Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[OH:31][CH2:32][CH2:33][C:34](O)=[O:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl-].[NH4+]>CN(C)C=O>[OH:35][CH2:34][CH2:33][C:32]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:31]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(O)CCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(CCO)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol) and 3-hydroxypropanoic acid (131 mg, 0.435 mmol) in N,N-dimethylformamide (5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (160 mg, 0.544 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) and precipitated from ethanol to give the title compound (30 mg, 17%) as a pale-green powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:17][C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cn1
Reactant: O=Cc1ncc[nH]1
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(NN=Cc2ncc[nH]2)nc1
Reaction time: 8 h

Procedure:
3.10 g (20.1 mmol) of 5-nitro-2-pyridylhydrazine and 2.00 g (20.8 mmol) of 2-imidazolecarbaldehyde were dissolved in 50 ml of ethanol. To this mixture, 1 ml of acetic acid was added and heated under reflux for 2 hours while being stirred. After the resultant reaction mixture was allowed to stand still overnight, coarse crystals precipitated were filtrated by the suction-filtration. The obtained coarse crystals were recrystallized from a hot ethanol solution to obtain a desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[Li])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20]([CH2:33][CH3:34])[C:21]([C:23]1[C:24]([O:31][CH3:32])=[N:25][CH:26]=[CH:27][C:28]=1[CH:29]=[O:30])=[O:22])[CH3:19].CN(C)CCN(C)C.CC1(C)CCCC(C)(C)N1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:29]([C:28]1[CH:27]=[CH:26][N:25]=[C:24]([O:31][CH3:32])[C:23]=1[C:21]([N:20]([CH2:18][CH3:19])[CH2:33][CH3:34])=[O:22])[OH:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]c1cc2cnccc2n1C(=O)OC(C)(C)C
Reactant: CCN(CC)C(=O)c1c(C=O)ccnc1OC
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN(C)CCN(C)C
Product: CCN(CC)C(=O)c1c(C(O)c2cc3cnccc3n2C(=O)OC(C)(C)C)ccnc1OC

Procedure:
Starting from 1-tert.butoxycarbonyl 2-lithio 5-aza indole and 3-diethylaminocarbonyl 4-formyl 2-methoxy pyridine as reagent with electrophilic character, prepared according to paragraph b (stabilization reagent: tetramethylethylenediamine; amine: 2,2,6,6-tetramethylpiperidine).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>>[F:16][C:17]([F:31])([F:32])[C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1

Procedure:
The colourless solid, (E)-ethyl 3-(3′,5′-bis-trifluoromethyl-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 3,5-bis-(trifluoromethyl)phenyl boronic acid by a procedure analogous to that described in example 91b.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O1CCCC1>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCO
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCOCc1ccccc1
Reaction time: 2 h
Yield: 48 %

Procedure:
While a suspension containing 2.5 g of 60% sodium hydride was in 50 ml of tetrahydrofuran was allowed to stand at room temperature, 5.7 g of 1,4-butanediol was slowly added dropwise thereto. Then, a solution containing 7.5 ml of benzyl bromide in 20 ml of tetrahydrofuran was added dropwise to the reaction mixture at room temperature, followed by stirring at the same temperature for 2 hours. After the addition of a 10% aqueous solution of HCl, the reaction mixture was extracted with diethyl ether. After the organic layer was washed with an aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using 150 g of silica gel [with an elution solvent comprising hexane-ethyl acetate (4:1)]. Thus, 5.5 g (48% yield) of the title compound was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:32])[CH2:16][N:17](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:11][C:10]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1)[OH:32]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Temperature: 25 °C

Procedure:
To a stirred suspension of N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Intermediate 7)(1.03g, 2 mmol) and 10% palladium on carbon (0.4 g) in methanol (100 mL) at room temperature was added anhydrous ammonium formate (1.26 g, 20 mmol) under a nitrogen atmosphere. The resulting mixture was refluxed for 2 hours. After cooling to room temperature the catalyst was removed by filtration through a celite pad and washed with methanol. The filtrate was evaporated under reduced pressure to give the titled compound (Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738) as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75 (dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7 Hz, 1 H), 6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0 Hz, 1 H), 7.16 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7 (MH+); HRMS Calcd. for C9H14N2O4S(M+): 246.0674. Found: 246.0672.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].I[CH2:12][CH2:13][CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][CH2:13][CH3:14])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CCCI
Product: CCCOc1ccc(C=O)cc1F

