Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[C:7]([C:20]([OH:22])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1>CN(C)C=O>[CH2:1]([C:5]1[S:9][C:8]2[N:10]=[C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[O:19])=[CH:15][N:16]3[C:20](=[O:22])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1cc(C(=O)O)c(Nc2ccc(C(=O)O)cn2)s1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 104 °C

Procedure:
A mixture of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid (Example 39), 3.2 g (0.01 mol) and 9.93 g (0.06 mol) of 1, 11 -carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide is heated in a wax bath under a nitrogen atmosphere with stirring at 100 to 108° C. for seventy minutes, cooled and stirred at room temperature for one hour. To the previous mixture is added 5-aminotetrazole monohydrate (Aldrich Chemical Company), 2.06 g (0.02 mol) and the mixture is heated at 100°-108° C. for ninety minutes. The solvent is evaporated and the residue dissolved in dimethylformamide, filtered, cooled and the precipitate collected and washed with methanol to give 1.2 g of 2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 293° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[C:19]=2[CH2:24][CH2:25]OS(C)(=O)=O)=[CH:14][CH:13]=1>CCO.CCOC(C)=O.O>[CH2:1]([S:8][CH2:25][CH2:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCOS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1CCSCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Benzyl mercaptan (0.06 mL, 0.45 mmol) and sodium hydroxide (0.030 g, 0.76 mmol) were combined in EtOH. Methanesulfonic acid 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]ethyl ester (0.161 g, 0.45 mmol) was added and the reaction was stirred at 70° C. for 2 hours. The mixture was diluted with EtOAc and H2O and separated. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.C([NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1)(=[O:36])=[O:35])(C)(C)C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:40]3[CH:41]=[CH:42][C:37]([S:34]([NH2:33])(=[O:36])=[O:35])=[N:38][CH:39]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1

Procedure:
Compound 31b was subjected to Suzuki coupling reaction conditions with compound 32b using the methods described in Example 1, Step G, and the resulting product was subjected to TFA deprotection using the methods described in Example 1, Step E, to obtain title compound 86. 1H-NMR (400 MHz, CD3OD) δ (ppm): 8.85 (s, 1H), 8.08-8.15 (m, 2H), 8.03 (d, J=9.0 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.59-7.65 (m, 1H), 7.43 (s, 1H), 7.35-7.41 (m, 2H), 6.95 (d, J=9.0 Hz, 1H), 5.64 (s, 2H), 4.32 (br. s., 4H), 3.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H23N7O4S: 518.1 (M+H). Found 518.2.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17][CH3:18])=[O:16].C(O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].CO>C(O)(C)C>[CH:6]1[C:5]2[C:10](=[CH:1][C:2]([C:15]([O:17][CH2:18][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:16])=[CH:3][CH:4]=2)[CH:9]=[CH:8][C:7]=1[C:11]([O:13][CH2:14][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:12]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: CO
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc2cc(C(=O)OCCCCCCCCCCCCCCCCCC)ccc2c1
Temperature: 160 °C
Yield: 85.8 %

Procedure:
To a 3 neck 100 mL round bottomed flask equipped with a Dean Stark trap and condenser, thermocouple and argon inlet was added dimethyl naphthalene-2,6-dicarboxylate (10 grams, 40.94 mmoles, available from Sigma Aldrich),stearyl alcohol (22.15 grams, 81.89 mmoles, available from Spectrum Chemical), Fascat 4100 (0.03 grams, 0.1 wt %, available from Arkema Inc) and Xylenes (50 ml, available from Sigma Aldrich). The mixture was slowly heated under argon to 160° C. during which reagents melted/dissolved. The temperature was raised to 180° C. The reaction mixture was stirred at 180° C. overnight (˜20 hours) during which 46 mL of a mixture of xylenes and methanol was collected. Vacuum was applied (1-2 mm-Hg) for about 10 minutes during which an additional 5 mL of a mixture of Xylenes and methanol was collected. The solution was cooled under argon to about 140° C. and discharged in an aluminum tray where it was allowed to cool to room temperature to give product as an off-white solid. The product was transferred to a 1 L Erlenmeyer flask, about 100 mL of isopropyl alcohol was added, heated to about 100° C. during which product dissolved. The solution was cooled to room temperature during which product crystallized out, filtered and dried on a vacuum pump overnight to give 25.33 grams product as an off-white solid (86% yield). The product was shown to be pure by 1H NMR with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2 above. The FIGURE shows the rheological profile.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][CH:13]=[CH:12][C:11]1=[O:16].C1(CNCC2CCCCC2)CCCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:8][C:3]1[C:2]([C:13]2[CH2:14][CH2:15][N:10]([CH3:9])[C:11](=[O:16])[CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: CN1CCC=CC1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: CN1CCC(c2cccnc2F)=CC1=O
Temperature: 100 °C
Yield: 12.3 %

