Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C@H:18]([CH3:19])[CH2:17][N:16]([C@H:20]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[C@@H:15]([CH3:41])[CH2:14]1)[CH:11]=[CH2:12].C(N(CC)CC)C>ClCCl>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C@H:20]([N:16]2[CH2:17][C@@H:18]([CH3:19])[N:13]([CH2:10][CH:11]=[CH2:12])[CH2:14][C@@H:15]2[CH3:41])[C:28]2[CH:29]=[CH:30][C:31]([C:32](=[O:33])[N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[CH:39][CH:40]=2)[CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(=O)c3ccccc3)c2)C[C@H]1C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Benzoyl chloride (0.33, 2.3 mmol) was added dropwise to a solution of (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.92 g, 2.1 mmol) (Example 6) and triethylamine (0.60 mL, 4.2 mmol) in 20 mL dichloromethane. The reaction mixture was stirred for 1 hour and then was washed twice with 20 mL of water, dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography on silica gel with dichloromethane:ethanol to give 0.92 g (74%) of (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylcarbamoyl)benzyl)phenyl benzoate. NMR (300 MHz, CDCl3): δ 0.9 (d, 3H); 1.2 (d, br t, 9H); 1.9 (t, J=11 Hz, 1H); 2.1 (dd, 1H); 2.5 (br m, 1H); 2.6 (m, 2H); 2.8 (m, 2H); 3.2-3.6 (br m, 5H); 5.2 (2d, 2H); 5.3 (s, 1H); 5.8 (m, 1H); 7-7.2 (2d, s, 3H); 7.3 (m, 3H); 7.5 (m, 4H); 7.6 (t, 1H), 8.2 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.[CH:20]1N=C[N:22](C(N2C=NC=C2)=O)[CH:21]=1.C(N)C>C1COCC1>[CH2:21]([NH:22][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[O:13][CH:14]([CH3:15])[CH3:16])=[O:19])[CH3:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc2ccc(OC)cc2c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 mg, 0.77 mmol in 5 mL of THF is added N,N-carbonyldiimidazole (162 mg, 1.00 mmol). The solution is heated at reflux for 1 hour and cooled slightly. Ethylamine (0.44 mL of a 70% aqueous solution) is added and the reaction mixture is stirred at room temperature for 30 minutes, followed by partitioning between ethyl acetate, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (2:1) to provide N-ethyl-7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxamide in 70% yield; mp 78°-79° C.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][N:52]=[C:51]([NH2:55])[CH:50]=2)=[N:46][C:45]=1[C:56]1[N:60](COCC[Si](C)(C)C)[CH:59]=[N:58][N:57]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][N:52]=[C:51]([NH:55][C:1](=[O:5])[CH2:2][CH3:3])[CH:50]=2)=[N:46][C:45]=1[C:56]1[NH:60][CH:59]=[N:58][N:57]=1
Reactant: CCC(=O)O
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(-c2ccnc(N)c2)oc1-c1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)Nc1cc(-c2nc(-c3nnc[nH]3)c(-c3ccccc3Cl)o2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A mixture of propanoic acid (0.0095 mL, 0.13 mmol), HATU (0.019 g, 0.051 mmol) and N-methylmorpholine (0.014 mL, 0.13 mmol) in DCM (1 mL) was allowed to stir at rt for 30 min. Solid 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine-2-amine (0.020 g, 0.043 mmol) and DMAP (0.016 g, 0.13 mmol) were then added and the reaction mixture was allowed to stir at 80° C. overnight. The reaction mixture was allowed to cool to rt and was diluted with DCM (3 mL) and washed with saturated aqueous NaHCO3 (2 mL). The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was redissolved in DCM (0.5 mL) and to this solution was added TFA (0.5 mL). The reaction mixture was allowed to stir at rt for 12 h and then concentrated to dryness. The residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]pyridine-2-yl}propanamide (Compound I-75) (3.5 mg, 21%). LCMS (FA): m/z=395 (M+H). 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 8.79 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.67 (dd, J=5.2, 1.5 Hz, 1H), 7.64 (dd, J=8.1, 1.2 Hz, 1H), 7.58 (td, J=7.7, 1.7 Hz, 1H), 7.50 (td, J=7.5, 1.3 Hz, 1H), 2.44 (q, J=7.5 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][N:3]=1.