Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>[Pd](Cl)Cl.C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C[SiH](Cl)Cl
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: Cl[Pd]Cl
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 272.7 %

Procedure:
After a reactor of 150 mL stainless steel tube was cooled under the dried nitrogen condition, 26.37 g (0.199 mol) of dicyclopentadiene, 34.34 g (0.299 mol) of methyldichlorosilane, 0.036 g (0.000203 mol) of palladium dichloride, 100 μL (0,000406 mol) of tributylphosphine and 30 mL of toluene and 10 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 180° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (98.3 g) of (2-cyclopentenyl)methyldichlorosilane (43.3 g, 80%), other unreacted reactants, toluene, hexadecane, and unidentified compounds.
Reaction SMILES: CC(C)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][S:16][CH2:17][CH:18]=2)=[C:9]([F:19])[CH:8]=1.[C:22]([O:25][C@H:26]([CH2:32]Cl)[CH2:27][NH:28][C:29](=[O:31])[CH3:30])(=[O:24])C.CC(C)([O-])C.[Li+].C(O)(=O)C>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CO.C1(C)C=CC=CC=1>[S:16]1[CH2:15][CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:32][C@H:26]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:25][C:22]3=[O:24])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1
Reactant: CC(C)COC(=O)Nc1ccc(C2=CCSCC2)c(F)c1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: 15 °C
Reaction time: 17 h
Yield: 78.5 %

Procedure:
To a mixture of [4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]carbamic acid 2-methylpropyl ester (17.89 g, 57.83 mmol), (S)-N-[2-(acetyloxy)-3-chloropropyl]acetamide (22.35 g, 115.42 mmol, 2.00 eq), methanol (3.66 g, 114 mmol, 1.97 eq), 2,6-di-tert-butyl-4-methylphenol (0.1365 g, 0.6194 mmol, 0.0107 eq), toluene (52 ml), isooctanes (49 ml), and N,N-dimetlhylformamide (34.3 ml) is added a solution of lithium t-butoxide (I 3.94 g, 174.1 mmol, 3.01 eq) in isooctanes (130 ml) over 1.6 h while maintaining 15° C. Isooctanes (20 ml) is added and the mixture stirred at 15 to 19° C. for 17 h. The mixture is cooled to 0° C. and acetic acid (6.7 ml, 117 mmol, 2.02 eq) added. The mixture is warmed to 21° C. and methanol (29 ml) added. The phases are separated and the upper washed twice with a mixture of methanol (29 ml) and water (9 ml). To the combined lower phases is added water (69 ml) and methylene chloride (69 ml). The phases are separated and the upper phase washed twice with methylene chloride (29 ml). The combined lower phases are concentrated under reduced pressure to 112 ml total volume. Methanol (69 ml) is added and the mixture concentrated to 112 ml. Methanol (69 ml) is added and the mixture concentrated to 75 ml then toluene (65 ml) is added. Water (65 ml) is added over ½ h while maintaining 19 to 30° C. The mixture is cooled to 9° C. and isooctanes (56 ml) added. The slurry is cooled to 0° C. and the precipitate collected by vacuum filtration, washed with water (22 ml) and isooctanes (22 ml) and dried in a nitrogen stream to give the title compound (15.909 g, 78.5%): HPLC retention time=2.77 min (column=Phenomenex Luna 5.0 micron C-8(12) 150×4.6 mm, flow rate=2.0 min/min, gradient elution from 40:60 A:B to 73.3:26.7 A:B over 15 minutes; A=acetonitrile; B=water).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:88])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][C@@H:24]([CH2:32][CH2:33][C:34](=[O:87])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54](=[O:86])[CH2:55][O:56][C:57]4[CH:62]=[CH:61][C:60]([C:63]5[NH:67][N:66]=[C:65]6[C:68]7[CH:69]=[CH:70][CH:71]=[C:72]([NH:76][C:77]([NH:79][N:80]8[CH2:85][CH2:84][O:83][CH2:82][CH2:81]8)=[O:78])[C:73]=7[C:74](=[O:75])[C:64]=56)=[CH:59][CH:58]=4)[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C(O)(C(F)(F)F)=O.S(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:88])[C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH2:32][CH2:33][C:34](=[O:87])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54](=[O:86])[CH2:55][O:56][C:57]4[CH:62]=[CH:61][C:60]([C:63]5[NH:67][N:66]=[C:65]6[C:68]7[CH:69]=[CH:70][CH:71]=[C:72]([NH:76][C:77]([NH:79][N:80]8[CH2:85][CH2:84][O:83][CH2:82][CH2:81]8)=[O:78])[C:73]=7[C:74](=[O:75])[C:64]=56)=[CH:59][CH:58]=4)[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][CH:20]=3)[N:8]=2)[N:3]=1
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSC
Product: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)O)cc1
