Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[CH:24]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[CH2:8]1)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product of Example 1E (26 mg, 0.09 mmole) in methanol (2 ml) was added acetone (132 μl, 1.8 mmole), and the mixture was stirred at room temperature for 1.5 hour. Sodium cyanoborohydride (28 mg, 0.44 mmole) was added and the mixture stirred overnight. The mixture was diluted with 2 ml 1N NaOH and extracted with dichloromethane (with 5% methanol) (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (elating with a mixture of 0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.63 (d, J=3.74 Hz, 4H) 7.50 (d, J=9.05 Hz, 2H) 6.64 (d, J=8.73 Hz, 2H) 4.16-4.22 (m, 1H) 3.48-3.55 (m, 1H) 3.31-3.38 (m, 1H) 2.90-3.01 (m, 2H) 2.74 (t, J=7.96 Hz, 1H) 2.46-2.52 (m, 2H) 2.31-2.39 (m, 1H) 2.10-2.20 (m, 1H) 1.90-1.99 (m, 1H) 1.06 (dd, J=6.24, 1.87 Hz, 6H); MS (M+H)+=332.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:4]([CH3:20])[N:3]=1.C(N(CC)CC)C.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:4]([CH3:20])[N:3]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: Cn1nc(N)c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(NC(=O)Cc2ccccc2)c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
338 mg of 3-amino-5-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole was dissolved in 20 ml of a tetrahydrofuran, followed by the addition of 140 mg of triethylamine. Then, 5 ml of a tetrahydrofuran solution containing 214 mg of phenylacetyl chloride was added dropwise thereto, followed by stirring at room temperature overnight. After the addition of water, the reaction mixture was extracted with chloroform. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 80 g of silica gel [with an elution solvent comprising chloroform-methanol (40:1)]. Thus, 310 mg (64% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.[CH3:19][CH:20]([CH:23]1[CH2:34][CH:33]=[CH:32][CH2:31][CH2:30][CH:29]=[CH:28][CH2:27][CH:26]([CH:35]([CH2:37][CH3:38])[CH3:36])[N:25]=[N:24]1)[CH2:21][CH3:22]>>[NH2:24][CH:23]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]([NH2:25])[CH:35]([CH3:36])[CH2:37][CH3:38])[CH:20]([CH3:19])[CH2:21][CH3:22]
Reactant: CCC(C)C1CC=CCCC=CCC(C(C)CC)N=N1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Product: CCC(C)C(N)CCCCCCCCC(N)C(C)CC
Yield: 84.7 %

Procedure:
The procedure described in (a) is repeated, starting from 87.3 g (0.31 mole) of 3,12-di-(2-butyl)-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) and using correspondingly reduced amounts of catalyst and solvent, affording as main fraction 74.7 g (85% of theory) of 4,13-diamino-3,14-dimethylhexadecane as a colourless oil [b.p. 143° to 145° C./0.05 torr; nD20 =1,4639; IR spectrum (liquid) includes bands at 3330, 1626 cm-1 ].
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]([CH3:19])=[C:11]2[S:12][CH2:13][CH2:14][CH2:15][N:10]2[C:9]1=[O:20])C1C=CC=CC=1.B(Br)(Br)Br.CO>C1(C)C=CC=CC=1>[CH3:19][C:16]1[C:17](=[O:18])[NH:8][C:9](=[O:20])[N:10]2[CH2:15][CH2:14][CH2:13][S:12][C:11]=12
Reactant: Cc1c2n(c(=O)n(Cc3ccccc3)c1=O)CCCS2
Agent: BrB(Br)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c2n(c(=O)[nH]c1=O)CCCS2
Reaction time: 0.5 h

