CH3:53][O:54][CH2:55][CH2:56][NH:57][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: COCCN
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 50.4 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15 mg of the title compound (46%).
Reaction SMILES: [H-].[Na+].[Br-].[CH2:4]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:30]1[C:34]2([CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>CS(C)=O>[CH:4](=[C:37]1[CH2:38][CH2:39][C:34]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:35][CH2:36]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a suspension of NaH (0.306 g, 12.8 mmol) in DMSO (10 mL), a solution of benzyl-triphenylphosphonium bromide (5.44 g, 12.8 mmol) in DMSO (30 mL) was slowly added at rt. The solution was stirred 30 min at rt and then further 30 min at 50° C. Upon the crude mixture turning into dark red color, a solution of 1,4-dioxaspiro[4.5]decan-8-one (2.0 g, 12.8 mmol) in DMSO (14 mL) was added. The solution was stirred at 50° C. for 16 h. The reaction mixture was quenched with water and the aqueous layer extracted with AcOEt (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give a crude product, which was purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy/AcOEt (from 100:0 to 40:60) to afford the title compound (1.8 g, 61%) as a white solid. 1H NMR (CDCl3): δ 1.66-1.73 (m, 2H), 1.77-1.84 (m, 2H), 2.40-2.47 (m, 2H), 2.49-2.57 (m, 2H), 3.99 (s, 4H), 6.31 (s, 1H), 7.17-7.23 (m, 3H), 7.28-7.35 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][NH2:9])C1C=CC=CC=1.C(N(CC)CC)C.[F:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1[CH2:26][C:27](Cl)=[O:28].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][N:8]([C:27](=[O:28])[CH2:26][C:19]1[C:20]([F:25])=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[F:17])[NH2:9]
Reactant: O=C(Cl)Cc1c(F)ccc(F)c1F
Reactant: NNCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(N)C(=O)Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
3.22 g (26.4 mmol) of benzyl hydrazine together with 4.4 ml (1.2 eq) of triethylamine and 0.16 g of DMAP (0.05 eq) were initially charged in 50 ml of dichloromethane, and 5.5 g of 2,3,6-trifluorophenylacetyl chloride in 50 ml of dichloromethane were then slowly added dropwise at 0° C. The mixture was then stirred at room temperature overnight, and ammonium chloride solution was added. The organic phase was separated off, dried and concentrated. Purification by column chromatography gave 6.2 g of 2,3,6-trifluorophenylacetic acid 1-methylhydrazide.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([N:24]1[CH:25]=[N:26][C:22]([CH3:21])=[N:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc[nH]n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 86.6 %

Procedure:
Trityl chloride (19.0 g) was added portionwise to a stirred solution of 3-methyl-1,2,4-triazole (5.6 g, commercial) and triethylamine (9.5 ml) in dichloromethane (200 ml). The mixture was diluted with dichloromethane (100 ml), washed with water (50 ml), dried over magnesium sulphate and evaporated under reduced pressure to give 1-trityl-3-methyl-1,2,4-triazole (19.0 g). Recrystallisation of a 2 g sample from toluene-hexane (1:1) gave pure material (1.32 g, m.p. 194-196° C.). NMR (CDCl3): δ 2.41(3H,s), 7.03-7.40(15H,m), 7.83(1H,s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][NH:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][N:29]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:26]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CN[C@@H]1CCNC1
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: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)[C@@H]3CCNC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added (R)—N-methylpyrrolidin-3-amine (50 mg, 0.50 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.[F-].[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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3)ccc2c1
Temperature: 85 °C

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol), 4-fluorophenyl boronic acid (3.8 g., 3.8 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (266 mg, 0.38 mmol) and cesium fluoride (2.6 g, 17.1 mmol) in 125 mL degassed acetonitrile and heat at 85° C. for 8 hours. Cool and filter and purify on an SCX column and elute with 2 N ammonia/methanol. Evaporate to an oil and purify on a silica gel column eluting with a gradient of 0-10% methanol/methylene chloride: mass spectrum (ion spray) m/z=470 (M+H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:23][CH2:24][C@@H:25]2[O:30][C:29]3[C:31]([OH:40])=[C:32]([NH:35][C:36]([O:38]C)=O)[CH:33]=[CH:34][C:28]=3[O:27][CH2:26]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:23][CH2:24][CH:25]2[CH2:26][O:27][C:28]3[CH:34]=[CH:33][C:32]4[NH:35][C:36](=[O:38])[O:40][C:31]=4[C:29]=3[O:30]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: COC(=O)Nc1ccc2c(c1O)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(=O)oc4c3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1′-Carbonyldiimidazole (6.45 g, 39.6 mmole) was added to a solution of {(2R)-8-hydroxy-7-[(methoxycarbonyl)amino]-2,3-dihydro-1,4-benzodioxin-2-yl}-methyl 4-methylbenzenesulfonate (5.40 g, 13.2 mmole) in methylene chloride (400 mL), the solution was refluxed for 4 hours under nitrogen. The solvent was then removed in vacuum and was replaced with 2N aqueous HCl (150 mL). After the mixture had been stirred for 0.5 hour at room temperature, a white solid precipitate, the (R)-enantiomer of the title compound, was removed by filtration, and was dried under high vacuum (5.0 g, >99%).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3C(F)(F)F)c21
Temperature: 0 °C
Yield: 46.5 %

