Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([O:10][PH:11](=[O:22])[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/[O-])=C/C(C)=[O:27].C(OO)(C)(C)C>ClC1C=CC=CC=1>[CH3:21][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:12]([PH:11](=[O:22])[O:10][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:27]
Reactant: CC(=O)/C=C(/C)[O-]
Reactant: Cc1cc(C)c(C[PH](=O)OC(O)Cc2ccccc2)c(C)c1
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)[PH](=O)OCCc2ccccc2)c(C)c1
Reaction time: 20 h
Yield: 55 %

Procedure:
To 26.5 g (0.08 mol) of α-hydroxy-(2,4,6-trimethylbenzyl)-phenylethoxy phosphine oxide and 1 g (38 mmol) of vanadyl(IV) bis-acetylacetonate in 110 g of chlorobenzene there were added 28 g (0.22 mol) of 70 wt % strength aqueous tert-butylhydroperoxide and the mixture was stirred for a period of 20 h. The product was isolated by distillation. Yield: 55%, bp 180° C. (0.1 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:13])[CH:5]=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl.O>C(O)C.CCOCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([OH:11])[C:6]([CH3:12])=[CH:5][C:4]=1[OH:13]
Reactant: COC1=C(OC)C(=O)C(C)=CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1c(O)cc(C)c(O)c1OC
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
In 28 ml of ethanol was dissolved 1.82 g (10 mmol.) of 2,3-dimethoxy-5-methyl-1,4-benzoquinone. To the solution was portionwise added at room temperature 240 mg (6.3 mmol.) of sodium borohydride. The mixture was stirred for 15 min. The mixture was then made acidic by addition of 3-N hydrochloric acid. To the mixture were added 50 ml of water and 100 ml of ether for performing extraction. The ether portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent to give 1.72 g of 2,3-dimethoxy-5-methylhydroquinone as a yellow oil, yield 93.5%. To the resulting oil were added 1.65 g (9.3 mmol.) of methyl 1-piperazinecarbodithioate and 280 mg (9.3 mmol.) of paraformaldehyde. The mixture was added to 17 ml of chloroform, and the resulting mixture was refluxed under heating for 6 hours. To the heated mixture was added water. The aqueous mixture was then extracted with chloroform. The chloroform extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was dissolved in 10 ml of ethanol. Insolubles were removed by filtration. The filtrate was placed under reduced pressure to distill off ethanol. The residue was then purified by means of silica gel column, to give 1.1 g of a pale yellow oil, yield 31.8%. The oil was crystallized from ethanol. The crystals were collected by filtration to give 790 mg of the desired compound as a yellow crystalline product, m.p. 135°-136° C.
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].F[B-](F)(F)F.[H+]>O1CCCC1.C(O)C.[Pt]=O>[CH2:1]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[NH:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: O=[Pt]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Yield: 45.4 %