Procedure:
To a solution of 7.21 g (25 mmol) of 7-benzyl-9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione in 200 ml of toluene, 12.5 g (50 mmol) of boron tribromide was added under ice cooling conditions, followed by refluxing for 16 hours. After the reaction mixture was cooled, 50 ml of methanol was added, followed by stirring for 30 minutes. After this mixture was concentrated to dryness, methanol-diethyl ether was added to the residue. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to yield 3.97 g (80.1%, light white crystal) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:18][CH:19]([O:25][CH:26]([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]=1[OH:8].[I:29]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[I:29][C:2]1[CH:3]=[C:4]([CH2:18][CH:19]([O:25][CH:26]([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]=1[OH:8]
Reactant: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(I)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
253 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was dissolved in 3 ml acetonitrile, and 157 mg of N-iodosuccinimide was added thereto. After stirring at room temperature for 2.5 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium thiosulfate, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 100 mg of ethyl 3-(3-iodo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was obtained from fractions eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:47]1([O:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[NH2:55])[CH2:51][CH2:50][CH2:49][CH2:48]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:55][C@@H:54]([CH2:56][C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:53]([O:52][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:63])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH3:34])[CH:28]=1
Reactant: Cc1cc(C(=O)c2ccc(=O)n(-c3c(F)cc(OCCCOS(C)(=O)=O)cc3F)c2N)ccc1F
Reactant: N[C@@H](Cc1ccccc1)C(=O)OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C(=O)c2ccc(=O)n(-c3c(F)cc(OCCCN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3F)c2N)ccc1F

Procedure:
From Intermediate 4D and L-phenylalanine cyclopentyl ester tosylate salt (Intermediate 16), LCMS purity 97%, m/z 648 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.20-1.90 (9H, m), 2.25 (2H, m), 2.35 (3H, s), 3.15 (1H, m), 3.45 (1H, m), 4.25 (2H, m), 4.40 (1H, d), 5.20 (2H, m), 5.82 (1H, d), 6.95 (2H, m), 7.20 (1H, m), 7.30-7.50 (7H, m), 7.75 (1H, d).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH3:14][O-:15].[Na+]>CO>[CH:8]([NH:7][C:5](=[O:6])[C:4]1[CH:11]=[CH:12][N:13]=[C:2]([O:15][CH3:14])[CH:3]=1)([CH3:10])[CH3:9]
Reactant: CC(C)NC(=O)c1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)NC(C)C)ccn1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
To a stirred solution of 19.44 g 2-chloro-N-isopropyl-isonicotinamide (97.86 mmol) as obtainable from example 12, in 165 mL methanol were added 27.82 g NaOMe (489.3 mmol, 5.0 eq) in four equal portions over 60 min. The solution was then heated to 80° C. and the reaction was monitored by HPLC. After 23 h (<2% area starting material 2-chloro-N-isopropyl-isonicotinamide), the mixture was cooled to room temperature and quenched by addition of 200 mL saturated aqueous NH4Cl. The product was extracted three times with 150 mL, in total 450 mL dichloromethane. The combined organic phases were dried over 40 g Na2SO4 (30 min) and filtered. The filter cake was washed with 80 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 22 mbar), the crude product (15.856 g, 83% w/w, HPLC purity 93.7% area) was obtained as a white solid.
Reaction SMILES: CSC1C=CNC(=O)N=1.[CH3:10][S:11][C:12]1[C:17]([Br:18])=[C:16](C)[NH:15][C:14](=[O:20])[N:13]=1.C(OC(=O)C)(=O)C.BrN1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:10][S:11][C:12]1[C:17]([Br:18])=[CH:16][NH:15][C:14](=[O:20])[N:13]=1
Reactant: CSc1nc(=O)[nH]c(C)c1Br
Agent: CSc1cc[nH]c(=O)n1
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSc1nc(=O)[nH]cc1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 28 %