[OH-:21].[K+]>C(O)(C)(C)C>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([Cl:15])[CH:12]=1)[O:8][C:7]1[C:2](=[O:21])[NH:3][CH:4]=[CH:5][C:6]=1[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Cl)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To 2-chloro-3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridine (2.10 g, 6.10 mmol) in tert-butanol (25 mL) was added potassium hydroxide (1.03 g, 18.4 mmol). The reaction mixture was placed in an oil bath and heated at 75° C. After 48 hours, the reaction mixture was allowed to cool to room temperature and was quenched with saturated aqueous ammonium chloride (25 mL) and diluted with water (25 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and the solvent was evaporated under reduced pressure to yield a solid. This was adsorbed onto silica and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 12.69 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.32-7.30 (m, 1H), 7.10-7.08 (m, 2H), 6.48 (d, J=6.8 Hz, 1H). HRMS (M+1)=323.9800.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].[C:25](O)(=O)C.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:23][CH2:22][C:21]([O:20][CH2:19][CH3:25])=[O:24])=[CH:12]/[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(=O)c1ccc(OC)cc1OC
Reactant: CC(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN/C(=C\C(=O)OC)c1ccc(OC)cc1OC
Temperature: 100 °C
Yield: 69.2 %

Procedure:
To a solution of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (5.0 g, 21 mmol) in EtOH (30 mL) was added glycine methyl ester hydrochloride (10.5 g, 83.9 mmol) followed by acetic acid (1.20 mL, 21 mmol) and triethylamine (8.5 g, 83.9 mmol) and the reaction mixture was heated at 100° C. for 18 hours. After cooling to room temperature, the residue was partitioned between EtOAc and saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in CH2Cl2 (10 mL) filtered through a plug of silica gel, eluting with 15-35% EtOAc in heptanes and dried under vacuum to give the title compound (4.7 g, 69%) as a yellow solid. This material was used in the next step without further purification.
Reaction SMILES: C1(=O)N([N:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([O-:11])=O)[CH2:7]2)C(=O)CC1.[CH2:17]([CH2:19][NH2:20])[OH:18].C(N(C(C)C)CC)(C)C.C(N)C.CN(C=O)C.C([O-])(=O)C1C=CC=NC=1.ON1C(=O)CCC1=O>CN(C=O)C>[OH:18][CH2:17][CH2:19][NH:20][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:6][CH:7]=1
Reactant: NCCO
Reactant: O=C([O-])C1=CC=CN(N2C(=O)CCC2=O)C1
Agent: CCN
Agent: O=C([O-])c1cccnc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cccnc1
Reaction time: 0.25 h

Procedure:
The N-succinimidyl-nicotinate compound described in Example 1 was reacted with the hydrochloric salt of ethanolamine, available commercially in its radioactive form. The ethanolamine salt was dissolved in dried DMF and chilled in an ice bath. To the mixture was added an equimolar of diisopropylethylamine (DIEA) and stirred for 15 minutes. An equimolar solution of N-succinimidyl-nicotinate was added to the ethylamine-DMF mixture dropwise under a nitrogen atmosphere. As the nicotinate was added the mixture turned milky and was slurried for at least another half hour. The milky substance was the N-hydroxy-succinimide precipitating, which was filtered off. The DMF-mixture was washed with ether to remove any precipitant. The solvent mixture was removed under high vaccum. The oily mixture was triturated with ether to yield a precipitant, N-(2-hydroxyethyl)nicotinamide. The radioactive compound was isolated and identified by its TLC.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:37][C:36]([C@@H:38]4[C@@H:43]5[CH2:44][C@@H:40]([CH2:41][CH2:42]5)[N:39]4C(OC(C)(C)C)=O)=[N:35][CH:34]=2)=[CH:29][CH:28]=1)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64]([O:66][CH3:67])=[O:65])[C:60]([OH:62])=O.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:67][O:66][C:64]([NH:63][C@@H:59]([C@H:58]([O:57][CH3:56])[CH3:68])[C:60]([N:39]1[C@H:38]([C:36]2[NH:37][C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:22]4[CH:23]=[C:24]5[C:19](=[CH:20][CH:21]=4)[C:17]4[NH:18][C:14]([C@@H:10]6[CH2:11][CH2:12][CH2:13][N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:52]([CH3:53])[CH3:54])=[N:15][C:16]=4[CH:26]=[CH:25]5)=[CH:28][CH:29]=3)=[CH:34][N:35]=2)[C@@H:43]2[CH2:44][C@H:40]1[CH2:41][CH2:42]2)=[O:62])=[O:65]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
