Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH3:48])[C:37]=2B2OC(C)(C)C(C)(C)O2)[N:32]([S:49]([C:52]2[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=2)(=[O:51])=[O:50])[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.O.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>[CH2:1]([N:8]1[CH2:28][CH2:27][C:11]2[N:12]=[C:13]([C:37]3[C:36]([CH3:48])=[CH:35][CH:34]=[C:33]4[C:38]=3[C:30]([CH3:29])=[N:31][N:32]4[S:49]([C:52]3[CH:58]=[CH:57][C:55]([CH3:56])=[CH:54][CH:53]=3)(=[O:50])=[O:51])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3c(B4OC(C)(C)C(C)(C)O4)c(C)ccc32)cc1
Reactant: CO[C@@H]1CCN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
Temperature: 100 °C

Procedure:
To a solution of (R)-6-benzyl-2-chloro-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.04 g, 12.6 mmol) in 1,4-dioxane (100 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole, Example 3, (6.16 g, 12.6 mmol), Pd(Ph3P)4 (2.18 g, 1.89 mmol) and a 2 M solution of sodium carbonate (18.9 mL, 37.7 mmol). The reaction mixture was heated at 100° C. under a nitrogen atmosphere for 16 h. The reaction mixture was then allowed to cool to rt and was diluted with EtOAc and water. The layers were mixed and then separated. The organic layer was washed with water and then brine. The separated organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was then purified via FCC (0-70% EtOAc/heptane) to give the title compound. MS (ESI+) m/z 665.6 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (65% yield). 1H NMR (400 MHz, CDCl3) δ 8.05, 7.98, 7.74, 7.27-7.24, 7.09-7.06, 7.00, 4.08-3.96, 3.94-3.68, 3.55, 3.36, 1.50, 0.79-0.69, 0.48-0.42, 0.11-0.09.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[CH:21]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=1>>[C:23]1([CH3:28])[CH:22]=[CH:21][C:26]([O:27][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(Oc2ccc(C(=O)Nc3ccccc3C(=O)O)cc2)cc1

Procedure:
In analogy to example 2,2-(4-p-Tolyloxy-benzoylamino)-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and p-cresol. MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:13][CH2:14][CH3:15])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[O:6].[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:16]=[O:17])[C:5]([N:7]([CH2:13][CH2:14][CH3:15])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[O:6]
Reactant: O=N[O-]
Reactant: CCCN(CC(O)CO)C(=O)NCCCl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCN(CC(O)CO)C(=O)N(CCCl)N=O
Yield: 50.5 %

Procedure:
3 g 1-(2-chloroethyl)-3-n-propyl-3-(2,3-dihydroxy-n-propyl)urea are dissolved in 10 ml of acetic acid, and 1.5 g of sodium nitrite are added thereto under stirring. The mixture is stirred at the same temperature for 4 hours. After the reaction, the mixture is treated in the same manner as described in Example 62-(2). 1.7 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-(2,3-dihydroxy-n-propyl)urea are thereby obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:17])[C:5]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][C:4]2[C:5]3[CH2:12][CH2:11][CH2:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1

Procedure:
The product from Example 59B (1.37 g, 6 mmol) was suspended in CH2Cl2 (100 mL), treated with TsCl (2.28 g, 12 mmol), treated with 4-dimethylaminopyridine (100 mg, 0.82 mmol), treated with triethylamine (2.2 mL. 16 mmol), and heated at reflux for 4 hours. The mixture was washed with H2O, dried (MgSO4), concentrated under reduced pressure and chromatographed on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound. 1H NMR (DMSO-d6) δ 1.99 (t, J=6.95 Hz, 2H), 2.23 (t, J=6.95 Hz, 2H), 2.45 (s, 3H), 2.47 (m, 2H), 6.91 (bs, 2H), 7.31 (m, 1H), 7.4 (m, 2H), 7.55 (dd, J=7.29, 1.87 Hz, 1H), 7.5 (d, J=8.48 Hz, 2H), 8.03 (d, J=8.14 Hz, 2H). MS (M+H)+ m/z 382.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].FC(F)(F)S(O[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22](=O)[CH3:23])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>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].CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[C:16](=[C:22]([CH3:23])[N:4]=[C:3]3[C:2]=2[CH:8]=[CH:7][CH:6]=[CH:5]3)[CH:17]=1
Reactant: CC(=O)c1cc(F)ccc1OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2c2ccc(F)cc12
Temperature: 85 °C
Yield: 27 %

