Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].C([Li])CCC.CCCCCC.[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a stirred solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-2-thienyl]-1H-imidazole (3.40 g, 10.1 mmol) in THF (80 mL) was added dropwise 2.50 M of n-butyllithium in Hexane (4.46 mL, 11.2 mmol) at −78° C. and the resulting solution was stirred for 30 min. A solution of tributyltin chloride (3.44 mL, 12.7 mmol) in THF (40.0 mL) was added dropwise into the cold solution and then the resulting mixture was stirred for 1 hr at −78° C. The reaction mixture was quenched by addition of water (150 ml) and the resulting mixture was extracted with EtOAc (200 ml×3). The combined organic layers were washed with brine, dried using Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-20% EtOAc in hexanes) to provide 3.5 g of product as a yellowish oil (71%). LC/MS (FA) ES+ 625. 1H NMR (400 MHz, d6 DMSO) δ: 7.67 (d, J=2.0 Hz, 1H), 7.34 (dd, J=2.0, 8.3 Hz, 1H), 7.24 (t, J=10.5 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.97 (d, J=1.2 Hz, 1H), 5.46-5.57 (m, 1H), 4.98 (dd, J=1.5, 10.2 Hz, 1H), 4.79 (dd, J=1.5, 17.1 Hz, 1H), 4.18-4.22 (m, 2H), 1.44-1.68 (m, 6H), 1.25-1.36 (m, 6H), 1.04-1.23 (m, 6H), 0.82-0.89 (m, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: OCC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCC(CO)CC1
Temperature: 80 °C
Yield: 81.1 %

Procedure:
A mixture of 2,5-dichloronitrobenzene (0.7 g), 4-piperidinemethanol (0.6 g) and potassium carbonate (1 g) in N,N-dimethylformamide (10 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/Acetone, 90/10) to afford 0.8 g of [1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]-methanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=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(N(CC)CC)C>ClCCl.O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A mixture of 3-amino-1-propanol (51 ml, 0.66 mol), chlorotriphenylmethane (184 g, 0.66 mol) and triethylamine (92 ml, 0.66 mol) in dichloromethane (1000 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and the layers separated. The aqueous phase was extracted with further dichloromethane (2×) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated well with diisopropyl ether, and the resulting solid was filtered and dried. This solid was then triturated with methanol, the suspension filtered, and the filtrate concentrated under reduced pressure, to give the title compound as a white solid, 139.1 g, 66% yield.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH:37]([CH3:39])[CH3:38])[N:24]=1>>[CH:37]([C:25]1[N:24]=[C:23]([N:18]2[CH2:19][CH2:20][CH:15]([N:5]3[C:6](=[O:14])[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=4)[N:3]([CH3:2])[C:4]3=[O:21])[CH2:16][CH2:17]2)[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=1)([CH3:39])[CH3:38]
Reactant: COc1cc2nc(C(C)C)nc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2nc(C(C)C)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 10 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-2-isopropyl-6,7-dimethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 50.3 mg (yield: 10%) of Compound 83 was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CC([O-])(C)C.[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Brc1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(N2CCOCC2)cc1
Yield: 82.1 %

Procedure:
According to General Procedure B, a mixture of bromobenzene (53 μL, 0.50 mmol), morpholine (52 μL, 0.60 mmol), NaOt-Bu (67 mg, 0.70 mmol), Pd2(dba)3.CHCl3 (10 mg, 0.01 mmol) and 12f (8 mg, 0.02 mmol) in PhMe (2.5 mL), was heated, cooled and filtered. Column chromatography (6:1:93 Et2O/Et3N/hexane, silica gel) gave 52h (67 mg, 82%) as a colorless solid. 1H NMR (600 MHz, CDCl3) δ 7.32 (t, 2H, J=4.2 Hz), 6.97-6.91 (m, 3H), 3.90 (t, 4H, J=2.4 Hz), 3.19 (t, 4H, J=2.4 Hz); 13C NMR (150.9 MHz, CDCl3) δ 151.3, 129.2, 120.1, 115.7, 67.0, 49.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[N:5]2.OO.C(O)(=[O:25])C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6](=[O:25])[NH:5]2
Reactant: CC(=O)O
Reactant: Brc1ccc2c(c1)ncc1nnc(-c3ccccc3)n12
Agent: OO
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
7-Bromo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline (7.4 g, 22.7 mmol), hydrogen peroxide (30%, 59 mL), and acetic acid (185 mL) were combined and heated at 50° C. overnight. Additional hydrogen peroxide (30%, 15 mL) was added to push the reaction to completion, and the mixture was stirred overnight at room temperature. The reaction was added to water (550 mL) and the precipitate was filtered and rinsed with water to give the desired product, 7a.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[S:19][C:20]([CH3:23])=[CH:21][CH:22]=1)=[O:17])[CH2:5][S:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9]>FC(F)(F)C(O)=O>[CH3:1][CH:2]([CH3:24])[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[S:19][C:20]([CH3:23])=[CH:21][CH:22]=1)=[O:17])[CH2:5][S:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(C(=O)N[C@H](CSCC(=O)OC(C)(C)C)CC(C)C)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N[C@H](CSCC(=O)O)CC(C)C)s1
Yield: 47.6 %