(1R,3S,4S)-tert-butyl 3-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (73 mg, 0.0997 mmol) was dissolved in DCM (5 mL) and treated with HCl (4M in dioxane, 1 mL). After 3 h, the reaction mixture was concentrated. The residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (23 mg, 0.120 mmol), COMU (51 mg, 0.120 mmol) and DMF (2 mL). DIPEA (0.090 mL, 0.499 mmol) was added and the reaction mixture was stirred for 25 min before being quenched with H2O and purified by HPLC to afford the title compound (22 mg, 28%). (ESI) m/z 805 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)[CH3:2].[CH3:10][C@@H:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.O>C1(C)C=CC=CC=1>[CH3:10][C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:18]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[CH2:1][CH3:2]
Reactant: CCC1CCCCC1=O
Reactant: C[C@@H](N)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC1CCCCC1=N[C@H](C)c1ccccc1

Procedure:
A solution of 2-ethylcyclohexanone (6.92 mol, 873 g), (R)-α-methylbenzylamine (6.92 mol, 839 g), and 19.6 mL of acetic acid were refluxed for 12 hours under nitrogen in 2 L of toluene with azeotropic removal of water. The toluene was removed on a rotary evaporator and the product was divided into two portions. The unreacted 2-ethylcyclohexanone was distilled through a short path (bp 30° C., <10 mm), and the remainder of the product was then distilled through a 5" vacuum jacketed Vigreux column affording first a low melting solid (bp 80°-90° C. 23 mm), and then the product (bp 128°-133° C. 21.0 mm, 1.303 kg from both distillations combined, 5.68 mol, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][CH:30]2[CH2:31][CH2:32]2)[C:24]([OH:26])=[O:25])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(CC1CC1)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (100 mg, 0.214 mmol) and lithium hydroxide monohydrate (27 mg, 0.642 mmol) in a MeOH/THF/Water solvent mixture (5 ml/5 ml 5/ml) was stirred for 3 h at room temperature. Upon completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 56% yield. (52.6 mg). 1HNMR (CDCl3): 7.71 (s, 4H); 7.42 (s, 1H); 7.23 (s, 1H); 3.68 (t, 1H); 3.41 (d, 2H); 1.93 (m, 1H); 1.77 (m, 1H); 0.97 (bs, 1H); 0.71 (bs, 1H); 0.42 (m, 4H); 0.12 (m, 2H); 0.1 (m, 2H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: C1COCCN1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCOCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and morpholine are converted to the named compound.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[O:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40](B4OC(C)(C)C(C)(C)O4)[CH:41]=3)[C:36]2=[O:53])[CH2:31][CH2:30]1>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:40]3[CH:41]=[C:42]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:53])[N:35]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH2:43]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CCOCC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CCOCC4)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=507.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13]1[CH:22]=[C:21]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20]2)[C:14]=1[CH:23]=[O:24].CCCCCC>O1CCCC1.O>[CH3:12][C:13]1[CH:22]=[C:21]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20]2)[C:14]=1[CH:23]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[OH:24]
Reactant: Cc1cscn1
