Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1)(O)[C:12]([F:15])([F:14])[F:13])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[CH:19][CH:18]=1)[C:12]([F:13])([F:14])[F:15])[CH3:2]
Reactant: CCOCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOCCn1cccc1C(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 32 mg (0.07 mmol) of N-(4-{1-[1-(2-ethoxyethyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-hydroxyethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 78) in 2 mL of CH2Cl2 at 0° C. were added 1.05 mL (6.57 mmol) of triethylsilane followed by 167 μL (1.32 mmol) of boron trifluoride diethyl etherate dropwise. The mixture was warmed to room temperature and stirred for 1.75 h. After this time, the reaction mixture was cooled to 0° C., quenched by the addition of a saturated aqueous solution of sodium bicarbonate, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 4:1) to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[C:10]([CH2:13][OH:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:30])[C@@H:18](/[CH:19]=[C:20](/[F:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@H:17]1[C:27](O)=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:30][C:16]1([CH3:15])[C@@H:18](/[CH:19]=[C:20](/[F:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@H:17]1[C:27]([O:14][CH2:13][C:10]1[CH:9]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:12][CH:11]=1)=[O:28]
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1coc(Cc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)OCc2coc(Cc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.50 g of 5-benzyl-3-furylmethyl alcohol, 0.62 g of (1R)-cis-2,2-dimethyl-3-((E)-3-ethoxy-2-fluoro-3-oxo-1-propenyl)-cyclopropanecarboxylic acid, 0.1 g of 4-dimethylaminopyridine and 7 ml of dichloromethane was added 0.60 g of N,N-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.69 g of 5-benzyl-3-furylmethyl (1R)-cis-2,2-dimethyl-3-((E)-3-ethoxy-2-fluoro-3-oxo-1-propenyl)cyclopropanecarboxylate (hereinafter, referred to as the present compound (1)).
Reaction SMILES: SC1C=C2C(=CC=1C)OC(O)CC2.[CH3:14][O:15][C:16](=[O:47])[CH2:17][CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([CH3:46])=[C:23]([S:28]CC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)[CH:24]=2)[O:19]1>>[CH3:14][O:15][C:16](=[O:47])[CH2:17][CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([CH3:46])=[C:23]([SH:28])[CH:24]=2)[O:19]1
Reactant: COC(=O)CC1CCc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)c(C)cc2O1
Agent: Cc1cc2c(cc1S)CCC(O)O2
Product: COC(=O)CC1CCc2cc(S)c(C)cc2O1

Procedure:
Compound 15D was prepared according to the method of example 1D utilizing compound 15C. MS: 251 (M−1)+. Preparation of 7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-2-yl-acetic acid methyl ester (Compound 15E)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:12][CH3:13])[C:9]([OH:11])=O.[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:12][CH3:13])=[CH:18][CH:17]=1)#[N:14]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccccc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1F