Procedure:
1H NMR and TLC and no starting material was present (2-iodoaniline). 2-Acetyl-4-fluorophenyl trifluoromethanesulfonate (7.9 g, 28 mmol) was added to the reaction mixture, along with aqueous sodium carbonate (2 M, 61 mL, 122 mmol) and additional [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.0 g, 1.22 mmol) and N,N-dimethylformamide (50 mL). The reaction mixture was degassed several times and heated at 85° C. for 18 hours. The mixture was cooled to room temperature and poured into water (250 mL). The suspension was extracted with diethyl ether (2×250 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. Purification by column chromatography (1:4 ethyl acetate:hexane) gave the product as a pale yellow solid (1.33 g, 27% ).
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1.CON(C)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[CH:7]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
In a 2 L three-necked bottle flushed with N2, Mg (26.5 g, 1.1 mol) was warmed to 50° C., 1-bromo-3-chloro-5-fluorobenzene (157 g, 0.75 mol) solution in anhydrous THF (1 L) was added dropwise, then the mixture was stirred at r.t. for 2 hr. To a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (120 g, 0.441 mol) in anhydrous THF (1.1 L) at −78° C. under nitrogen was added dropwise the above Grignard reagent. The reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (163 g), which was used immediately without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1)#[N:21]
Reactant: N#Cc1ccccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-hydroxybenzonitrile (22 mg, 0.184 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-cyano-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (26 mg, 76%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.00 (br. s., 1H), 7.95 (d, J=8.2 Hz, 2H), 7.75 (dd, J=7.5, 1.5 Hz, 1H), 7.54-7.65 (m, 3H), 7.33 (d, J=8.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 5.37 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].N1C=CC=CC=1>O>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:21])[CH3:19]
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cc(=O)c3cccnc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (212 mg, 0.89 mmol), Ac2O (99 mg, 0.97 mmol), and pyridine (5 mL). The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The organic layer washed with water, dried and concentrated to afford 4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate (240 mg, 96%). MS (ES) m/z: 282.89 (M+1), 281.92 (M); Mp. 167-169° C.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>O>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1nc(C=O)n(C)n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: O
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(F)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1), where 2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl-2-methyl-propionitrile.from step 3 below, was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-Dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.49–1.69 (m, 8 H), 1.72 (s, 6 H), 2.06 (s, 3 H), 2.11 (s, 3 H), 2.12–2.13 (m, 2 H), 2.34–2.42 (m, 1H), 2.55–2.66 (m, 3H), 2.80 (d, J=17 Hz, 1 H), 3.42–3.65 (m, 2 H), 7.08–7.18 (m, 2 H), 7.35–7.40 (m, 1 H). Anal. Calcd. For C27H33FN4O3.0.25 H2O: C, 66.85; H, 6.96; N, 11.55; Found: C, 66.88; H, 6.99; N, 11.60. ESIMS (MH+): 481.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:10]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1NC(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc(F)cc2F)ccc1C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(2,4-difluorophenyl)-2-(4-fluorobenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 46 mg of 4-(2,4-difluorophenyl)-2-(4-fluorobenzamido)benzoic acid as white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=3[C:19]#[N:20])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[CH:33]1([C:37](O)=[O:38])[CH2:36][CH2:35][CH2:34]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:19]([C:18]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:17]=1[O:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:37]([CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:38])[CH2:3][CH2:4]2)[CH2:15][CH2:14]1)#[N:20]
Reactant: N#Cc1cc(F)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1OC1CCN(CCC2CCC(NC(=O)C3CCC3)CC2)CC1

Procedure:
The title compound was prepared analogously to example 1 (1.5) from Trans 2-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-5-fluoro-benzonitrile; trifluoro-acetic acid salt and cyclobutanecarboxylic acid using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate and N-ethyldiisopropylamine in dimethylformamide (DMF). The residue was taken up on methanol and purified with preparative HPLC on reversed phase eluting with acetonitrile/water. MS (m/e): 428.0. (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:22][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I, 5.0 g, 0.017 moles, 1.0 equivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1 equivalent) and DMF (100 mL) are mixed. To this heterogeneous mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 equivalent) and the contents are then stirred at 20-25° overnight. Once the reaction is complete as measured by HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed to stir for 1 hr. The contents are stirred for 30 min then cooled to 0° and filtered. The solids are washed with cold water (20 mL) and dried under reduced pressure to give the title compound.
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:14][O:13][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[Br:3])[CH2:10][CH2:9][CH2:8]2.[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13]
Reactant: O=C([O-])[O-]
Agent: Oc1cc2c(cc1Br)CCC2
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)CCC2
Temperature: 51 °C
Yield: 74 %

