Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6]1)=[O:4].C[O-].[Na+].O>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a sol. of compound 4-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.21 g, 0.38 mmol) in MeOH (2 mL) under Ar was added NaOMe (6 mg, 0.11 mmol). The mixture was stirred for 3 days at 70° C. Water was added, and the mixture was extracted with EtOAc. The org. phase was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound (150 mg, 72%) was not further purified. LC-MS: tR=1.18 min, ES+=538.32.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.44 g) in dichloromethane (7 mL) was added TFA (7 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as an off-white solid (0.2 g, 38%). MS (ISN) 528.0 [(M−H)−]; mp 204° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][S:16][CH2:15]2)=[O:13])=[CH:5][CH:4]=1.[N:19]#[C:20][NH2:21]>C(O)C>[ClH:1].[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][S:16][CH2:15]2)=[O:13])=[CH:7][CH:8]=1)[C:20]([NH2:21])=[NH:19]
Reactant: Nc1ccc(CCCC(=O)N2CCSC2)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1ccc(CCCC(=O)N2CCSC2)cc1
Temperature: 70 °C
Yield: 64 %

Procedure:
1 mmol of N-[4-(4-aminophenyl)butanoyl]thiazolidine hydrochloride prepared in Example 20 and 1 mmol of cyanamide were dissolved with 5 ml of anhydrous ethanol. The solution was stirred under heating at 70° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crystalline residue, which was recrystallized from an ethanol-ether mixed solvent to obtain 210 mg of colorless crystals of N-[4-(4-guanidinophenyl)butanoyl]thiazolidine hydrochloride (yield: 64%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.[C:13](OCC)(=[O:15])C>>[C:1]([C:5]1[CH:6]=[C:7]([N:8]=[C:13]=[O:15])[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(C)(C)c1cccc(N=C=O)c1

Procedure:
3-(tert-Butyl)aniline (0.054 g, 0.36 mmol) was dissolved in ethyl acetate (2 mL) and added dry hydrogen chloride in ethyl acetate twice (3.5 M, 3 mL+2.5 mL). After 15 min the mixture was concentrated to dryness and co-evaporated three times from toluene (3×5 mL). The residue was added toluene (2.5 mL) and flushed with nitrogen for about 10 min. before diphosgene (0.43 mL) was added. Then the mixture was gently refluxed for 1 hour under a nitrogen atmosphere. The mixture was cooled and concentrated in vacuo. This was repeated twice to remove excess of diphosgene. The mixture was concentrated to dryness and co-evaporated three times from toluene (5 mL each time). The residue was concentrated to dryness and co-evaporated twice from toluene. Then it was redissolved in toluene 2.5 mL) and flushed with nitrogen for about 10 min, before diphosgene (0.43 mL) was added. The mixture was gently refluxed under nitrogen for 1 hour. After cooling, the mixture was concentrated and co-evaporated twice from toluene to remove excess diphosgene to afford 3-tert-butyl-phenyl isocyanate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[OH:6].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([O:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:4]([F:3])([F:18])[F:19])[N:24]=[CH:23][N:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccccc1-c1ccco1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccco1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
Sixty percent NaH (12 mg, 0.3 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-furan-2-yl-phenyl)-ethanol (55 mg, 0.2 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, after which 4,6-dichloro-pyrimidine (29 mg, 0.2 mmol) was added. The mixture was then heated at 110° C. until the reaction was complete. After cooling, 5 ml of water was added, and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 60 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-furan-2-yl-phenyl)-ethoxy]-pyrimidine (yield 80%).
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11](=O)[C:10]2[C:15]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[O:17][C:9]1=2)C1C=CC=CC=1.P(Cl)(Cl)([Cl:41])=O>>[Cl:41][C:11]1[CH:12]=[CH:13][N:8]=[C:9]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccn(Cc2ccccc2)c2oc(-c3ccc(OCCN4CCOCC4)cc3)c(-c3ccccc3)c12
Product: Clc1ccnc2oc(-c3ccc(OCCN4CCOCC4)cc3)c(-c3ccccc3)c12
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A resealable tube was charged with 7-benzyl-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-7H-furo[2,3-b]pyridin-4-one (4c) (0.100 g, 0.197 mmol) and phosphorous oxychloride (2.0 mL). The system was flushed with argon and the tube was sealed. The mixture stirred at 110° C. for 1.5 h. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane and ice water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange brown oil. This oil was purified via preparative thin layer chromatography (eluting with 90:10:1, dichloromethane/methanol/ammonium hydroxide) to afford 4-chloro-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridine 6c as an off white solid. MS (MH+) 435.0; Calculated 434 for C25H23ClN2O3.
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[O:25]>>[O:22]=[C:14]1[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:2]3([CH3:1])[CH2:6][CH2:5][N:4]([C:24]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[O:25])[CH2:3]3)[CH2:8][CH2:9]2)[C@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]2[NH:15]1
Reactant: CC#CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNC1
Product: CC#CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)C1
Yield: 33.9 %

