Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13]C3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH2:11]([C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]2[N:8]=1)[CH3:13]
Reactant: C1COCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCOCC3)n2n1
Temperature: 25 °C
Yield: 50 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and morpholine (36 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAC to give the titled compound (43 mg, 50% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.87 (s, 2H), 8.05-7.92 (m, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 6.19 (s, 1H), 5.18 (s, 1H), 3.91-3.79 (m, 4H), 3.77-3.69 (m, 4H), 2.74 (q, J=7.6 Hz, 2H), 1.45 (s, 6H), 1.35-1.23 (m, 3H); ESI-MS: m/z 410 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (31 mg, 0.2 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (5 mg, 10%). 1H-NMR (MeOD): 1.69 (m, 2.5H), 2.01 (m, 3H), 2.51 (m, 1H), 2.72 (m, 1H), 3.42 (d, 2H), 3.52 (m, 3H), 3.90 (m, 2H), 4.15 (m, 1.5H), 7.02 (d, 1H), 7.59 (t, 1H), 7.68 (m, 2H), 7.94 (m, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CO[C:10](=[O:30])[CH:11]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)=O>N1C=CC=CC=1>[CH3:21][S:20][C:16]1[N:15]=[C:14]([C:12]2[N:4]3[CH2:5][CH2:6][CH2:7][N:3]3[C:10](=[O:30])[C:11]=2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:19]=[CH:18][N:17]=1
Reactant: C1CNNC1
Reactant: COC(=O)C(Oc1ccccc1C)C(=O)c1ccnc(SC)n1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(Oc3ccccc3C)c(=O)n3n2CCC3)n1
Temperature: 110 °C
Yield: 10 %

Procedure:
To a solution of pyrazolidine-bishydrochloride (1.7 g, 11.6 mmol) in pyridine (30 mL) was added 3-(2-Methylsulfanyl-pyrimidin-4-yl)-3-oxo-2-ortho-tolyloxy-propionic acid methyl ester, 1, (2.0 g, 5.78 mmol). The reaction mixture is heated to 110° C. for 18 h. The solvent is removed in vacuo and the resulting residue is purified by silica gel chromatography (10% MeOH/EtOAc, followed by 20% MeOH/EtOAc) to afford 220 mg (10%) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.4 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.10 (dd, J=7.5, 7.5 Hz, 1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 4.22 (t, J=6.6 Hz, 2H), 4.05 (t, J=6.9 Hz, 2H), 2.72 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H), 2.48 (s, 3H); ESI+ MS: m/z (rel intensity) 355.0 (100, M++H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:21](=O)[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>CC(O)C>[C:22]([C:21]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH3:20])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C(Cl)C(=O)C(C)(C)C
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C(C)(C)C
Yield: 77.1 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B(v), methyl 2-chloro-4,4-dimethyl-3-oxopentanoate (950 mg, 4.9 mmol) produced above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11-B (vi), the title compound (330 mg, 76%) was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C>[O:1]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc[nH]c2c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.6 %