Procedure:
2-(n-Pentadecyl)indole-6-carboxylic acid (16.0 g) was dissolved in a mixture of tetrahydrofuran (400 ml) and ethanol (100 ml), containing aqueous fluoroboric acid (100 ml, of strength 40% w/v). The stirred mixture was hydrogenated over platinum oxide (2.0 g) at room temperature and atmospheric pressure. After 6 hours the mixture was filtered, the residue was washed with diethyl ether (100 ml) and the combined filtrates were concentrated in vacuo until a solid separated. The mixture was adjusted to pH 7 by treatment with an aqueous solution of sodium hydroxide (strength 50% w/v) and was then adjusted to pH 4-5 with glacial acetic acid. The mixture was extracted with diethyl ether (3×100 ml), and the ether solution was dried over magnesium sulphate and, on evaporation in vacuo, gave a solid. The solid was recrystallised from a mixture of toluene and hexane (equal parts by volume) to give (RS)-2-(n-pentadecyl)-indoline-6-carboxylic acid (7.3 g), in the form of a colourless solid, m.p. 119°-122° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:3][CH:4]=2)[N:11]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccc(N3CCCCC3)nc2)cs1
Temperature: 90 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 0.25 mL (2.5 mmol, 3 eq) piperidine and 2 mL DMF were combined. The reaction mixture was heated at 90° C. for 16 h, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 50% EtOAc/Hexanes) gave 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2-piperidin-1-ylpyridine (L-001106455). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C16H17N3S 283, observed m/e 284.3 (M+H)+. 1H-NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.92-7.93 (m, 2H), 7.30 (d, 1H), 3.73 (m, 4H), 2.68 (s, 3H), 1.61-1.66 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:37][CH3:38])[CH:3]=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][N:23]=5)(=[O:20])=[O:19])=[CH:15][CH:16]=4)[CH:11]=[CH:10][N:9]=3)=[C:4]([O:37][CH3:38])[CH:3]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OC)nccc3c2)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2ccc(F)cc2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
A vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE BBBBB, 42.9 mg, 0.078 mmol), (4-fluorophenyl)boronic acid (21.95 mg, 0.157 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.610 mg, 3.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (2.97 mg, 3.92 μmol), and potassium phosphate (49.9 mg, 0.235 mmol). The vial was flushed with Ar (g), then THF (0.4 mL) and water (0.04 mL) were added in sequence. The vial was sealed and placed in a 110° C. heating bath overnight, then the mixture was cooled and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in DCM (1 mL), TFA (0.5 mL), and triflic acid (0.05 mL) (8:40 am). After 45 min, the mixture was concentrated. The residue was taken up in EtOAc. The organic solution was washed with saturated aq. sodium bicarbonate solution (2×), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 10% MeOH/DCM) to give 1-(4′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (28.7 mg, 0.059 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.04 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.64 (d, J=1.5 Hz, 1H), 8.56 (s, 1H), 8.23 (d, J=6.2 Hz, 1H), 8.09 (d, J=5.4 Hz, 1H), 7.95 (dd, J=1.9, 8.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.78 (d, J=8.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.38-7.31 (m, 2H), 7.02 (d, J=6.4 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 487.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5].[H][H]>[Pd].C1C=CC=CC=1>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:4]([C:3]1[CH:2]=[CH:19][CH:18]=[C:17]([NH2:20])[CH:16]=1)=[O:5].[ClH:1]
Reactant: O=C(c1ccc(Br)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: Cl
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1

Procedure:
In a closed glass vessel there are charged 38.6 g (0.1 moles) of 2-chloro-4'-bromo-5,3'-dinitro benzophenone, 1 g of palladium black catalyst and 300 ml of benzene. While the mixture being stirred at 65°-70° C., hydrogen is introduced into the vessel so that 13.8 l (0.62 moles) of hydrogen is absorbed in the mixture during 8 hours. Then, there are added 90 g (0.24 moles) of 15% aqueous solution of NaOH and 2 g of 90% aqueous solution of trioctyl methyl ammonium chloride, and then, there is introduced again hydrogen, while the mixture is being stirred at a temperature of 65°-70° C., so that 4.5 l (0.2 moles) of hydrogen is absorbed during about 5 hours. By filtering the reaction liquid at 65°-70° C. the catalyst is removed, and organic phase is separated from the filtrate. After the organic phase is added with magnesium sulfate for water removal, it is introduced with dry hydrochloric gas until saturated with the gas. The crystals thus formed are filtered, washed with 50 ml of benzene and dried to give 3,3'-diamino benzophenone in the form of hydrochloric acid salt. Yield 21.7 g (76%). Recrystallization from 20% aqueous isopropanol yield slightly yellow needle-like pure crystals of the benzophenone. M.P. 267° C. (decomposed).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[CH3:20][N:21]([CH3:30])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][N:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:13][C:12]1[C:7]2[N:6]=[C:5]([NH:29][C:25]3[C:26]([CH3:28])=[CH:27][C:22]([N:21]([CH3:30])[CH3:20])=[N:23][CH:24]=3)[N:4]([CH2:1][CH:2]=[CH2:3])[C:8]=2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=1
Reactant: Cc1cc(N(C)C)ncc1N
Reactant: C=CCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 26 %