Procedure:
4-Methylthiopyrimid-2-one (prepared as described in Wheller, L. H. and Johnson, B. T. J. Amer. Chem. Soc. 42 (1909) (30), (0.01 mol) was dissolved at ca. 80° C. in acetic acid (30 ml) containing 2% acetic anhydride. The temperature was lowered to ca. 55° C. and N-bromosuccinimide (0.013 mol) added and the reaction mixture stirred at this temperature for 40 min. Ice-cold water (150 ml) containing a little sodium bisulphite was then added and the precipitated collected and recrystallised from water; yield 28%, m.p. 260° C.;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.N1C=CC=C[CH:34]=1.C1COCC1>ClCCCl>[CH3:34][C:19]1[N:18]=[C:17]([NH:20][C:21]([NH:23][C:24](=[O:32])[CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])[CH:16]=[CH:15][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:12]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)CC4CCOCC4)nc3)ccn2)cn1
Reactant: c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)NC(=O)CC2CCOCC2)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A solution of crude 2-(tetrahydro-2H-pyran-4-yl)acetyl isocyanate (0.110 g, 0.650 mmol, see Example 4) in DCE (7 mL) was treated with Example A6 (0.183 g, 0.650 mmol) and stirred at RT overnight. Pyridine (0.11 mL, 1.3 mmol) was added, the mixture stirred at RT for 4 h, treated with THF, then washed with satd. NaHCO3 and brine, dried over MgSO4 and concentrated to dryness. The resulting material was treated with MeCN, and the solid collected via filtration and dried to afford N-((6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide (56 mg, 19%) as a pale tan solid. MS (ESI) m/z: 451.2 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH3:18][O:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][CH2:29][CH3:30])[C:22]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[C:23]([CH2:28][CH2:29][CH3:30])[C:22]=1[OH:31]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCCc2cccc(OC)c2OC)ccc(C(=O)OC)c1O
Yield: 82.9 %

Procedure:
A mixture of 29.2 g (0.097 mol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 18.5 g (0.088 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 18.2 g (0.13 mol) of anhydrous potassium carbonate and 21.9 g (0.13 mol) of potassium iodide in 550 mL of anhydrous acetone was stirred at reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 8% ethyl acetate-hexane to give 31.4 g (83% yield) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.
Reaction SMILES: C[O:2][C:3]1([O:50]C)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[C:17]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[C:23]([O:31]C)([O:29]C)[C:22]5=[O:33])[CH:16]=[C:15]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[C:39](=[O:43])[C:38]([O:46]C)([O:44]C)[C:37]5=[O:48])[CH:14]=3)[CH:9]=2)[C:4]1=[O:49].C(O)(=O)C.Br>O>[OH:31][C:23]1([OH:29])[C:22](=[O:33])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]3[CH:16]=[C:15]([C:34]4[CH:35]=[C:36]5[C:40](=[CH:41][CH:42]=4)[C:39](=[O:43])[C:38]([OH:46])([OH:44])[C:37]5=[O:48])[CH:14]=[C:13]([C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[C:4](=[O:49])[C:3]([OH:50])([OH:2])[C:11]5=[O:12])[CH:18]=3)[CH:20]=2)[C:24]1=[O:28]
Reactant: COC1(OC)C(=O)c2ccc(-c3cc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)cc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)c3)cc2C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(-c3cc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)cc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)c3)cc2C(=O)C1(O)O
Temperature: 110 °C
Yield: 87.3 %

Procedure:
1,3,5-tris(2,2-dimethoxy-1,3-dioxoindan-5-yl)benzene (26) (101 mg, 0.146 mmol) was suspended in a solvent mixture of 2 ml of acetic acid and 2 ml of water, and the suspension was mixed with 2 ml of 47% hydrobromic acid. The mixture was refluxed at 110° C. for 1.5 hours. After it was cooled to room temperature, the reaction solution was diluted with water, and the resulting solid was filtered and dried, to obtain 77.3 mg (87%) of 1,3,5-tris(2,2-dihydroxy-1,3-dioxoindan-5-yl)benzene (27) in the form of a gray solid. The readings for this compound are as follows.
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=[CH:2]1.C1(C(OC)=O)CCC(C(OC)=O)CC=1.C(Cl)Cl>[Pd].C(O)C>[CH:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][CH:1]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)C1C=CC(C(=O)OC)CC1
Agent: [Pd]
Agent: COC(=O)C1=CCC(C(=O)OC)CC1
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)C1CCC(C(=O)OC)CC1