Procedure:
3-Fluoro-4-propoxybenzaldehyde was synthesized starting from 3-fluoro-4-hydroxybenzaldehyde (0.83 g, 5.95 mmol) and 1-iodopropane (1.16 ml, 11.9 mmol) according to reaction conditions described by Liou et al., J. Med. Chem. 2004, 47(11), 2903.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:14][C:13]1[CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=[CH:18][C:12]=1[O:11]2.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:14][C:13]1[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=1[O:11]2
Reactant: COC(=O)c1ccc2c(c1)CC1(O2)C(=O)Nc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CC1(O2)C(=O)Nc2ncccc21
Temperature: 25 °C

Procedure:
A mixture of methyl 2′-oxo-1′,2′-dihydro-3H-spiro[benzofuran-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate (100 mg, 0.34 mmol) and aqueous 6 N sodium hydroxide solution (0.17 mL, 1.0 mmol) in MeOH (5 mL) is heated at reflux for 1 h. The mixture is allowed to cool to ambient temperature before it is acidified to pH ˜6 with aqueous 1 N hydrochloric acid solution. The resulting mixture is filtered, and the filtrate is concentrated. The residue is partitioned between water (10 mL) and 2-methyltetrahydrofuran (2-MeTHF, 10 mL). The aqueous layer is extracted with 2-MeTHF (5×10 mL), and the combined organic layers are dried over sodium sulfate and concentrated to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]2[C:38](=[O:39])[C:33]3[N:34]=[C:35]([CH3:37])[O:36][C:32]=3[CH2:31][CH2:30][C:29]=2[CH:40]=1)[CH3:24]>O1CCCC1>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:38]2([OH:39])[C:33]3[N:34]=[C:35]([CH3:37])[O:36][C:32]=3[CH2:31][CH2:30][C:29]3[CH:40]=[C:25]([CH2:23][CH3:24])[CH:26]=[CH:27][C:28]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2=O
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A stirred solution of the product from example 1 step (vi) (3.60 g) in tetrahydrofuran (30 ml) at −70° C. was treated dropwise with n-butyllithium (4.75 ml of a 2.5M solution in hexanes) and stirred for 30 minutes. A solution of the product from example 3 step (vi) (2.60 g) in tetrahydrofuran (30 ml) was added dropwise and the reaction stirred at room temperature for 3 hours. The reaction was partitioned between brine and ethyl acetate and the organics dried (MgSO4) and evaporation under reduced pressure gave a brown oil. Purification was by column chromatography eluting with 50% ethyl acetate in isohexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:18]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C(F)(F)F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=302.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+]([O-])=O)[CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1N
Solvent: CCO
Product: Cc1ccccc1Nc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
81 ml of o-toluidine was added to absolution of 10 g of 1-chloro-3,4-dinitrobenzene in 50 ml of ethanol, and it was refluxed for 72 hours. It was concentrated by evaporation in a vacuum, the residue was taken up in ethyl acetate and 2N aqueous hydrochloric acid. The organic phase was extracted three more times with 2N aqueous hydrochloric acid, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:35])=[C:25]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])[N:26]=2)=[CH:18][CH:17]=1>>[CH3:35][C:24]1[O:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[CH:17][CH:18]=2)=[N:26][C:25]=1[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH3:34]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-triflouromethoxy phenyl boronic acid (295 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 63 mg (51%). MS (m/e) 431.2 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[CH3:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: COc1cc(C)c(B(O)O)cc1Cl
Product: COc1cc(C)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1Cl
Yield: 47 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (774 mg, 2.81 mmol) and 2-methyl-5-chloro-4-methoxyphenylboronic acid (prepared as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503) (620 mg, 3.09 mmol) were treated substantially as described in Part A of Example 19a to give 1.15 g (47%) of 2-benzyloxy-4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J=5.1 Hz, 1 H), 7.45–7.42 (m, 2H), 7.39–7.30 (m, 3H), 7.13 (s, 1H), 6.82 (d, J=5.1 Hz, 1 H), 6.79 (s, 1 H), 5.54 (s, 2 H), 3.90 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:5][CH:6]=1.[Cu](C#N)[C:12]#[N:13].N>CN(C)C=O>[CH3:9][C:8]([CH3:10])=[CH:7][C:4]1[S:3][C:2]([C:12]#[N:13])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(Br)s1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Product: CC(C)=Cc1ccc(C#N)s1
Reaction time: 2 h
Yield: 34 %