Procedure:
Following the procedure used in example 16 and starting from (3aS,7aS)-3-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 0.6 g, 1.75 mmol) and but-2-ynyl chloroformate (0.218 mL, 1.92 mmol), the title compound (0.239 g, 33.9%) was obtained after purification by preparative LC/MS (high pH) as a mixture of diastereomers. MS (M+1): 403.3
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[CH3:23][C:24]([C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=1)=[O:25]>C1COCC1>[F:32][C:30]1[CH:31]=[C:26]([C@H:24]([OH:25])[CH3:23])[CH:27]=[C:28]([F:34])[C:29]=1[F:33]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of (+)-DIP-chloride (11.8 g) in THF (200 ml) cooled to −30° C., 3,4,5-trifluoroacetophenone (5.0 g) [CAS 220141-73-1] was added dropwise in a nitrogen atmosphere. The reaction solution was stirred at the same temperature for five hours and at room temperature at one hour, and then THF was evaporated under reduced pressure. 6.5 ml of diethanolamine was added dropwise to a solution of the resulting residue in diethyl ether (150 ml), and the reaction solution was stirred at room temperature overnight. The insoluble matter was removed by filtration, and then the solvent was evaporated. Hexane was added to the resulting residue, and the insoluble matter was removed by filtration again. The filtrate was purified by silica gel column chromatography (heptane:ethyl acetate=19:1 to 4:1) to obtain 3.69 g of the title compound.
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:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[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.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>C(Cl)Cl.CN(C=O)C>[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64](=[O:65])[O:66][CH3:67])[C:60]([N:36]1[C@H:35]([C:33]2[NH:32][C:31]3[C:49]4[C:27]([CH:28]=[CH:29][C:30]=3[N:34]=2)=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:52]([CH3:54])[CH3:53])=[N:18][CH:17]=3)=[CH:24][CH:23]=2)=[CH:51][CH:50]=4)[C@@H:40]2[CH2:41][C@H:37]1[CH2:38][CH2:39]2)=[O:62]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[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]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c54)c3)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL). (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (24 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (54.6 mg). LCMS-ESI+: calc'd for C44H52N8O7: 804.93 (M+); Found: 806.23 (M+H+).
Reaction SMILES: C([O:8][C:9](=[O:48])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.C(O)=O>[Pd].CO>[CH:9]([OH:48])=[O:8].[C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:32]=[CH:33][N:29]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH2:10][C:9]([OH:48])=[O:8])[CH:30]=3)=[CH:35][CH:36]=2)=[CH:45][CH:44]=1)#[N:47]
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 89.9 %

Procedure:
A mixture of palladium on carbon and 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester (72 mg, 0.112 mmol) in MeOH with formic acid afforded 30 mg (49%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid formate salt as a solid, mp 134-6° C. 1H NMR (DMSO-d6): δ 8.39-8.35 (m, 3H), 7.81 (d, 2H, J=5.9 Hz), 7.63 (s, 2H), 7.34-7.23 (m, 4H), 7.28 (d, 2H, J=10.3 Hz), 7.24 (s, 1H), 6.96-6.92 (m, 1H), 6.52 (dddd, 1H, J=1.8, 2.9, 4.8, 7.4 Hz), 5.35-5.29 (m, 1H), 3.39-3.18 (bm, 1H), 3.09-2.91 (bm, 1H), 1.06 (s, 9H). IR (KBr): 2966, 2225, 1719, 1654, 1594, 1560, 1507, 1396, 1196cm−1. HRFABMS: Calculated for C28H31N4O4 (M+H+): 550.2454. Found: 550.2450. Anal. Calculated for C32H31N5O4•1.0 HCO2H•2.5 CH3OH: C, 63.10; H, 6.41; N, 10.36. Found: C, 63.03, H, 6.75; N, 10.38.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][N:15]([CH3:21])[C:16](=[O:20])[CH2:17][C:18]#[N:19].C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:14][N:15]([CH3:21])[C:16](=[O:20])[C:17]([C:18]#[N:19])=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1
Reactant: CN(C)C(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CN(C)C(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenz-aldehyde, 1.2 g of N,N-dimethylcyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. Yield 1.1 g (40%), m.p. 183°-185° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][NH:16][CH2:15][CH2:13][OH:14])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: Clc1ccc(CCCBr)cc1Cl
Reactant: NCCO
Product: OCCNCCCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-(3-Bromopropyl)-1,2-dichlorobenzene (Chem Abs No. 29648-26-8, 1.30 g) was added to ethanolamine (2.8 ml) and the mixture stirred at 60° C. under nitrogen for 2 h. The mixture was concentrated under vacuum at 80° C. and the residue was partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The phases were separated, the aqueous layer was re-extracted with ethyl acetate (100 ml) and the combined organic extracts were washed with water (2×100 ml) and brine then dried (Na2SO4). The solution was concentrated under vacuum to give the title compound as a pale yellow liquid (1.10 g).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1(C)C=CC(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=1.[H-].[Na+]>CCOCC.CS(C)=O.CCOCC.O>[CH3:4][C:3]1[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:18][NH:19][CH:20]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c[nH]cc1C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A solution of 11.86 g (0.1 moles) of ethyl crotonate and 19.50 g (0.1 moles) of p-toluenesulfonylmethylisocyanide in 500 mL of a 2:1 ether/dimethylsulfoxide was added dropwise into a suspension of 6.8 g of sodium hydride (60% mineral oil dispension, 0.17 moles) in ether at room temperature. Upon completion of addition the reaction mixture was stirred for 30 min and diluted with 400 mL of water. The aqueous layer was extracted with 3×100 mL of ether. The combined ether extracts were passed through a column of alumina eluting with dichloromethane. The organic solvent was evaporated and the resulting residue was solidified on standing. The solid was washed with hexane and dried at 40° C. in vacuum oven overnight to yield 12.38 g (80%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[NH:25]C(=O)OC(C)(C)C)[C:14]([F:33])=[CH:13][N:12]=3)=[CH:9][N:8]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[CH2:18][NH:17][C:15]1[C:14]([F:33])=[CH:13][N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:9]=2)[N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1