Procedure:
(RS)-(2-Fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-phenyl)-2-methoxy-acetamide. Colorless oil. MS 299.2 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:46])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:47])[C:3]=1[C:48]([O:50][CH3:51])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:44])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C:35](=[N:39][OH:40])[C@@H:34]([O:41][CH3:42])[C@H:33]([CH3:43])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:45].Cl.O(N)[CH3:54].N1C=CC=CC=1>CO>[CH3:38][O:37][C@H:36]1[C@@H:31]([NH:30][C:14]2[C:13](=[O:44])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:46])([C:9]4=[O:45])[C:7]4[C:2]([OH:1])=[C:3]([C:48]([O:50][CH3:51])=[O:49])[C:4]([CH3:47])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=2)[O:32][C@@H:33]([CH3:43])[C@H:34]([O:41][CH3:42])/[C:35]/1=[N:39]/[O:40][CH3:54]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)C(=NO)[C@H]1OC)C4=O
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CO/N=C1/[C@@H](OC)[C@H](C)O[C@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)OC)c(O)c5[C@]3(O)C4=O)C2=O)[C@@H]1OC
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of the ketone from Step A of the preparation of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate [Isomer A] (Example 48) (53 mg, 0.076 mmol) in methanol (1 mL) was added methoxylamine hydrochloride (6.4 mg, 0.076 mmol) and pyridine (0.1 mL) at room temperature. The mixture was stirred under nitrogen for 2 h. The reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 11-((2S,3R,5R,6S,Z)-3,5-dimethoxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (30 mg, 54%) as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.15 (s, 1H), 12.09 (s, 1H), 8.20 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.98-4.94 (m, 2H), 4.67-4.64 (m, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.71 (d, J=9.5 Hz, 1H), 3.59 (s, 3H), 3.57-3.52 (m, 2H), 3.47 (s, 3H), 3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 2.40 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 725 (M+H); HPLC 95.9% (AUC), tR 17.05 min.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)[CH2:17][CH2:16]2)[N:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(N2CCN(CC3COc4ccccc4O3)CC2)n1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (4.7 g, 20 mmole) and 2,6-dichloropyrazine (3.0 g, 20 mmole) were combined in 200 ml of dimethylformamide and 2.6 g (20 mmole) of diisopropylethylamine was added. The mixture was heated under nitrogen at 60° C. for 24 hours. The solvent was then removed in vacuum and the residue filtered through 75 g of silica gel with chloroform as the eluent. The product-containing fractions were concentrated in vacuum and the residue was crystallized from methanol with addition of 4N isopropanolic HCl and recrystallized from methanol to give 4.26 g of the title compound as the monohydrochloride, m.p. 270°-280° C.
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26]>C(Cl)Cl>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:26][C:11](=[O:13])[CH2:10][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:9]
Reactant: COC(=O)CN
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of Boc-sarcosine (9.0 g, 048 mol) in 70 ml of CH2Cl2 at −20° C. was added isobutyl chlorofomate (7.1 g, 0.052 mol) and N-Methylmorpholine (4.8 g, 0.047 mol). After 2 min glycine methyl ester, hydrochloride (7.19g, 0.057 mol) and N-methylmorpholine (5.76g, 0.057 mol) in CH2Cl2 (60 ml) was added. The reaction was stirred at −10° C. for 1 h and allowed to warm to room temperature. After 4h at room temperature, the reaction was filtered and washed with salt. NaHCO3 (100 ml), 1N NaHCO3 100 ml, twice with 1N KHSO4 (100 ml), water (100 ml) and brine (70 ml). The organic phase was dried with Na2SO4 and evaporated. The yield of Boc sarcosyl-glycine methyl ester was 89%.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.CO.CCOC(C)=O>CO.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([I:1])[CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)c(Cl)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)c(I)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of silver sulfate (0.97 g, 3.11 mmol) and iodine (0.79 g, 3.11 mmol) in MeOH (20 ml) at room temperature, a solution of methyl 2-chloro-4′-methoxybiphenyl-4-carboxylate (0.86 g, 3.11 mmol) in 1:1 mixture of MeOH/EtOAc (10 ml) was added. The mixture was stirred at room temperature for 6 h until color of the reaction turned to pale. The solid was filtered off and the filtrate was concentrated. The title compound was obtained after flash column using EtOAc:hexane/5:95 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 8.15 (d, J=1.5 Hz, 1H), 7.97 (dd, J=8, 2 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 7.46 (dd, J=8.5, 2 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 3.98 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:16]C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([NH2:16])[CH2:15][CH2:14][CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CCCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(N)CCCC2(CC1)OCCO2
Yield: 76.9 %

Procedure:
66 mg of 8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester was dissolved in methanol and hydrogenated in an H-cube™ hydrogenation reactor (ThalesNano, Budapest, Hungary) at a hydrogen pressure of 100 bar at 40° C. over a cartridge with 10% palladium on charcoal. The mixture was evaporated to dryness to yield the crude title compound (32 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.N1C=CC=CC=1.O=S(Cl)[Cl:33]>C1COCC1>[Cl:33][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-phenylindolin-2-one (30 g, 0.094 mol) in THF (300 mL) was added pyridine (40 mL) followed by SOCl2 (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and quenched by the addition of saturated ammonium chloride solution (50 mL). The organic layer was washed with saturated ammonium chloride (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford target compound (25 g, 79%). 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 7.37-7.53 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 2.30 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)[CH:7]=1.[CH2:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[CH2:35][CH2:36][CH3:37]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:41]3[CH:42]=[CH:43][C:38]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:39][CH:40]=3)=[CH:28][CH:27]=2)[CH:7]=1
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: COC(=O)CNc1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1
Product: CCCCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(NCC(=O)OC)c3)cc2)cc1