Procedure:
Four oven dried 40 mL vials with Teflon lined caps were used in parallel for the reaction. The sealed vials were used to avoid loss of MeI. Each of the the vials was loaded with a fourth of 6-bromoindan-5-ol (12.01 g, 56.36 mmol), K2CO3 (15.58 g, 112.72 mmol), DMF (147.5 mL) and MeI (14.03 mL, 225.45 mmol) respectfully. The vials were sealed and heated on the orbital shaker for a total of 11 hours at 51° C. The reactions in the four vials were combined, poured in water and extracted twice with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to give 12.6 grams of a crude yellow oil. The crude was purified using the in two batches (120 g columns, 5% ethyl acetate). Like fractions were combined to give 9.53 grams (74%) of 6-bromo-2,3-dihydro-1H-inden-5-yl methyl ether as a white solid and 2.29 grams (19%) of recovered 6-bromoindan-5-ol. IR (diffuse reflectance) 2958, 2468, 2428, 2415, 2350, 2337, 1482, 1466, 1392, 1311, 1278, 1260, 865, 835, 733 cm−1. Anal. Calcd for C10H11BrO: C, 52.89; H, 4.88; Br, 35.18. Found: C, 52.87; H, 4.79; N, 0.21. Found: Br, 35.27. X-Ray supports the structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.[C:15](O)(=[O:17])[CH3:16]>C(OC(=O)C)(=O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:5][N:6]=1
Reactant: Nc1ccc(Sc2cnc(N)s2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Sc2cnc(N)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 2-amino-5-(4-aminophenylthio)thiazole, (4.0 g) in a mixture of acetic acid (40 ml) and acetic anhydride (2.2 g) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-acetylaminophenylthio)thiazole (2.1 g, yield: 44.2%). mp: 240°-245° C. (dec.)
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@@H:15]([CH:16]([CH:18]=O)O)[O:14][C@@H:13]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CS(C)=O.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Si:3]([O:10][C@@H:11]1[C@@H:15]([CH:16]=[CH2:18])[O:14][C@@H:13]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:12]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C(O)C=O)O2)c(=O)[nH]c1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
A suspension of sodium hydride (60% in mineral oil, 2.88 g, 72 mmol) in anhydrous DMSO (100 ml) after stirring at 65° C. for 1.5 h under nitrogen was changed to a clear solution, which was cooled to room temperature and transferred to a cold, stirred suspension of methyltriphenylphosphonium bromide (27.0 g, 75.6 mmol) in DMSO (20 ml) under nitrogen. The reaction mixture was stirred at room temperature for 45 min. and a solution of 3′-O-t-butyldimethylsilyl-5′-formylthymidine (8.50 g, 24 mmol) in DMSO (40 ml) added with cooling. The reaction mixture was stirred at room temperature for 2 h, diluted with ethyl acetate (2 L), washed with brine (5×800 ml), dried (Na2SO4), concentrated. The crude was purified by chromatography on silica (EtOAc-hexane, 30:70) to give 6.79 g (80.2%) of 3′-O-t-butyldimethylsilyl-5′-deoxy-5′-methylidene-thymidine as a colorless solid, m.p. 122° (recrystalization from ethyl acetate and hexane).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:14][C:15]([NH:17]C(=O)C2C=CC=CC=2)=[S:16])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[N:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccnc(-c2sc(NC(=S)NC(=O)c3ccccc3)nc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccnc(-c2sc(NC(N)=S)nc2C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a suspension of N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-benzoylthiourea (700 mg) in methanol (7 ml) was added an aqueous sodium hydroxide solution (1N, 1.9 ml) dropwise. The mixture was stirred at 60° C. for 1 hour, cooled to ambient temperature, and the pH was adjusted to 8.0 with 1N hydrochloric acid. The mixture was diluted with water (50 ml) and stirred for 5 minutes. The precipitate was collected by filtration, washed with water and diisopropyl ether and dried under reduced pressure to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)thiourea (438 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:32]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49](O)=[O:50])=[O:38])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:50])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Yield: 65.8 %

Procedure:
The procedure of Example 77 was followed using the product of Example 106 (400.0 mg, 0.90 mmol), 1-[(tert-butyloxycarbonyl)methyl]indole-2-carboxylic acid (200 mg, 0.73 mmol), NMM (0.1 ml), HOBt (246 mg, 1.63 mmol), and EDAC (304 mg, 1.60 mmol) in methylene chloride to prepare the titled product (341 mg, 68%).