Procedure:
1.83 g (0.005 mol) (S)-1,1-dimethylethyl [[4-methyl-2-[[[5-methyl-2-thienyl]carbonyl]amino]pentyl]thio]acetate and 10 ml trifluoroacetic acid are reacted according to the procedure for Example 4 to give 0.75 g of (S)-[[4-methyl-2-[[(5-methyl-2-thienyl)carbonyl]amino]pentyl]thio]-acetic acid as a viscous oil. [α]D25 +57.3° (c 0.52, methanol).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[CH:43]([OH:45])=[O:44].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:43]([OH:45])=[O:44].[Cl:27][C:23]1[CH:22]=[C:21]([N:20]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:11]=3)=[CH:17][C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])=[N:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CN1CCN(CCCOc2cccc(-c3cc(C(=O)N4CNC(=O)C4)nn3-c3cccc(Cl)c3)c2)CC1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and 1-methylpiperazine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 45 mg (38% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:26]I.[Cl-].[NH4+]>C1COCC1>[I:26][C:15]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:12]=[CH:13][CH:14]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)n2nccc2I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
A solution of 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (2.0 g, 9.0 mmol) in THF (50 ml) was cooled to −78 C under a nitrogen atmosphere. To this was added tert butyl lithium (5.9 ml) in pentane (1.7M, 10 mmol). After 10 minutes iodine (2.53 g, 10 mmol) in THF (10 ml) was added and the reaction mixture was stirred for a further 30 minutes before allowing to warm to ambient temperature followed by stirring for 12 hours. A saturated solution of ammonium chloride was added and the mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 20-100% dichloromethane in hexane to give the product as a solid (0.96 g, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[S:21][C:20]([C:22]#[N:23])=[CH:19][C:18]=1[CH3:24]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:17]3[S:21][C:20]([C:22]#[N:23])=[CH:19][C:18]=3[CH3:24])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile using the coupling procedures in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.87 (s, 1H), 7.41-7.36 (m, 2H), 7.22 (d, J=8.32 Hz, 1H), 4.29 (s, 2H), 2.29 (s, 3H), 1.58 (s, 6H); MS (FI) m/z 311 ([M−H]−, 20%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 19.6 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 15, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (28.8 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 20% (24 mg, 0.047 mmol) of the title compound.
Reaction SMILES: COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[N:32]1([C:37]([C:39]2[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=2)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>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.O>[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:30]=[CH:29][C:28]([C:42]4[CH:41]=[CH:40][C:39]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36]5)=[O:38])=[CH:44][CH:43]=4)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)cc1)N1CCCC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 475.6 %

Procedure:
1,2-dimethoxyethane (3.0 ml) and aqueous 2 N sodium carbonate solution (1.0 ml) were added to 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine (176 mg, 0.54 mmol), and then 4-(pyrrolidin-1-ylcarbonyl)phenylboronic acid (142 mg, 0.065 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) were added thereto and stirred in a nitrogen atmosphere at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, and water was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-200, chloroform:methanol=10:1) to obtain the entitled compound (130 mg, 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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].C(Cl)Cl>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CSc1nccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CSc1nccc(-c2ccnc(F)c2)n1
Temperature: 85 °C
Yield: 90.5 %

Procedure:
A suspension of 4-bromo-2-(methylthio)pyrimidine (7.00 g, 34.1 mmol), 2-fluoropyridin-4-ylboronic acid (5.05 g, 35.8 mmol), Na2CO3 (10.9 g, 102 mmol) and Pd(dppf)Cl2 CH2Cl2 (1.40 g, 1.71 mmol) in dioxane/H2O (100 mL; 1:1) was heated to 85° C. under an Ar balloon for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (1×). The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (3:1) to give 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 90%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.85 (d, J=5.2 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.11 (m, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 2.62 (s, 3H); m/z (APCI-pos) M+1=222.1.
Reaction SMILES: C(O)(CC)(C)C.[NH2:7][C:8]1[S:9][C:10]([C:16]2[C:21]([F:22])=[CH:20][C:19]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:18][C:17]=2[F:27])=[CH:11][C:12]=1[C:13]([NH2:15])=[O:14].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+].Br[C:69]1[N:74]=[C:73]([CH2:75][O:76][CH2:77][C:78]([CH3:81])([OH:80])[CH3:79])[CH:72]=[CH:71][CH:70]=1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:22][C:21]1[CH:20]=[C:19]([C:23]([OH:26])([CH3:24])[CH3:25])[CH:18]=[C:17]([F:27])[C:16]=1[C:10]1[S:9][C:8]([NH:7][C:69]2[CH:70]=[CH:71][CH:72]=[C:73]([CH2:75][O:76][CH2:77][C:78]([OH:80])([CH3:79])[CH3:81])[N:74]=2)=[C:12]([C:13]([NH2:15])=[O:14])[CH:11]=1
Reactant: CC(C)(O)COCc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: CCC(C)(C)O
Product: CC(C)(O)COCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 105 °C