Reaction time: 1 h

Procedure:
Compound 30 (0.45 g, 0.37 mmol) was treated with 20 ml of a cleavage cocktail (10:10:1:1 TFA:CH2Cl2:Me2S:H20). After one hour, the solvent was removed and the residue purified by RPHPLC. Fractions containing the product were combined, concentrated to a small volume and lyophilized to yield a yellow solid (0.23 g, 0.18 mmol, 49%, compound 32).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:32])=[CH:26][CH:27]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:19])([CH3:20])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1cc2c(cc1C)C(C(=O)OCC)=CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)cc3)c(C)cc21

Procedure:
Following General Procedure B and using 6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 185, 0.126 g, 0.47 mmol), 4-iodo phenyl acetic acid methyl ester (0.13 g, 0.47 mmol), triethyl amine (2 mL), copper(I)iodide (0.029 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-12% ethyl acetate in hexane as the eluent, the title compound was obtained as a viscous oil (0.144 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.N1C=CC=CC=1.[C:24]1([O:30]C(Cl)=O)C=CC=CC=1.CN1CCCC1.[C:40]1([CH:46]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:47][CH2:48][NH:49][CH2:50][CH2:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[Cl:17][C:4]1[S:3][C:2]([NH:1][C:24](=[O:30])[N:49]([CH2:48][CH2:47][CH:46]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:50][CH2:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:6][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1
Reactant: Nc1nc(-c2ccc(S(N)(=O)=O)cc2)c(Cl)s1
Reactant: c1ccc(C(CCNCCC2CCOCC2)c2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN1CCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-c2nc(NC(=O)N(CCC3CCOCC3)CCC(c3ccccc3)c3ccccc3)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-amino-5-chlorothiazol-4-yl)benzenesulfonamide (0.100 g, 0.35 mmol) and pyridine (0.084 ml, 1 mmol) in 1 ml DMF was cooled to 0° C. and phenylcarbonochloridate (0.041, 0.33 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. At this point 1-methylpyrrolidine (0.11, 1 mmol) and 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine (0.11 g, 0.33 mmol) were added to the reaction mixture consecutively. The reaction mixture was heated to 60° C. and stirred overnight after which it was cooled to room temperature and purified directly over silica (eluted with 0-50% Ethylacetate in hexanes) to give 4-(5-chloro-2-(((3,3-diphenylpropyl)(2-(4-tetrahydropyranyl)ethyl)carbamoyl)amino)-1,3-thiazol-4-yl)benzenesulfonamide. LC-MS ESI (pos.) m/e: 638.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid (5 mmol) and dichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25 mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH3:24])[CH2:6][C@H:7]1O[C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:22])[C@@H:8]1[OH:23])#[N:2].Cl.[NH2:26][OH:27].[OH-:28].[K+]>CO.CN(C=O)C>[OH:27][NH:26][C:1]([CH2:3][CH2:4][N:5]([CH3:24])[CH2:6][C@H:7]1[O:28][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:22])[C@@H:8]1[OH:23])=[NH:2]
Reactant: NO
Reactant: CN(CCC#N)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(CCC(=N)NO)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 18b (470 mg, 1.4 mmol) in 20 mL of anhydrous MeOH and 4 mL of anhydrous DMF under nitrogen was added hydroxylamine hydrochloride (258 mg, 3.7 mmol) and potassium hydroxide (206 mg, 3.7 mmol) and the resulting suspension was stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness and the crude product was extracted with EtOAc (2×40 mL) and washed with brine solution (20 mL). The organic layer was dried over Na2SO4, filtered, washed with EtOAc and concentrated to dryness. The product was purified by column chromatography. The column was eluted with 4:1:0.5 chloroform:methanol:NH4OH and the desired fractions were combined, concentrated, and dried in vacuo to give a solid: yield 165 mg (32%), MS: m/z 367 (M+H)+; 1HNMR (DMSO-d6) δ 8.70 (bs, 1H, NOH), 8.33 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.27 (bs, 2H, 6-NH2), 5.86 (d, 1H, H-1′, J1′,2′=5.3 Hz), 5.43 (d, 1H, 2′-OH, J2′-2′=6.0 Hz), 5.35 (bs, 2H, C—NH2), 5.20 (d, 1H, 3′-OH, J3′-3′OH=5.2 Hz), 4.63 (ddd, 1H, H-2′, J1′,2′=5.3 Hz, J2′,3′=4.9 Hz, J2′-2′OH=6.0 Hz), 4.10 (ddd, 1H, H-3′, J2′,3′=4.9 Hz, J3′,4′=3.5 Hz, J3′-3′OH=5.2 Hz), 3.96-4.0 (m, 1H, H-4′), 2.64-2.75 (bm, 2H, 5′-CH2), 2.56 (t, 2H, N(CH3)—CH2), 2.20 (s, 3H, N—CH3), 2.09 (t, 2H, C—CH2). Anal. (C14H22N8O4.1.2C2H5OH.0.2CH3OH) C, H, N.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17]O)[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([CH2:17][Br:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(Br)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1CBr