Procedure:
{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (55 mg, 0.1 mmol) was coupled with 4-n-butyl-phenylboronic acid (36 mg, 0.2 mmol) according to general procedure G to give {3-[2-(4′-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.O>O1CCOCC1.Cl.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>[C:38]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:40])[CH3:39]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1cccc2[nH]c(CC3CCCCN3C(=O)c3nc(C)sc3-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a deoxygenated solution of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E66 (200 mg, 0.39 mmol) in anhydrous 1,4-dioxane (10 ml) was added tributyl(1-ethoxyvinyl)tin (155 mg, 0.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The resultant mixture was refluxed under argon for 20 h. Further tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) was added and refluxing continued for a further 24 h. On cooling, water (15 ml) and 5N hydrochloric acid (10 drops) were added and the mixture stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% ethyl acetate-hexane then 2-5% methanol-ethyl acetate) afforded the title compound as a pale orange solid (62 mg, 33%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>C(O)C>[Cl:16][C:17]1[N:22]=[C:21]([N:6]2[CH2:7][CH2:8][N:3]([CH:1]=[O:2])[CH2:4][CH2:5]2)[CH:20]=[CH:19][N:18]=1
Reactant: O=CN1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
1-Formylpiperazine (38.5 g) and triethylamine (34 g) in ethanol (500 ml) were added slowly to a stirred solution of 2,4-dichloropyrimidine (50 g) in ethanol (2.5 ml) at room temperature. The mixture was stirred at room temperature for 24 hours then evaporated in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and the combined aqueous phases extracted with chloroform. The combined chloroform extracts were dried (Na2SO4), evaporated in vacuo and the residue was crystallized twice from ethyl acetate to give 2-chloro-4-(4-formylpiperazino)pyrimidine, (24 g), m.p. 125°-126° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[CH:16]=[C:11]3[C:10]([CH3:30])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:30][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ncc(-c3ccc(N4CCN(C)CC4)cc3)cc12
Temperature: 50 °C

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-3-methyl-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine (160) in CHCl3 (20 mL) was added trifluoroacetic acid (5 mL) and heated at 50° C. for 12 hours. After completion of the reaction the solvents were removed, diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform twice. The organic layer was washed with brine solution and dried over sodium sulphate and the solvent completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound in 10% MeOH/CHCl3 as pale yellow solid compound 161 (8 mg).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29](I)[N:24]3[N:23]=2)[CH2:21][CH2:20]1>[Cu](I)I.CC(O)C>[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]3[N:23]=2)[CH2:21][CH2:20]1
Reactant: COc1ccc(I)n2nc(C3CC3)nc12
Reactant: C1CCNCC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1ccc(N2CCCCC2)n2nc(C3CC3)nc12
Temperature: 80 °C

Procedure:
Copper iodide (1.0 mg, 0.005 mmol) and potassium phosphate (42.5 mg, 0.200 mmol), kept under argon, was added 2-propanol (200 μL), ethylene glycol (12.4 mg, 0.200 mmol), piperidine (10.1 mg, 0.12 mmol) and 2-cyclopropyl-5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (31.5 mg, 0.100 mmol). The resulting suspension was heated to 80° C. for 4 days. The mixture was allowed to reach room temperature before it was extracted with dichloromethane (3 mL). The organic phase was washed with brine, dried (Na2SO4) and filtered before it was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene to 40% EtOAc in toluene) to give 2-cyclopropyl-8-methoxy-5-piperidin-1-yl-[1,2,4]triazolo[1,5-a]pyridine (2.2 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1.[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([CH3:27])[CH:16]=[CH:17][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][C:4]3[CH:14]=[CH:13][C:7]4[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=4[CH:5]=3)[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C2CCNCC2)cc1
Reactant: O=C1COc2ccc(CCCl)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C2CCN(CCc3ccc4c(c3)NC(=O)CO4)CC2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a 20 mL screw cap vial was added 123 (100 mg, 0.472 mmol), 4-p-tolylpiperidine (83 mg, 0.472 mmol), K2CO3 (131 mg, 0.945 mmol) in DMF (2 mL). The reaction was stirred at 80° C. for 4 h. The reaction was filtered and the crude material was purified by prep HPLC-MS using a 25-95% MeCN in water gradient. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.79 (br. s., 1H), 9.27 (br. s., 1H), 7.14 (br. s., 4H), 6.94 (br. s., 1H), 6.80-6.87 (m, 1H), 6.78 (br. s., 1H), 4.56 (br. s., 2H), 3.65 (br. s., 2H), 3.27 (br. s., 2H), 3.08 (br. s., 2H), 2.94 (br. s., 2H), 2.78 (br. s., 1H), 2.28 (br. s., 3H), 2.00 (br. s., 2H), 1.82 ppm (br. s., 2H). ESI-MS: m/z 351.2 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[F:13].[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([CH:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[O:14]1[C:18]2([CH2:19][CH2:20][CH:21]([CH:24]3[CH2:29][CH2:28][C:27]([C:3]4[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=4[F:13])([OH:30])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)[O:17][CH2:16][CH2:15]1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: CCOc1ccc(Br)c(F)c1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
First Step: 6.1 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 59.7 g of 1-bromo-4-ethoxy-2,3-difluorobenzene (1) dissolved in 300 mL of THF was slowly added dropwise thereto at a temperature range of from 40 to 60° C., followed by stirring for 60 minutes. Thereafter, 50.0 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexanone (2) dissolved in 150 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 60° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 900 mL of a 3% ammonium chloride aqueous solution and 500 mL of toluene cooled to 0° C. in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 100.1 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol (3). The resulting compound (3) was a yellow solid.