Procedure:
In 300 ml of toluene and 200 ml of 30% potassium hydroxide were combined 8.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 3.20 g of tetrabutylammonium hydrogen sulfate. The biphasic mixture was mechanically stirred and warmed to reflux (90° C.) and 30.0 g of 2-trifluoromethylbenzyl bromide in 50 ml of toluene was added dropwise over 1 hour. After the addition, heating was maintained for 2 hours during which the reaction went to completion. It was poured into 500 ml of ice and the layers were separated. The aqueous phase was extracted with DCM. The organic solutions were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to an oil which was purified by preparative HPLC (ethyl acetate). The product-containing fractions were evaporated to a solid which was recrystallized from 1:1 ethyl acetate/hexanes to yield 6.49 g of solid, mp 167° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[S:5][CH:6]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][NH:18][N:17]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][C:16]1[C:20]([C:2]2[N:3]=[C:4]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)[S:5][CH:6]=2)=[CH:19][NH:18][N:17]=1
Reactant: Cc1cccc(Oc2nc(Br)cs2)n1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Oc2nc(-c3c[nH]nc3C)cs2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
According to Scheme 4: A mixture of 2-(4-bromothiazol-2-yloxy)-6-methylpyridine (0.37 mmol, 100 mg), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.44 mmol, 92 mg), Pd (dppf) (37 μmol, 30 mg) and N-ethyl-N-isopropylpropan-2-amine (0.74 mmol, 0.13 mL) in dioxane/water (1:1, 2.5 mL) was stirred at 120° C. for 1 hour under microwave conditions. To complete the reaction, PdCl2(dppf) (37 μmol, 30 mg) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.44 mmol, 92 mg) were added and the reaction mixture was stirred at 120° C. for 1.5 hour under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 93:6.4:0.6) as eluent to yield 4-(3-methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (95 μmol, 26 mg, 26%) as an orange solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[OH:12])[CH2:2][CH2:3][CH3:4].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C1C=CC=CC=1.CCCCCC>[CH2:13]([O:12][C:6]1[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A mixture comprising 31.12 g of the above phenol, 18.81 g of benzyl bromide, 18.24 g of potassium carbonate and 300 ml of acetone, was stirred at room temperature for 2 days. Acetone was distilled off, and water was added to the residue. The mixture was extracted with benzene. The benzene layer was washed with a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a pale yellow oily substance. This substance was subjected to silica gel column chromatography by using benzene-n-hexane (1:9, v/v) as the developer, whereby 30.07 g of (2-n-butyl-4-bromophenyl) benzyl ether was obtained as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH:33]=[CH2:34])[CH2:28][CH2:27]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cl-].[NH4+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]2/[CH:34]=[CH:33]\[C:32]([N:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2cc(OCc3ccccc3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(/C=C\C(=O)N2CCOCC2)c2cc(OCc3ccccc3)ccc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 5-(benzyloxy)-3-bromo-1H-indole-1-carboxylate (2.011 g), 1-morpholinoprop-2-en-1-one (0.776 g), palladium acetate (31 mg), tri-o-tolylphosphine (187 mg) and triethylamine (1.14 mL) in N,N-dimethylformamide (14 mL) under nitrogen atmosphere was stirred at 100° C. overnight. The mixture was diluted with ethyl acetate and saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (80% ethyl acetate-hexane) to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:21](OC(=O)C1C=C([N+]([O-])=O)C=CC=1Cl)[CH3:22].FC1C=CC(O)=CC=1>>[CH2:21]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=1[O:6][C:5]1[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:22]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Agent: Oc1ccc(F)cc1
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1

Procedure:
2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid can be prepared by a similar method to that described in the literature (e.g. WO9938845) by reaction of 2-Chloro-5-nitro-benzoic acid ethyl ester [16588-17-3] with 4-Fluoro-phenol [371-35-7] yielding 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester. 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester can then be hydrolysed with sodium hydroxide for example to yield the title compound. MS (m/e): 276.1 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:31])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:34][CH2:33][CH2:32][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:31])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Yield: 99 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[l-hydroxy-2-(4-methoxyphenoxy)ethyl]pyrrolidine (10.94 g) was subjected to DMSO-DCC oxidation in the same manner as in Example 1, D) to give 10.78 g of the title compound (See Table 6).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([NH:24][CH2:23][CH:20]2[CH2:22][CH2:21]2)=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: NCC1CC1
Product: CCN(CC(=O)NCC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethylglycine and 1-cyclopropylmethanamine: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.6 Hz, 1H), 6.79 (dd, J=8.8, 2.8 Hz, 1H), 6.06 (bs, 1H), 3.97 (s, 2H), 3.56 (q, J=7.1 Hz, 2H), 3.13 (t, J=6.3 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H), 0.87 (m, 1H), 0.45 (m, 2H), 0.14 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][O-:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([O:16][CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 39 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 285 mg, 1.038 mmol), sodium methoxide (1.402 mL, 5.19 mmol) in MeOH (5 mL) was stirred at rt for 3 days. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and concentrated to afford a yellow solid that was chromatographed on a 24 gm silica gel cartridge, eluting with a 0-100% EtOAc/hexanes gradient. Fractions containing the product were concentrated to afford the title compound (112 mg, 0.405 mmol, 39.0% yield) as a yellow solid. HPLC (condition M): retention time=1.70 min.; LCMS (ES+) m/z: 271.9 (bromine pattern); H 1NMR (400 MHz, CDCl3) δ ppm 4.44 (s, 3 H), 5.71 (brs, 1 H), 6.99 (d, J=1.8 Hz, 1 H), 7.22 (brs, 1 H), 7.81 (d, J=1.8 Hz, 1 H), 8.69 (s, 1 H).