Procedure:
Into a sealed tube were placed 3-bromo-2-fluoropyridine (0.106 g, 0.602 mmol), 1-methyl-5,6-dihydropyridin-2(1H)-one (0.134 g, 1.205 mmol), bis(tri-tert-butylphosphine)palladium (0) (0.046 g, 0.090 mmol), N,N-dicyclohexylmethylamine (0.129 mL, 0.663 mmol), and 1,4-dioxane (0.5 mL). After the mixture was degassed for 5 min, the reaction was heated at 100° C. for 3 h. The cooled reaction was concentrated in vacuo, and the brown residue was directly purified via flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) to give 4-(2-fluoropyridin-3-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one (0.0153 g, 12.32% yield) as a tan solid. [M+1]=207.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][OH:16])=[C:13]([CH:17]([CH3:19])[CH3:18])[O:12][N:11]=1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:31]=[CH:30]3)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][O:16][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:31]=[CH:30]4)=[CH:25][CH:26]=2)=[C:13]([CH:17]([CH3:19])[CH3:18])[O:12][N:11]=1
Reactant: CC(C)c1onc(Cc2c(Cl)cccc2Cl)c1CO
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(Cc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A solution of [3-[(2,6-dichlorophenyl)methyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.105 g, 0.35 mmol), ethyl 6-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.102 g, 0.35 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and diisopropyl azodicarboxylate (0.063 mL, 0.35 mmol) in toluene (3.5 mL) was placed in microwave reaction tube and heated to 80° C. for 500 seconds. The solution was concentrated and purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes) to provide the title compound (0.126 g, 60.9% as 0.2 EtOAc). 1H NMR (DMSO-d6): 8.79 (d, J=9 Hz, 1H), 8.28 (d, J=2 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.09 (d, J=7 Hz, 1H), 7.98 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 7.61 (t, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 2H), 7.32 (t, J=8 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 5.08 (s, 2 H), 4.40 (q, J=7 Hz, 2 H), 4.29 (s, 2 H), 3.34 (septet, J=7 Hz, overlapping H2O 1 H), 1.37 (t, J=7 Hz, 3 H), 1.22 (d, J=7 Hz, 6 H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>CN(C=O)C.C(OCC)(=O)C.Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 38 %