Reactant: Cc1cc2cccccc-2c1C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1csc(C(O)c2c(C)cc3cccccc2-3)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-Methyl thiazole 4 (837 μL, 9.2 mmol) was added to 20 mL of tetrahydrofuran (THF). The mixture was cooled to −78° C. and stirred for 20 min. Afterward, 2.5 M nBuLi (2.45 mL, 6.1 mmol) was added slowly over the course of 15 min. The resultant mixture was stirred at −78° C. for 1 h, after which a freshly made solution of 2-methylazulene-1-carbaldehyde 3 (522 mg, 3.1 mmol) in THF was added slowly at −78° C. The reaction was stirred for 30 min and checked by TLC (50:50 Hexanes/EtOAc). Hexane was added at −78° C. and the reaction was warmed to room temperature. Water was added to quench the reaction and the organic layer was extracted into ethyl acetate. The extracts were washed with water and brine, dried with MgSO4 and purified using flash chromatography (ethyl acetate and hexane). The purified material was dried down into a purple solid. Yield: 768 mg, 93%. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=9.85 Hz, 1H), 8.19 (d, J=9.54 Hz, 1H), 7.52 (t, J=9.82 Hz, 1H), 7.19-7.13 (m, 3H), 6.78 (s, 1H), 6.64 (s, 1H), 2.56 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 174.2, 152.2, 149.1, 140.6, 137.2, 136.1, 134.8, 132.4, 125.3, 123.8, 123.6, 118.7, 114.1, 67.8, 16.9, 15.6. HRMS (ES) 152.2, 149.1, 140.6, 137.2, 136.1, 134.8, 132.4, 125.3, 123.8, 123.6, 118.7, 114.1, 67.8, 16.9, 15.6. HRMS (ES) calcd. [M-H2O+H]+ (C16H14NS) 252.0925. found 252.0836.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC(C)=CC=1C(O)=O.CC1C=CC(C)=CC=1C(Cl)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][C:51]=1[C:57]([N:59]=[C:60]=[S:61])=[O:58]>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:51]2[CH:52]=[C:53]([CH3:56])[CH:54]=[CH:55][C:50]=2[CH3:49])=[S:61])=[CH:44][CH:43]=1
Reactant: Cc1ccc(C)c(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccc(C)c(C(=O)Cl)c1
Agent: Cc1ccc(C)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)ccc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,5-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,5-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 91%).
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:38][C@H:39]1[C@@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@H:42](OC(=O)C)[O:41][C@@H:40]1[C:52]1[N:56]=[C:55]([CH2:57][CH3:58])[O:54][N:53]=1)(=[O:37])[CH3:36]>>[C:45]([O:44][C@@H:43]1[C@H:39]([O:38][C:35](=[O:37])[CH3:36])[C@@H:40]([C:52]2[N:56]=[C:55]([CH2:57][CH3:58])[O:54][N:53]=2)[O:41][C@H:42]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=2[NH:10][CH2:9][CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:47])[CH3:46]
Reactant: CCc1nc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: Cl
Product: CCc1nc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and (2R,3R,4R,5S)-4,5-bis(acetoxy)-2-(5-ethyl-1,2,4-oxadiazol-3-yl)tetrahydro-3-furanyl acetate (Preparation 38).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3nccs3)c(=O)n12
Temperature: 120 °C
Yield: 71.7 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.32 mmol), and 2-(tributylstannyl)-1,3-thiazole (143 mg, 0.382 mmol) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol). The reaction mixture was heated at 120° C. overnight. After cooling to room temperature, the mixture concentrated under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (73 mg, 72%). LCMS calculated for C12H11N6OS2(M+H)+: m/z=319.0. Found: 319.0.
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)(=[O:21])[CH2:19][CH3:20]
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Reactant: CCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
From 12 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide, 5 g. propionyl chloride and 6.6 g. triethylamine in chloroform, there is obtained, after heating under reflux for 3 hours and then working up the reaction mixture in the usual manner, the desired 3-(propionyl-imino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from ethyl acetate, melts at 170°C.