Procedure:
A mixture of 1-allyl-2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazole (1.19 g, 4.00 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (1.21 g, 8.00 mmol) and p-toluenesulfonic acid monohydrate (760 mg, 4.00 mmol) in 1-methyl-2-pyrrolidinone (12 mL) was irradiated by microwave at 180° C. for 1 hr. After cooling, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (430 mg, 1.04 mmol, 26%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li+].CC([N-][CH:23]([CH3:25])[CH3:24])C.Cl>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])[C:15](=[O:17])[CH:14]([CH2:24][CH2:23][CH2:25][CH2:25][CH2:23][CH2:24][CH:14]1[CH2:13][C:5]3[C:4](=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[C:15]1=[O:17])[CH2:13]2
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OC)C(=O)C(CCCCCCC1Cc3cc(OC)c(OC)c(OC)c3C1=O)C2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3,4,5-trimethoxyphenyl)propionic acid (12 g) in THF (200 ml) was dropwise added LDA (1.9 M/THF solution; 60 ml) while temperature of the reaction mixture was kept under −10° C. After being stirred at 0° C. for 3 hr, the reaction mixture was acidified to pH3 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated in vacuo. Polyphosphoric acid (100 ml) was added to the residue and the reaction mixture was stirred at 60° C. for 4 hr. After being cooled, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then water, dried and concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with crystallization from ethyl acetate-hexane to yield the entitled compound (4.5 g). The compound recrystallized from ethanol gave following melting point.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:21])=[C:18]([SH:20])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=3)[S:20][C:18]=2[CH:19]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: COc1ccc(N)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Temperature: 170 °C
Yield: 22.3 %

Procedure:
A mixture of 4-methylaminobenzoic acid (11.5 g, 76.2 mmol) and 5-methoxy-2-aminothiophenol (12.5, g, 80 mmol) was heated in PPA (˜30 g) to 170° C. under N2 atmosphere for 1.5 hr. The reaction mixture was then cooled to room temperature and poured into 10% K2CO3 solution. The precipitate was filtered under reduced pressure. The crude product was re-crystallized twice from acetone/water and THF/water followed by the treatment with active with carbon to give 4.6 g (21%) of 6-Methoxy-2-(4-methylaminophenyl)benzothiazole as a yellow solid. 1HNMR (300 MHz, acetone-d6) δ: 7.84 (d, J=8.7 Hz, 2H, H-2′ 6′), 7.78 (dd, J1=8.8 Hz, J2=1.3 Hz, 1H, H-4), 7.52 (d, J=2.4 Hz, 1H, H-7), 7.05 (dd, J1=8.8 Hz, J2=2.4 Hz, H-5), 6.70 (d, J=7.6 Hz, 2H, H-3′ 5′), 5.62 (s, 1H, NH), 3.88 (s, 3H, OCH3), 2.85 (d, J=6.2 Hz, 3H, NCH3)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][C:3]=1[CH3:10].[CH2:11]([Mg]Br)[CH3:12].Cl.[O:16]1CCOCC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:16])[CH2:11][CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: C1COCCO1
Reactant: CC[Mg]Br
Reactant: Cc1cc(C#N)ccc1Br
Agent: Cl
Product: CCC(=O)c1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
24.7 g (126 mmol) of 4-bromo-3-methylbenzonitrile are dissolved in 400 ml of anhydrous dioxane and the medium is then cooled to 0° C. 124 ml (372 mmol) of ethylmagnesium bromide are added dropwise and the medium is then warmed to room temperature and stirred for 4 hours. The reaction medium is treated with 250 ml of 3N HCl and then extracted with a water/ether mixture. A white solid is obtained after trituration from heptane (m=14.5 g, Y=52%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39]([CH3:42])[C:35]=2[N:36]=[CH:37][N:38]=1.C(O)C.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][N:39]([CH3:42])[C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:27])([F:29])[F:28]
Reactant: Cn1ccc2c(I)ncnc21
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc2c(C(=O)c3ncc(Cl)cc3NS(=O)(=O)c3ccc(Cl)c(C(F)(F)F)c3)ncnc21