Procedure:
4-Aminophenol (1.9 g, 17 mmol) was diluted with DMF (40 mL) followed by the addition of pyridine (0.978) (1.4 mL, 17 mmol) and 3,4-dichlorobenzoyl chloride (3.0 g, 14 mmol) in 5 mL of DMF. After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The aqueous layer was extracted once with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, filtered and concentrated onto silica gel. The material was purified using a biotage 40M column eluting with hexanes:ethyl acetate (9:1) using 2 L and then (60:40) 1 L to yield 3,4-dichloro-N-(4-hydroxyphenyl)-benzamide (1.5 g, 37% yield) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=1>>[C:18]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Product: O=C(/C=C/c1ccc(-c2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 3-biphenyl-4-yl-acrylic acid were processed as described in Example 17 to provide the title compound. MS (DCI/NH3) MS m/z 437 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 1.99 (m, 2 H), 3.06 (m, 2 H), 3.53 (m, 2 H), 3.72 (m, 2 H), 4.76 (t, J=5.93 Hz, 2 H), 6.91 (m, 1 H), 7.40 (m, 1 H), 7.50 (m, 2 H), 7.64 (m, 2 H), 7.75 (m, 7 H), 8.18 (s, 1 H), 8.31 (s, 1 H), 9.56 (br s, N H)
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH3:18].OS(O)(=O)=O.B(O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@H:7]([CH3:11])[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])=[CH:12][CH:13]=1
Reactant: CCCCCO
Reactant: C[C@@H](Oc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)[C@@H](C)Oc1ccc(O)cc1
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of the (R)-2-(4-hydroxyphenoxy)propionic acid (11 mmole) in toluene (30 ml), 1-pentanol (30 mmole), 98% H2SO4 (0.2 ml) and boric acid (0.1 g) was heated to reflux and water removed by azeotropic distillation on a Dean & Stark apparatus. After 3 hours the excess toluene was allowed to distil. The residue was allowed to cool and diluted with dichloromethane, washed with dilue HCl, water and saturated NaHCO3 solution, dried (MgSO4) and the crude product isolated by evaporation. This was distilled (Kugelrohr b.p. 150°-60° C. at 0.05 mbar) to give PHPP (yield 57%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:33]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[C:6]=1[CH3:39])=[O:4].[OH-].[Li+]>CO.O.C(Cl)Cl.O>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[C:6]([CH3:39])=[C:5]([C:3]([OH:4])=[O:2])[N:33]([CH:34]5[CH2:35][CH2:36][CH2:37][CH2:38]5)[C:8]=4[N:9]=3)=[N:15][CH:16]=2)[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a suspension of 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (250 mg, 0.467 mmol) (prepared as described in the procedure for the synthesis of Example 384), in MeOH/H2O/DCM (70 mL) is added a solution of lithium hydroxide (39.2 mg, 0.93 mmol) in water (15 mL). The reaction mixture is heated to reflux for 4 hours. The reaction mixture is allowed to cool to room temperature and concentrated in vacuo. The resulting solution is acidified to pH˜3 using saturated aqueous citric acid solution. The solution is evaporated and the residue is purified by preparative HPLC to give 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a yellow solid (105 mg, 53%). [M+H]+=522.3
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][N:25](C)[CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1.C(N(CC)CC)C.C>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:23][CH2:24][N:25]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:26][CH2:27]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:29]=1
Reactant: CN1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=C2c3ccc(F)cc3CCc3cccnc32)CC1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Ethyl chloroformate (8.5 mL, 9.65 g, 0.089 mole) is slowly added at 80° C. to a solution of 8-fluoro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5.4 g, 0.0175 mole) and triethylamine (3.6 mL, 2.61 g, 0.026 mole) in 60 mL of toluene. Following complete addition, the temperature is maintained at 80° C. for 1 hour. The reaction mixture is treated with charcoal, filtered, and concentrated to a residue. Following purification by silica gel chromatography and crystallization from pentane, 4.10 g (0.011 mole) of 8-fluoro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[-1,2-b]pyridine is obtained in 63% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](=O)[CH3:19])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[CH:18]([NH2:27])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(C(C)N)n(-c2cccc(F)c2)c2ccccc12
Temperature: 65 °C
Yield: 96.6 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-3-methyl-1H-indol-2-yl]ethanone (0.165 g, 0.617 mmol) and ammonium acetate (0.476 g, 6.17 mmol) in methanol (2.0 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.12 g, 1.9 mmol) was added to the resultant mixture. The reaction was heated at 65° C. over the weekend. The reaction was cooled to room temperature and quenched with saturated NaHCO3 solution and then extracted with dichloromethane, dried over MgSO4 and concentrated to give the crude amine (0.16 g), which was used directly in next step. LCMS calculated for C17H18FN2(M+H)+: m/z=269.1. Found: 252.1.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[CH2:26][C:27](OCC)=[O:28])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[CH2:26][C:27]([NH:10][C:9]([NH2:11])=[NH:8])=[O:28])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 40 h
Yield: 57.3 %