Procedure:
A solution of dimethyl cyclohex-2-ene-1,4-dicarboxylate and dimethyl cyclohex-1-ene-1,4-dicarboxylate is hydrogenated under balloon pressure at room temperature over Pd/C catalyst. If methylene chloride is used as the solvent, primarily the 2-ene tautomer is reduced, whereas most of the 1-ene tautomer remains unreacted. If ethanol is used as the solvent both tautomers are reduced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13](B(O)O)[C:14]([F:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O=O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:10][C:11]1[CH:12]=[C:13](/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:14]([F:17])=[N:15][CH:16]=1
Reactant: C=Cc1cccc(F)c1
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Fc1cccc(/C=C/c2cc(Br)cnc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round bottom flask was added 1-fluoro-3-vinylbenzene (1.2 g, 9.82 mmol), 5-bromo-2-fluoropyridin-3-ylboronic acid (3.24 g, 14.74 mmol), and Sodium carbonate (2.60 g, 24.56 mmol) in dimethylformamide (32.7 ml). The reaction vessel was sealed and purged with oxygen via a balloon for 5 min. After purging with oxygen, palladium (II) acetate (0.221 g, 0.982 mmol) added and immediately purged with oxygen for (15 min.). The reaction was kept under a blanket of oxygen and left to stir overnight at room temperature. The reaction was then quenched with water and extracted with ethylacetate (3×). The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude oil was loaded onto 90 g silica gel cartridge and the product was eluted with 5% DCM/Hex. The product fractions were collected and concentrated to afford 0.712 g (22%) as an off white crystalline solid. 1H-NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 8.09 (dd, J=8.5, 2.3, 1H), 7.42-7.29 (m, 2H), 7.27-7.17 (m, 2H), 7.11-7.01 (m, 2H), LC/Mass spec. (Analytical HPLC method 2): RT=2.88 min. Mass=296.01 (MH)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCCl

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 120 ml of methylisobutylketone, 3.5 g of potassium carbonate, and 3.2 ml of 1-bromo-5-chloropentane, a reaction similar to that conducted in Example 106 was carried out. As a result, 5.86 g of N-(trans-4-methylcyclohexyl)-4-(5-chloropentyloxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:80][C:81]1[CH:87]=[CH:86][C:84]([NH2:85])=[CH:83][CH:82]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:80][C:81]1[CH:87]=[CH:86][C:84]([NH:85][C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]2)=[O:13])=[CH:22][CH:21]=3)=[O:25])=[CH:83][CH:82]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-fluoroaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a yellow solid (43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13]O>>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[CH3:13]
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CCO
Product: CCOC(=O)Cc1cccc(N)c1

Procedure:
3-Aminophenylacetic acid (2 g, 13 mmol) was esterified with EtOH using Method B to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][O:80][CH2:79][CH2:78]5)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0136 g (0.135 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0349 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(tetrahydro-pyran-4-yl)-benzamide (I-197).
Reaction SMILES: CC([C@]1(O)[C@@]2(C)[C@]3(O)[C@]45O[C@@]2(O)C[C@@](C)([C@@]4(O)CCC([C@H]5[OH:19])=C)[C@]3(O)[C@@H]1OC(C1NC=CC=1)=O)C.IC1C=CC(C(NCCC(O)=O)=O)=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:65]1([N:71]=[C:72]=[N:73][CH:74]2[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]2)[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O1CCCC1.O>[C:72]([NH:71][CH:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1)([NH:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)=[O:19]
Reactant: C=C1CC[C@]2(O)[C@]3(C)C[C@]4(O)O[C@@]2([C@@H]1O)[C@]1(O)[C@@]3(O)[C@H](OC(=O)c2ccc[nH]2)[C@](O)(C(C)C)[C@@]14C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CCNC(=O)c1ccc(I)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dehydroryanodine (100 mg, 0.2 mmol), N-(p-iodobenzoyl)-β-alanine (50 mg, 0.22 mmol) and DMAP (2 mg, 0.02 mmol), all dried over P2O5, were dissolved in a solvent mixture of CH2Cl2 (10 ml) and tetrahydrofuran (0.1 ml) dried over Molecular Sieve. To the stirred solution, dicyclohexylcarbodiimide (DCC, 52 mg., 0.25 mmol) was added at once and the stirred reaction maintained at room temperature for 6 hours. Water (0.1 ml) was added to inactivate excess DCC and stirring was continued for 30 minutes. The crystals of dicyclohexylurea thus formed were filtered off and washed twice with CH2Cl2.