Procedure:
t-Amyl alcohol (41 mL) was placed in a flask and argon was bubbled through it for several minutes. 2-Amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (2.50 g, 8.0 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.90 g, 4 mmol), Pd2(dba)3 (0.73 g, 0.8 mmol), and potassium carbonate (1.22 g, 8.8 mmol) were placed in a reaction vessel that was purged with argon. Degassed t-amyl alcohol (10 mL) was used to transfer 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (2.08 g, 8.0 mmol) to the reaction vessel and the remaining t-amyl alcohol was added. Seven argon/vacuum cycles were performed. The solution was heated at 105° C. overnight. The reaction was then cooled to ambient temperature, diluted with methanol, and silica gel was added. The resulting mixture was concentrated in vacuo and then purified by column chromatography (silica, 0-5% methanol/ethyl acetate). Purification via mass guided reverse phase HPLC (Agilent 1100 HPLC-MSD, Phenomenex Gemeni-C18, 10 μM, 250 mm×50 mm i.d. column, 20-95% acetonitrile/water+0.01% formic acid modifier, 75-100 mL/min flow rate) afforded the title compound.
Reaction SMILES: [OH:1][CH2:2][NH:3][C:4](=[O:6])[CH3:5].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13](O)=[O:14]>>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][C:13]([O:1][CH2:2][NH:3][C:4](=[O:6])[CH3:5])=[O:14]
Reactant: CC(=O)NCO
Reactant: O=C(O)Cc1cccs1
Product: CC(=O)NCOC(=O)Cc1cccs1
Yield: 44.4 %

Procedure:
N-(Hydroxymethyl)-acetamide (13.4 g, 0.15 mol) and thiolacetic acid (14.3 g, 0.188 mol) were heated for 3 days at 40° C. The resulting mixture was chromatographed on silica gel (63-200 um, 700 g) with toluene-ethyl acetate 4:1 and 1:1 to give pure crystalline acetamidomethyl thiolacetate (14.2 g, 64%), m.p. 93-94° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[CH3:23][S-:24].[Na+].O.CCOCC>C(Cl)(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH3:23][S:24][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(SC)ncn1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
(E)-Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g), was treated with sodium methanethiolate (1.09 g) at room temperature in chloroform (15 ml) and water (10 ml) in the presence of a catalytic amount of tetrabutylammonium bromide. After stirring overnight, the chloroform layer was separated and the remaining aqueous layer was further extracted with chloroform. The combined chloroform layers were washed with water, dried and concentrated to give an orange oil. Chromatography using a mixture of ether and hexane (2:1) gave (E)-methyl 2-[2-(6-methylthiopyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (0.92 g, 89% yield) as a pale yellow oil; 1H NMR: δ 2.52(3H,s), 3.59(3H,s), 3.73(3H,s), 6.55(1H,s), 7.17(1H,d), 7.20-7.55(3H,m), 7.45(1H,s), 8.57(1H,s) ppm.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][CH:17]([NH:19][CH2:20][C@H:21]([OH:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:5])C.[OH-].[Na+:32]>CO>[OH:30][C@H:21]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][NH:19][CH:17]1[CH2:16][CH2:15][CH2:14][C:13]2[C:8]([O:7][CH2:6][C:4]([O-:5])=[O:3])=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:18]1.[Na+:32]
Reactant: CCOC(=O)COc1cccc2c1CCCC(NC[C@H](O)COc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])COc1cccc2c1CCCC(NC[C@H](O)COc1ccccc1)C2

Procedure:
A solution of (2S)-1-[(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (103 mg) in methanol (5.0 ml) and 0.1N sodium hydroxide aqueous solution (2.5 ml) was stirred for 22 hours and evaporated in vacuo. The residue was triturated in diethyl ether and the precipitated powder was collected by filtration to afford sodium [6,7,8,9-tetrahydro-6-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-5H-benzocyclohepten-1-yloxy]acetate (98 mg) as a pale yellow powder.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]2)=[O:8])[N:6]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]2)=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(Br)n2)C1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2csc(-c3ccccc3F)n2)C1

Procedure:
In a microwave safe sealed tube was charged a mixture of ((S)-tert-butyl 1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (96.5 mg, 0.2 mmol), 2-Fluorophenylboronic acid (33.6 mg, 0.24 mmol), 1,1′-Bis(diphenylphosphino)ferrocene palladium (II) chloride (81.7 mg, 0.1 mmol), 1.00 M of Potassium acetate in Water (0.3 mL, 0.3 mmol), 1.00 M of Sodium carbonate in Water (0.3 mL, 0.3 mmol) in acetonitrile (5 mL). The mixture was irradiated at 300 W 110° C. for 15 minutes. The reaction mixture was then concentrated and the residue was purified on silica eluting with 0 to 5% MeOH in DCM with 1% NH4OH (90.0 mg, 90.4%). ESIMS m/z=498.2 (M+1).