Procedure:
A solution of the tert-butyl trans-2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate, 14e, (0.52 g) in CH2Cl2 (5 mL) was treated with TFA (2.5 mL) for 30 min. the solution was concentrated in vacuo and the resulting crude material was taken up in CH3CN and concentrated in vacuo several times to remove excess TFA and to provide the desired amine, 14f, as racemic mixture of trans isomers, as the TFA salt, which was sufficiently pure for use in the next reaction.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:1]1([CH2:4][N:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[C:7]([O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:34](=[O:37])[CH2:35][CH3:36])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Reactant: CCC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCC(=O)OC[C@H]1O[C@@H](Oc2nn(CC3CC3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 405.5 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.40 g) in 2,4,6-trimethylpyridine (1.5 mL) was added propionyl chloride (0.0088 g) at 0° C., and the mixture was stirred for 3 hours. Citric acid monohydrate (3.3 g) and water were added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-(cyclopropylmethyl)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.20 g).
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][CH:17]=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[CH3:28].S1C2C=CC=CC=2N=N1>>[CH3:28][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:20]=1[C:17]1[S:16][C:14]2[C:13]([N:18]=1)=[CH:12][CH:11]=[C:10]([C:7]1([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]1)[N:15]=2)[C:24]#[N:25]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: c1ccc(C2(c3ccc4ncsc4n3)CC2)cc1
Agent: c1ccc2snnc2c1
Product: Cc1cc(C#N)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
3-Methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzonitrile was synthesized from 5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (48.3 mg, 191 μmol) and 4-bromo-3-methylbenzonitrile (45.0 mg, 230 μmol) according to Reference T and the general procedure for azabenzothiazole 2-arylation as a light yellow solid. MS (ESI) m/z: Calculated: 367.1; Observed: 368.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li][CH2:12][CH2:13][CH2:14]C.C(I)CC>O1CCCC1.CCCCCC>[CH2:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[CH2:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COc1cccc(OC)c1
Solvent: CCCI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1c(OC)cccc1OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1,3-Dimethoxybenzene (20 g, 145 mmol) in 200 mL of dry tetrahydrofuran was cooled to -10° C. To this solution at -10° C. added nBuLi (100 mL of a 1.6M solution in Hexane, 160 mmol) over 20 min. The reaction was then stirred for 2.5 hours at 0° C. At 0° C., propyliodide (24.65 g, 145 mmol) was added slowly over 15 min. When the addition was complete, the reaction was allowed to warm to room temperature and stirred overnight. After stirring overnight, the reaction was refluxed for 1.5 hour then cooled to room temperature and quenched with ice. The THF was remove under vacuum, and the resulting aqueous layer was extracted several times with Et2O. The organic extract was dried over MgSO4 and filtered to give a clear oil after solvent removal (26.11 g). The oil was purified by vacuum distillation (24.0 g, 92%). Bpt. 80°-82 ° C. at 10 mmHg.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[S:7]1(=[O:14])=[O:13].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:11][C:8]1([CH3:12])[S:7](=[O:14])(=[O:13])[NH:6][CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCC(C)(C)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCNS1(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a 0° C. solution of 2-(2,4-dimethoxybenzyl)-5,5-dimethylisothiazolidine-1,1-dioxide (0.220 g, 0.7 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (3.591 mL, 48.3 mmol) and the resulting red solution was stirred at 0° C. for 3 hrs and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20-80% ethyl acetate/hexanes) to give a clear oil (0.087 g, 86%). 1HNMR (300 MHz, CDCl3) δ 4.61 (br s, 1H), 3.32-3.26 (td, 2H, J=5.1, 7.1 Hz), 2.25-2.20 (t, 2H, J=7.2 Hz), 1.43 (s, 6H).