Procedure:
A mixture of 5.5 g 6-hydroxyindole, 7.47 g tert-butyldimethylsilyl chloride, 7.03 g imidazole, and 25 mL dimethylformamide is stirred at ambient temperature for 20 h. The reaction is diluted with ethyl acetate, washed with water (2×), dried (MgSO4), and the solvent removed under reduced pressure to provide an oil. The oil is chromatographed, eluting with ethyl acetate/heptane, to afford 9.05 g (88%) of 6-(tert-butyldimethylsiloxy)-1H-indole as a white solid: TLC Rf 0.4 (silica, 1:9 ethyl acetate/heptane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH2:21])(=[O:11])=[O:10].Cl.[N:27]1([C:32](N)=[NH:33])C=CC=N1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:16][CH2:17][CH2:18][CH2:19][O:20][NH:21][C:32]([NH2:33])=[NH:27])(=[O:11])=[O:10]
Reactant: N=C(N)n1cccn1
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCON)c1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propoxyamine (74 mg, 0.20 mmol, prepared in the preceding step) and 1H-pyrazole-1-carboxamidine hydrochloride (60 mg, 0.41 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at ambient temperature overnight. Additional 1H-pyrazole-1-carboxamidine hydrochloride (30 mg, 0.20 mmol) was added, and the reaction was stirred at ambient temperature for 3 days. N,N-Dimethylformamide was removed in vacuo, then the residue was treated with acetonitrile. The mixture was filtered to remove excess 1H-pyrazole-1-carboxamidine hydrochloride, and the filtrate was concentrated in vacuo. The residual oil was partitioned between diethyl ether (10 mL) and water (10 mL). The aqueous layer was washed with diethyl ether (2×10 mL), adjusted to pH 8 with 2N NaOH, and extracted with ethyl acetate (2×10 mL). The ethyl acetate extracts were washed with pH 7 buffer (2×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and evaporated to give the title compound (64 mg, 78%) as a colorless oil. 1H-NMR (300 MHz, DMSO-d6) δ7.76 (ddd, 1H, J=8.4, 7.4, 1.8 Hz), 7.69 (dd, 1H, J=7.9, 1.6 Hz), 7.37 (d, 1H, J=7.7 Hz), 7.09 (dt, 1H, J=7.9, 1.0 Hz), 6.69 (s, 1H), 6.47 (s, 1H), 6.33 (t, 1H, J=2.1 Hz), 4.00 (s, 3H), 3.92 (t, 2H, J=6.5 Hz), 3.70 (t, 2H, J=6.1 Hz), 2.20 (s, 3H), 1.88 (pentet, 2H, J=6.3 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H23N3O6S: 410.1 (M+H), 432.1 (M+Na). Found: 410.1, 432.6.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[C:24]([Cl:27])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[NH4+]>O1CCOCC1.O>[Cl:27][C:24]1[S:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:18]=2[C:25]=1[CH3:26]
Reactant: Cc1c(Cl)sc2ncnc(Cl)c12
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(Cl)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 25 °C
Yield: 11.3 %

Procedure:
4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.057 g, 0.27 mmol), 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (0.06 g, 0.27 mmol, CA56844-14-5) and para-toluene sulfonic acid (0.005 g, 0.03 mmol) were heated at 90° C. in anhydrous 1,4-dioxane (1.5 mL) for 18 hours. The solution was cooled to ambient temperature, diluted with water (2 mL) and adjusted to pH 10 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as yellow solid (0.012 g, 11%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39](=[O:45])[CH2:40][CH2:41][C:42](O)=[O:43].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:42]([O:35][C@@H:20]1[C:21]([CH3:34])=[CH:22][C@@H:23]2[C@:28]([OH:29])([C@H:27]([CH3:30])[CH2:26][CH2:25][C@@H:24]2[C:31]([CH3:33])=[CH2:32])[C@H:19]1[O:18][C:16]([C@H:14]1[NH:13][C@@H:8]2[O:9][N:10]([CH3:12])[C:11]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C@:7]2([OH:36])[CH2:15]1)=[O:17])(=[O:43])[CH2:41][CH2:40][C:39]([O:38][CH3:37])=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: COC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)[C@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)CCC(=O)OC)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reaction time: 18 h
Yield: 19.1 %

Procedure:
A mixture of (1S,2R,4aS,5R,8R,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 139, 100 mg, 0.19 mmol), commercially available 4-(methyloxy)-4-oxobutanoic acid (50 mg, 0.38 mmol), 4-dimethylaminopyridine (60 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.58 mmol) and dichloromethane (5 ml) was stirred for 18 h and the reaction mixture concentrated in vacuo. The crude product was purified by chromatography on a Biotage® 12M column eluting with dichloromethane:diethyl ether (4:1). The pure fractions were combined and the solvent removed in vacuo to give the title product (23 mg, 18%).
Reaction SMILES: [NH:1]1[C:10](=O)C2NC=NC=2N[C:2]1=O.O=P(Cl)(Cl)Cl.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[C:20](Cl)[N:19]=1.CNC>>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][NH:24]2)=[C:20]([N:1]([CH3:10])[CH3:2])[N:19]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: CNC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1nc(Cl)nc2[nH]cnc12