Procedure:
2-Bromo-5-(2-methylpropenyl)-thiophene described in Preparation Example 143 (60 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (1 mL), copper cyanide (62 mg, 0.69 mmol) was added at 160° C., and the solution was stirred for 2 hours. The reaction solution was cooled, then, concentrated aqueous ammonia (5 mL) was added, and the solution was extracted with diethyl ether (10 mL). The organic layer was washed, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5), and the title compound (15 mg, 0.092 mmol, 34%) was obtained as a colorless oil.
Reaction SMILES: C([NH:8][C@H:9]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([Br:21])=[CH:20][C:14]=2[N:13]=1)[CH2:10][OH:11])(OC(C)(C)C)=O.Cl>C(OCC)(=O)C.O1CCOCC1>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[NH:16][C:12]([C@@H:9]([NH2:8])[CH2:10][OH:11])=[N:13][C:14]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.00 g (5.62 mmol) (1R)—N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine in 40 ml of ethyl acetate are combined with 8.0 ml 4-molar hydrochloric acid in dioxane while cooling in the ice bath and stirred for 16 hours at ambient temperature. The reaction mixture is evaporated down and the resulting precipitate is filtered off.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[N:13]4[CH2:21][CH2:20][N:19]=[C:14]4[S:15][C:16]=3[CH:17]=[O:18])[CH:10]=[CH:11][C:4]1=2.O>CO>[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:12]3[N:13]4[CH2:21][CH2:20][N:19]=[C:14]4[S:15][C:16]=3[CH2:17][OH:18])[CH:10]=[CH:11][C:4]1=2
Reactant: O=CC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14.8 %

Procedure:
Sodium borohydride (0.13 g) was added in portions at 0-5° C. to a stirred suspension of 3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.67 g) in methanol (20 ml), then the mixture was stirred at this temperature for 45 minutes and at ambient temperature for 1.5 hours. Water (10 ml) was added dropwise, the mixture was stirred at ambient temperature for 1 hour, and the resulting solid was collected by filtration and washed with water. The solid was dissolved in ethanol, the solvent was removed in vacuo, and the residue was triturated with dichloromethane 10 ml). The resulting solid was collected by filtration and dried in vacuo to give [3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]-thiazol-2-yl]methanol (0.1 g) as a pale yellow solid, m.p. 149-150° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13]C)=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH2:22][CH2:21][NH:20][C:11](=[O:13])[C:10]2[CH:15]=[C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Reactant: NCCN1CCOCC1
Product: COC(=O)c1cc(C(=O)NCCN2CCOCC2)cc(-n2cccc2)c1
Temperature: 120 °C
Yield: 25.6 %