Procedure:
(−)-N-[(2-Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-y)acetyl]guanidine is prepared as described in Example 1, starting with 2.6 g of potassium tert-butoxide, 2.6 g of guanidinium chloride and 1.25 g of ethyl (−)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-y)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 40 hours and is then filtered. The filtrate is taken up in 80 cm3 of water and 120 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted with twice 120 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 40° C. The evaporation residue is taken up in 30 cm3 of diethyl ether and the precipitate formed is filtered off and then washed three times with 5 cm3 of diethyl ether. The solid is dried under reduced pressure (10 Pa) at a temperature in the region of 45° C. 0.75 g of (−)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of an off-white solid melting at 264° C. (αD20=−10.2°±0.6 in methanol at 0.5%). Mass spectrum EI: m/e 288 (M+), m/e 245, m/e 201, m/e 132.
Reaction SMILES: C([O-])(=O)C.[CH3:5][NH3+:6].[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12](F)[C:9]=1[C:10]#[N:11]>CNC=O>[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:6][CH3:5])[C:9]=1[C:10]#[N:11]
Reactant: C[NH3+]
Reactant: N#Cc1c(N)cccc1F
Agent: CC(=O)[O-]
Solvent: CNC=O
Product: CNc1cccc(N)c1C#N

Procedure:
The title compound is prepared by heating a 10 molar excess of methylammonium acetate and 2-amino-6-fluorobenzonitrile in N-methyl formamide at 140° C. for 5 hrs.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:17])=[CH:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.[OH-].[K+].O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:17])=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C(C)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 16.6 g. of ethyl 3-(4-nitrophenyl)-2-butenoate, 75 ml. of ethanol and 94.7 ml. of 1.5 N potassium hydroxide was heated on a steam bath for 70 minutes, and then it was cooled to room temperature. To the reaction mixture was added 200 ml. of water and 200 ml. of ethyl acetate. The aqueous phase was recovered and acidified with concentrated hydrochloric acid, and then the solid was recovered by filtration. This latter solid was recrystallized from aqueous ethanol to give 9.8 g. (67% yield) of the title compound, m.p. 167°-169° C.
Reaction SMILES: C(OC(=O)[NH:5][CH2:6][CH:7]1[C:10]2=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=[C:9]2[CH2:8]1)C.O.[OH-].[Na+]>O1CCCC1>[O:14]1[C:13]2[CH:17]=[C:9]3[CH2:8][CH:7]([CH2:6][NH2:5])[C:10]3=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: CCOC(=O)NCC1Cc2cc3c(cc21)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCC1Cc2cc3c(cc21)OCO3
Reaction time: 2 h
Yield: 45.1 %

Procedure:
7.5 g (30 mmoles) of the product of Step 1 are dissolved in 15 mL of anhydrous tetrahydrofuran. The solution is poured dropwise into a suspension comprising 1.48 g (1.3 equivalents) of AlLiH4 suspended in 38 mL of anhydrous tetrahydrofuran. Stirring is carried out at 25° C. for 2 hours. The mixture is hydrolysed in the cold state using 2.7 mL of water, 2.7 mL of NaOH (20%) and then 2.7 mL of water. Filtration and evaporation of the filtrate to dryness are carried out. There are obtained 2.4 g of a residue which is purified by column chromatography over silica (eluant: CH2Cl2/ethanol/NH4OH: 95/5/0.5. The expected product is obtained in the form of a brown oil.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[CH2:17][C:16]=2[CH:32]=1
Reactant: CCOC(=O)CC1Cc2ccc(CCCCOC3CCCCO3)cc2Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1Cc2ccc(CCCCO)cc2Cc2ccccc21
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-[4-(2-tetrahydropyranyloxy)-1-butyl]-5H-dibenzo[a,d]cycloheptene-10-acetate (456.0 mg, 1.04 mmole) and p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmole) in absolute EtOH (10 mL) was stirred at RT. After 2 hr, the reaction was quenched with 5% NaHCO3 (1 mL) and concentrated to remove the EtOH. The residue was diluted with H2O (2 mL) and extracted with CH2Cl2. Drying (MgSO4), concentration, and silica gel chromatography (1:1 EtOAc/hexanes) gave the title compound (342.4 mg, 93%) as a colorless oil: TLC (1:1 EtOAc/hexanes) Rf0.49; 1H NMR (250 MHz, CDCl3) δ6.85-7.25 (m, 7 H), 4.34 (d, J=15.1 Hz, 1 H), 4.08-4.30 (m, 2 H), 3.75-3.95 (m, 2 H), 3.53-3.72 (m, 2 H), 3.33 (dd, J=15.1, 4.1 Hz, 1 H), 2.95 (dd, J=15.1, 9.4 Hz, 1 H), 2.40-2.75 (m, 4 H), 1.45-1.80 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 353 (M+H)+.