Procedure:
Xanthine (2,6-dihydroxy-9H-purine) is converted by reaction with phosphorus oxytrichloride in accordance with G. B. Elion and G. H. Hitchings, J. Am. Chem. Soc. 78, 3508 (1956) into the 2,6-dichloro-9H-purine and the latter is reacted with N,N-dimethylamine in accordance with J. A. Montgomery and L. B. Holum, J. Am. Chem. Soc. 80, 404 (1958) to form 2-chloro-6-(N,N-dimethylamino)-9H-purine.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].Br[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1>CN1C(=O)CCC1>[C:3]([CH:5]([C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:4]
Reactant: COC(=O)CC#N
Reactant: Clc1cnc(Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C(C#N)c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
NMP (7 mL) was added to a round bottom, placed under nitrogen and cooled to 0° C. NaH (1.16 g, 29.1 mmol) was added portionwise followed by the addition of methyl cyanoacetate (1.31 ml, 14.5 mmol) (in 3 mL of NMP) dropwise. After stirring for 30 minutes at 0° C., 2-bromo-3,5-dichloropyridine (3.0 g, 13.2 mmol) was added and the reaction was heated to 130° C. for 5 hours. The reaction was allowed to cool, poured into ice and extracted twice with ethyl acetate. The ethyl acetate was combined, dried over MgSO4, filtered and concentrated. The amorphous material was crystallized from methanol to afford the desired compound (700 mg, 2.86 mmol, 21.6% yield) as light brown needles.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>>[OH:13][C@@H:12]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:11]1[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-chlorobenzaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-chlorophenyl)methylphosphonate as a final product in a yield of 90%. The chemical reaction in this Example is shown in chemical formula 28.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:15])([F:14])[C:8]([OH:13])([CH2:11][CH3:12])[C:9]#[N:10].[OH2:16]>C(OCC)C>[F:6][C:7]([F:15])([F:14])[C:8]([OH:13])([CH2:11][CH3:12])[C:9]([NH2:10])=[O:16]
Reactant: CCC(O)(C#N)C(F)(F)F
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCC(O)(C(N)=O)C(F)(F)F
Temperature: 115 °C
Reaction time: 0.33 h