Procedure:
A mixture of dimethyl 5-(pyrrol-1-yl)isophthalate (1.0 g) and 4-(2-aminoethyl)morpholine (0.65 g) was heated at 120° C. for 2 hours. The residue was purified by column chromatography on silica gel (50 g) with chloroform-methanol (30:1) as an eluent. The fractions containing object product were combined and evaporated in vacuo. The crystalline residue was recrystallized from ethanol-ether to afford N-[2-(morpholin-4-yl)ethyl]-3-methoxycarbonyl-5-(pyrrol-1-yl)benzamide (353 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:53]([F:56])([F:55])[F:54])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([N:16]([CH2:20][C@@H:21]4[C@H:25]5[O:26]C(C)(C)[O:28][C@H:24]5[C@H:23]([N:31]5[C:35]6[N:36]=[CH:37][N:38]=[C:39]([NH:40]CC7C=CC(OC)=CC=7OC)[C:34]=6[CH:33]=[CH:32]5)[CH2:22]4)[CH:17]([CH3:19])[CH3:18])[CH2:13]3)[NH:7][C:6]=2[CH:52]=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O>[NH2:40][C:39]1[C:34]2[CH:33]=[CH:32][N:31]([C@@H:23]3[CH2:22][C@H:21]([CH2:20][N:16]([CH:14]4[CH2:13][CH:12]([CH2:11][CH2:10][C:8]5[NH:7][C:6]6[CH:52]=[C:2]([Cl:1])[C:3]([C:53]([F:55])([F:54])[F:56])=[CH:4][C:5]=6[N:9]=5)[CH2:15]4)[CH:17]([CH3:19])[CH3:18])[C@@H:25]([OH:26])[C@H:24]3[OH:28])[C:35]=2[N:36]=[CH:37][N:38]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (525 mg, 0.683 mmol) was dissolved in a mixture of Trifluoroacetic Acid (9 ml) and Water (1 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to RT. After 4 h at RT, the mixture was concentrated. The residue was taken up in 20 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 15 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 15 drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight. The crude material was purified by flash chromatography (SiO2, eluting with 12% 7N NH3 in CH3OH/CH2Cl2) to give a colorless glass/stiff foam. 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1H), 7.89 (d, J=2.07 Hz, 1H), 7.69 (d, J=2.28 Hz, 1H), 7.21 (dd, J=3.42, 1.76 Hz, 1H), 6.59 (d, J=3.52 Hz, 1H), 4.33 (t, J=6.84 Hz, 1H), 3.89 (q, J=5.25 Hz, 1H), 3.03 (m, 0.5H), 2.89 (m, 2H), 2.70 (m, 0.5H), 2.49 (m, 1H), 2.40 (m, 2H), 2.27 (br. s., 2H), 2.16 (d, J=7.26 Hz, 4H), 2.06 (m, 2H), 1.91 (m, 2H), 1.62 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32].O>O1CCCC1>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
Solid carbonyldiimidazole (79.10 g, 0.488 mol) was added to a room temperature solution of N-benzyloxycarbonyl-glycine (117.11 g, 0.560 mol) in anhydrous tetrahydrofuran (THF, 600 mL). The resulting solution was stirred for 45 minutes until C02 evolution had ceased. A solution of L-phenylalanine methyl ester (79.65 g, 0.444 mol) in anhydrous THF (~200 mL) was then added. The reaction temperature was maintained below 40° C. by application of a water bath to the exterior of the reaction vessel. After two hours, a small portion of water (1.5 mL, ~0.08 mol) was added to the reaction mixture to hydrolyze any remaining acylimidazolides and the resulting solution was left to stir overnight. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (~1 L). This ethyl acetate solution was extracted with 1 N HCI (2×300 mL--the first aqueous extract was acidified to a pH of 1 by addition of 6 N HCl), water (300 mL), saturated aqueous sodium carbonate (300 mL), half-saturated aqueous sodium carbonate (250 mL), and brine (250 mL). The organic phase was dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to constant weight. Field desorption mass spectrometry (FDMS) of the resulting oil (160.88 g, ~0.434 mol, 98%) indicated the presence of a single component (M+=370). This material was not further purified, but was instead converted directly into cyclo-glycyl-L-phenylalanine (8) by catalytic hydrogenation (vide infra).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.NCCC1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[S:40]([C:37]1[CH:38]=[CH:39][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:35][CH:36]=1)(=[O:42])(=[O:41])[NH2:43]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: NS(=O)(=O)c1ccc(CCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 4-(2-aminoethyl)benzenesulfonamide instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.31 (1H, s) 8.23 (1H, t, J=5.86 Hz) 8.02 (1H, d, J=5.37 Hz) 7.68-7.83 (3H, m) 7.48 (1H, d, J=5.47 Hz) 7.42 (2H, d, J=8.30 Hz) 7.32 (1H, d, J=2.93 Hz) 7.28 (2H, s) 6.83 (1H, d, J=5.37 Hz) 6.44 (1H, dd, J=3.51, 1.95 Hz) 3.50 (2H, q, J=7.13 Hz) 2.91 (2H, t, J=7.27 Hz)