Procedure:
Prepared from 227 mg (0.45 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 129 mg (0.45 mmol) of 90% 4-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.23 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone (80 mg) was used in the second step with 2 mL ethanol and 2 mL 6N hydrochloric acid mixture to give after purification 45 mg of the final product as a yellow solid.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH3:16])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>COCCOC.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>[CH3:16][C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:7]1[S:6][C:5]2=[N:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=3)[N:9]2[N:8]=1
Reactant: Cc1ccncc1-c1nn2c(I)cnc2s1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccncc1-c1nn2c(-c3cnc(N)c(C(F)(F)F)c3)cnc2s1
Temperature: 120 °C
Yield: 40.1 %

Procedure:
A mixture of 5-Iodo-2-(4-methyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (18 mg, 0.053 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (20 mg, 0.068 mmol, 1.3 eq), Pd(PPh3)2Cl2 (9 mg, 0.011 mmol, 0.2 eq) and sat aq K2CO3 (0.22 mL) in DME (0.5 mL) was heated under microwave irradiation at 120° C. for 30 min. On cooling, DCM was added and the mixture was washed with water. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM/MeOH 95:5) to afford the desired product (8 mg, 40%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.32 min, [M+H]+ m/z 377.1; 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.70 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=5.0 Hz, 1H), 5.39 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](Br)[CH:11]=1>CN(C=O)C>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([O:4][CH3:3])[CH:11]=1
Reactant: CO
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A suspension of NaH (0.47 g, 19.6 mmol) in DMF (20 mL) was cautiously treated with methanol (0.59 g, 18.4 mmol). After 30 minutes, the mixture was treated with a solution of 3,5-dibromopyridine (4.0 g, 16.9 mmol) in DMF (5.0 mL). After stirring overnight, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with diethyl ether (200 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (CH2Cl2) to provide the title compound (2.24 g, 70% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](Cl)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:41][CH2:42][CH2:43][N:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][NH2:47]>C1C=CC=CC=1>[CH2:1]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([NH:47][CH2:46][CH2:45][N:44]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:42][OH:41])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Reactant: NCCN(CCO)CCO
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)NCCN(CCO)CCO
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A mixture of N,N-dioctadecylcarbamyl chloride (2.9 g.), N,N-bis(2-hydroxyethyl)-1,2-ethanediamine (4.0 g.) and benzene (50 ml.) is refluxed and stirred for three hours. The mixture is then cooled, concentrated in vacuo and the residue taken up on chloroform (100 ml.). The chloroform solution is washed successively with water (2× 50 ml.), aqueous sodium hydroxide (1× 50 ml. of 1 N) and water (2× 50 ml.), then dried (Na2SO4). Removal of the chloroform in vacuo leaves the crude product as an oil (3.3 g.).
Reaction SMILES: CC.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][C@@H:34]([OH:38])[C:35]([OH:37])=[O:36])[NH:18][C:19]([C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[CH:22]=3)=[O:20])=[CH:12][CH:11]=2)[CH:9]=1.CCN([CH2:45][CH3:46])CC.C[C:48](C)=[O:49]>>[CH3:48][O:49][CH2:45][CH2:46][O:36][C:35](=[O:37])[C@H:34]([OH:38])[CH2:33][N:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[CH:9]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=2[F:39])=[CH:11][CH:12]=1)[NH:18][C:19]([C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:22]=1)=[O:20]
Reactant: CCN(CC)CC
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: CC(C)=O
Agent: CC
Product: COCCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Ethane, 1-bromo-2-methoxy (5.7 mL, 0.1 mmol) was added to a mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (20.0 mg, 38 μmol) and Et3N (13.2 μL, 0.1 mmol) in acetone (1.0 mL, 14 mmol), and resulting mixture was stirred at 50° C. overnight. The mixture was concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (10.7 mg, purity 95.7%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H26ClF2N3O6, 586.15. found 585.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:19]1([C:22]2[NH:23][C:24]3[C:25]([N:32]=2)=[N:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:32]3[C:25]4=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]4[N:23]=[C:22]3[CH:19]3[CH2:21][CH2:20]3)=[CH:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Reactant: CCOC(=O)C1(c2ccc(CBr)cn2)CCCC1
Product: CCOC(=O)C1(c2ccc(Cn3c(C4CC4)nc4c(C)cc(C)nc43)cn2)CCCC1

Procedure:
The product of Example 10, Step 3, above (45), was alkylated as described in Example 1, Step 5, using 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine (13) to produce the title compound (48).