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4.0 g N-bromosuccinimide are slowly added to a solution of 5.0 g of 4-bromo-1-chloro-2-hydroxymethyl-benzene and 5.9 g triphenylphosphine in 50 ml of tetrahydrofuran chilled to 5° C. After 1 h stirring at ambient temperature the precipitate is filtered off and the solvent is eliminated in vacuo. The residue is purified through silica gel (cyclohexane/ethyl acetate 50:1).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[F:14])C.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:19]([O:18][C:16]([NH:15][CH:5]([CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[F:14])[C:4]([OH:23])=[O:3])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Cc1cc(C)ccc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(CC(NC(=O)OC(C)(C)C)C(=O)O)c1

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-(2-fluoro-5-methylphenyl)-propionic acid ethyl ester (7.7 g, 24 mmol) in 60 mL of THF and 60 mL of MeOH is added lithium hydroxide (1.5 g, 35.6 mmol) in H2O (15 mL). The reaction is stirred at room temperature for 1.5 hr after which time 1M HCl is added until the mixture reaches pH 4. The product is extracted into dichloromethane and the combine the organic layers are dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[O:19][CH3:20])=[N:6][CH:7]=1.CN1[C:27](=[O:28])[CH2:26][CH2:25]C1.[CH3:29][CH2:30]OC(C)=O>CCCCCC>[CH2:29]([CH:27]([O:28][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[O:19][CH3:20])=[N:6][CH:7]=1)[CH2:26][CH3:25])[CH3:30]
Reactant: CN1CCCC1=O
Reactant: COc1cc(OC(F)(F)F)ccc1-c1ncc(Br)cc1C
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(CC)Oc1cnc(-c2ccc(OC(F)(F)F)cc2OC)c(C)c1
Temperature: 120 °C

Procedure:
Compound 42 (3.62 g, 10 mmol) is added to a solution of sodium 3-pentoxide in NMP (1M, 30 ml, 30 mmol). The resulting mixture is heated to 120° C. for 2.5 h, and then cooled to room temperature, diluted with 50% EtOAc in hexane, washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatography (eluted with 6% EtOAc in hexane) to give the product as colorless oil. 1H NMR (CDCl3) δ 0.98 (t, J=7.6 Hz, 6H), 1.72 (m, 4H), 2.15 (s, 3H), 3.77 (s, 3H), 4.17 (m, 1H), 6.79 (s, 1H), 6.91 (dd, 1H), 7.07 (d, J=1.6 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H). LCMS 370.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.O.C(#N)C>CN(C=O)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)[C:12](=[O:24])[CH:13]=1
Reactant: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(furan-2-ylmethoxy)-1H-pyridin-2-one in 1.5 mL DMF is added 42 μL (0.52 mmol) pyrrolidine at RT. The reaction mixture is stirred for 2 h at RT and is directly added to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][N:14]1[CH:18]2[CH2:19][C:20]([CH2:22][CH:15]1[CH2:16][CH2:17]2)=O.OP(O)(O)=O>C(O)(=O)C>[CH3:13][N:14]1[CH:15]2[CH2:16][CH2:17][CH:18]1[CH2:19][C:20]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=1)=[CH:22]2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN1C2CCC1CC(=O)C2
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CN1C2C=C(c3c[nH]c4ccc([N+](=O)[O-])cc34)CC1CC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 30.9 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in glacial acetic acid (10 mL) was treated with tropinone (0.85 g, 6.617 mmol), followed by 2 M H3PO4 in glacial acetic acid (5 mL) at 100° C. and the resulting solution was stirred at same temperature for 24 h. The reaction was brought to room temperature, poured in to ice-cold 10% NH4OH solution (50 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 89 (0.27 g, 31%) as a solid. mp 234-236° C.; 1H NMR (DMSO-d6) δ 1.51-1.60 (m, 1H), 1.79-1.86 (m, 1H), 1.95-2.14 (m, 4H), 2.32 (s, 3H), 2.76-2.83 (m, 1H), 3.43 (t, 1H, J=5.4 Hz), 6.31 (d, 1H, J=5.1 Hz), 7.54 (d, 1H, J=8.7 Hz), 7.61 (s, 1H), 8.01 (dd, 1H, J=2.1, 9.0 Hz), 8.68 (d, 1H, J=2.4 Hz), 11.86 (s, 1H); ESI-MS m/z (%): 284 (MH+, 100). N-(3-(8-Methyl-8-azabicyclo[3.2.1]oct-3-en-3-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (90): A solution of compound 89 (0.25 g, 0.882 mmol) in dry ethanol (10 mL) was treated with Pd—C (0.025 g) and purged with hydrogen gas. The reaction was stirred under hydrogen atm. (balloon