Procedure:
Concentrated sulfuric acid (15.3 g) was added, under an argon atmosphere, to a 100 ml flask and the starting compound 3,3,3-trifluoro-2-hydroxy-2-ethylpropiononitrile (Fluorchem) (8 g) was then added dropwise. The reaction mixture was heated at 115° C. for 15 min and then cooled down to 8° C.; distilled water (21.8 g) was then added slowly. Diethyl ether was then added and the whole was stirred for 20 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:38](=[O:39])[CH2:37][C:32]2[NH:31][C:30]3[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=3[S:34](=[O:35])(=[O:36])[N:33]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(4-fluorobenzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (100.6 mg, 0.345 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 120.8 mg, 0.362 mmol), 4-dimethylaminopyridine (10.6 mg, 0.086 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (70.9 mg, 0.362 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0M aqueous hydrochloric acid solution to pH 1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo, and dried under high vacuum to afford the crude product, (1S,2R,3S,4R)-3-{(4-fluorobenzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a faintly yellow oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C27H31FN4O7S2 606.16, found 607.2 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:21])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27].[Na+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([O:29][C:25](=[O:28])[CH2:26][CH2:27][C:12]([C:11]1[CH:14]=[C:15]([I:21])[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:13])[CH3:31]
Reactant: C=CC(=O)OCC
Reactant: CCCOc1c(I)cc(C=O)cc1OCc1ccccc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)OCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a solution of 3-benzyloxy-4-propoxy-5-iodo benzaldehyde (25.5 g, 0.064 mol) in DMF (155 ml) was added sodium cyanide (0.78 g, 0.016 mol) and stirred at room temperature for 45 min under nitrogen atmosphere. Ethyl acrylate (5.21 g, 0.057 mol) in DMF (30 ml) was added slowly and stirred at room temperature for 30-40 mints. Ethyl acetate (185 ml) and 15% NaCl solution were added to the reaction mixture and the two layers were separated. The aqueous phase was extracted with ethyl acetate (250 ml). The combined organic extracts were washed with saturated aqueous NaHCO3 (125 ml) followed by 5% aqueous NaCl (180 ml). The ethyl acetate layer was dried Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using ethyl acetate:light petroleum (1:12) as eluent to give ethyl-4-(3-benzyloxy 4-propoxy-5-iodophenyl)-4-oxo-1-butanoate as a syrup (23.80 g, 74%). TLC: Ethyl acetate:light petroleum (1:9), Rf=0.4; 1H NMR (CDCl3, 200 MHz): δ 1.05 (t, J=7.4 Hz, 3H), 1.3 (t, J=6.97 Hz, 3H) 1.78 (m, 2H), 2.7 (t, J=6.5 Hz, 2H), 3.1 (t, J=6.5 Hz, 2H), 4.06 (t, J=5.6 Hz, 2H), 4.18(q, J=7.1 Hz, 2H), 5.12 (s, 2H), 7.33-7.43 (m, 5H), 7.58 (d, J=1.62 Hz, 1H), 7.97 (d, J=1.62 Hz, 1H); IR (neat): 2970, 2930, 1735, 1690, 1585, 1550 cm−1
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[C:12]([OH:14])=O.[CH3:15][N:16]1[C:20]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[CH:19][N:18]=[C:17]1[CH3:28].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][N:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH:24][C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[O:14])[CH:25]=[CH:26][CH:27]=2)=[CH:19][N:18]=[C:17]1[CH3:28]
Reactant: Cc1[nH]c2c(C(=O)O)cccc2c1C
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1[nH]c2c(C(=O)Nc3cccc(-c4cnc(C)n4C)c3)cccc2c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
To a suspension of 2,3-dimethylindole-7-carboxylic acid (95 mg) and 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) in dichloromethane (3 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred at ambient temperature for 18 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-[3-(1,2-dimethyl-1H-imidazol-5-yl)-phenyl]-2,3-dimethyl-lH-indole-7-carboxamide (73 mg, 40.8%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.Cl[C:26]1[C:27]2[C:34]([CH3:35])=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:26]4[C:27]5[C:34]([CH3:35])=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:21][CH2:22]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C(Nc1cccc(Oc2ccc(F)cc2)c1)C1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCC(C(=O)Nc4cccc(Oc5ccc(F)cc5)c4)CC3)c12
Temperature: 190 °C
Yield: 68.8 %

Procedure:
A mixture of piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide hydrochloride (2.51 g, 7.16 mmol) and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.97 mmol) in iso-propanol (15 mL) was placed in a microwave vessel, followed by addition of triethylamine (2.5 mL, 18 mmol). The microwave vessel was sealed then heated in the microwave at normal absorbance at 190° C. for 60 min. The mixture was concentrated to remove most of the iso-propanol and triethylamine. The residue was washed with methanol (2×15 mL) to afford a brown solid. The solid was washed with water (3×30 mL) and dried overnight to afford 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide (1.83 g, 69%) as a light-brown solid ((M+H)+: 446.3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N.[CH3:12]O>>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cncc(O)c1
Agent: N
Product: COC(=O)c1cncc(O)c1
Reaction time: 24 h

Procedure:
A mixture of 1 g of 5-hydroxynicotinic acid, 2 g Amberlyst 15 ion-exchange resin and 150 mL of methanol was heated to reflux with stirring for 24 hrs, cooled, basified with 10% ammonia in methanol, filtered and concentrated under reduced pressure. The residue was taken up in 50 mL of chloroform and dried over MgSO4. Concentration under reduced pressure gave a tan crystalline solid: MS (m+1)=154.1; 1H NMR (400 MHz, CDCl3) 8.68 (s, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 3.94 (s, 3H).