pressure) for overnight (14 h). The solid was filtered off using celite bed and washed with ethanol (2 5 mL). The combine d ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.5 g, 1.764 mmol) at room temperature and stirred for 24 h. Ethanol was evaporated and crude material was basified with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 90 (0.14 g, 44%) as a solid. mp 93-95° C.; 1H NMR (DMSO-d6) δ 1.60-1.65 (m, 1H), 1.84-1.90 (m, 1H), 2.02-2.26 (m, 4H), 2.41 (s, 3H), 2.83-2.89 (m, 1H), 3.46-3.55 (m, 1H), 6.20 (brs, 2H), 6.67 (d, 1H, J=7.8 Hz), 7.10 (s, 1H), 7.23-7.31 (m, 3H), 7.60-7.72 (m, 2H), 10.99 (s, 1H); ESI-MS m/z (%): 363 (MH+, 65), 182 (100), 119 (48); ESI-HRMS calculated for C21H23N4S (MH+), Calculated: 363.1633; Observed: 363.1637.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([NH:28][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccccn1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a cooled solution of picolinic acid (3.6 g, 29.2 mmole, Aldrich) and triethylamine (8 mL, 57.4 mmole) in 80 mL of methylene chloride at 0° C. was added pivaloyl chloride (3.8 mL, 30.8 mmole). The mixture was stirred for 1 hour at 0° C., t-butylamine (4.0 mL, 38.1 mmole) was added, and stirring was continued for 1 hour at 0° C. and 1 hour at room temperature. Saturated NaHCO3 (30 mL) was added, the layers were separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic solutions were dried and concentrated, and the residue was chromatographed in silica gel, eluting with 30 to 60% ethyl acetate in hexane, to provide 5.2 g of the title compound as an oil. MS: 179 (M+H)+ ; 1H NMR (CDCl3) δ: 8.52 (m, (1H), 8.18 (dm, J=7.5 Hz, 1H), 8.0 (s, br, 1H), 7.84 (dt, J=7.5, 1.5 Hz, 1H), 7.40 (ddd, J=7.5, 5.0, 1.5 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][C@@H:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:51]([NH:53][CH3:54])=[O:52]>CN(C=O)C>[CH3:56][C:55]([CH3:58])([CH3:57])[C@H:50]([NH:49][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:51](=[O:52])[NH:53][CH3:54]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cc(OC2COC2)c(Cl)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid (Example 23a, 35 mg, 152 μmol) in DMF (1 mL) was added HATU (58 mg, 152 μmol) and DIEA (66.6 μL, 381 μmol). The reaction mixture was then stirred at room temperature for 30 min, followed by addition of (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0, 22 mg, 152 μmol). The reaction mixture was stirred for 3 h. The crude reaction mixture was directly purified by preparative HPLC to deliver the desired compound (17.5 mg, 32%) as a yellow oil. MS (ESI, m/z): 356.5 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CC([O-])(C)C.[K+].O>CS(C)=O.CC(O)(C)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=3)=[CH:6][N:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=c1cc(-c2ccc(Cl)nc2)cn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3cn[nH]c(=O)c3)cn2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of 5-(6-chloropyridin-3-yl)-2H-pyridazin-3-one (73 mg, 0.35 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.70 mmol) in 2.7 mL of DMSO was stirred as KOtBu in 2-methyl-2-propanol (1.0 M, 14.4 mL) was added dropwise. After stirring at 110° C. overnight, the reaction was cooled to rt, and 2 mL of water was added. The mixture was extracted with CH2Cl2 (3×10 mL), the extracts combined and dried over Na2SO4. The crude product was purified by prep. TLC with 10% MeOH in CH2Cl2 to give 71 mg (54%) of 4-[5-(6-oxo-1,6-dihydropyridazin-4-yl)-pyridin-2-yloxy]piperidine-1-carboxylic acid tert-butyl ester; MS m/z 273 (M-Boc-H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH2:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:12][C:13]#[CH:14]>CN(C=O)C.C(N(C(C)C)CC)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: C#CCCOCCCCCCBr
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(C#CCCOCCCCCCBr)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
A mixture of 1-iodo-3-nitrobenzene (3 g), 6-bromohexyl but-3-ynyl ether (3 g), bis(triphenylphosphine)palladium (II) chloride (0.421 g), copper (I) iodide (0.114 g) in DMF (10 ml) and diisopropylethylamine (4 ml) was stirred under nitrogen at 20° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was diluted in EtOAc and washed with 2M HCl, NaHCO3, brine and dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with ether:petroleum ether(40–60° C.) (1:9) to give the title compound (4.12 g). LCMS RT=4.14 min