Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH2:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:15]2[C:33](O)=[CH:34][CH:35]=[C:36]([CH3:37])[C:14]=2[N:13]=1)[CH2:9][CH2:10][CH3:11].C(Cl)(=O)C>N1C=CC=CC=1>[C:3]([O:5][C:33]1[C:15]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:12]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:13][C:14]=2[C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:4])[CH3:2]
Reactant: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CCCCc1nc2c(C)ccc(OC(C)=O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 2 h

Procedure:
0.55 g (1 mmol) of 4'-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate is dissolved in 20 ml of pyridine. 0.5 ml (7 mmol) of acetyl chloride is added dropwise to the mixture at 5° C. with stirring. The mixture is stirred for 1 hour at 5° C. and then for 2 hours at ambient temperature. The pyridine is distilled off in vacuum on a rotary evaporator. The residue is mixed with water and filtered under suction. After washing with water, it is dried at 50° C. in vacuum.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.[BH4-].[Na+]>CN(C=O)C>[CH3:2][CH:3]1[CH2:4][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CBr)C4)c3)ncnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1

Procedure:
3-(Bromomethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.65 g, 0.0013 mol) was reacted with sodium tetrahydroborate (0.096 g, 0.0026 mol) in DMF (5.2 mL) (˜0.5 M) at rt under nitrogen for 3h. The reaction was quenched with water and extracted with dichloromethane. The organic layers were washed with water, brine, dried over MgSO4 and concentrated to give a yellow oil, the desired product as cis- and trans-isomer mixtures. LCMS calculated for C22H31N6OSi(M+H)+: 423.2; Found: 423.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:25][CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(OCCOC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300 mg, 0.797 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium hydride (60% in oil, 35.0 mg, 0.877 mmol), and the mixture was stirred at room temperature for 10 min. To the mixture was added 2-bromoethyl methyl ether (166 mg, 1.19 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (218 mg, 0.502 mmol, 63%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13](S(C2C=CC=CC=2)(=O)=O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1-c1c[nH]c2ccccc12
Temperature: 100 °C
Yield: 24.3 %

Procedure:
3-(2-tert-Butylphenyl)-1-(phenylsulfonyl)-1H-indole (172.6 mg, 0.443 mmol) was combined with tetrahydrofuran (2.0 mL) and 1 M tetrabutylammonium fluoride solution (2.21 mL) and heated to 100° C. for 20 minutes. The cooled reaction is charged to a silica gel column and purified by eluting with a gradient of ethyl acetate and hexanes to give 3-(2-tert-butylphenyl)-1H-indole (26.8 mg, 26%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.CCCCCC.C([Li])CCC.CON(C)[C:21](=[O:23])[CH3:22]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:21](=[O:23])[CH3:22])=[N:4][CH:3]=1
Reactant: CON(C)C(C)=O
Reactant: Cc1cncs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ncc(C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
Commercially available 5-methyl-1,3-thiazole (218 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution which was then cooled to −78° C. A hexane solution (1.56 M) (1.4 ml) of n-butyllithium was slowly added to the cooled solution over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. N-Methoxy-N-methylacetamide (206 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution which was then slowly added thereto over a period of 10 min, followed by stirring at −78° C. for 2 hr. The cooling bath was removed, an aqueous saturated ammonium chloride solution (5 ml) was added, and the mixture was stirred for 30 min. Further, water (5 ml) was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was removed, and the residue was purified by chromatography on silica gel using hexane/ethyl acetate for development to give the title compound (267 mg, 86%).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:19]1([S:25][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[C:9]([S:25][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cccc(Sc3ccccc3)c2C(=O)c2cccc(Sc3ccccc3)c21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
1,5-Dichloroanthraquinone (100 parts) is added at room temperature with stirring to a mixture of dimethylformamide (474 parts), thiophenol (135 parts) and potassium carbonate (63 parts). The suspension is heated at 125° C. for 3 hours, cooled to room temperature and then cooled to 5° C. for 1 hour. The precipitate is filtered off and washed with a 50/50 mixture of 95% ethanol and 8% sodium hydroxide solution (2×250 parts). The filter cake is then slurried with a further 500 parts of the ethanol/sodium hydroxide solution mixture. After stirring at room temperature for 1 hour, the precipitate is filtered off and washed again with ethanol/sodium hydroxide solution mixture (5×100 parts), followed by water (250 parts) containing glacial acetic acetic acid (25 parts) and finally water (3×250 parts). The filter-cake is dried at 70° C. giving 140.4 parts of 1,5-bis(phenylthio) anthraquinone, mp (melting point) 256° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.42 g, 5.08 mmol), 4-fluorobenzenethiol (0.663 ml, 6.10 mmol) and K2CO3 (1.054 g, 7.62 mmol) in ACN (12.71 mL) was stirred at 85° C. overnight. The reaction mixture was filtered by suction and the solvent removed gave tert-butyl 4-((4-fluorophenyl)thio)piperidine-1-carboxylate (1.5 g, 95%) as a white solid.
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][C:26]#[N:27])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([CH:31]([CH2:34][CH2:35][CH3:36])[CH:32]=O)[CH2:29][CH3:30].[OH-].[Na+].CCOC(C)=O>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:28]([CH:31]([CH2:34][CH2:35][CH3:36])[CH:32]=[C:25]([C:22]1[N:23]=[N:24][N:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:21]=1)[C:26]#[N:27])[CH2:29][CH3:30]
Reactant: CCCC(C=O)CCC
Reactant: N#CCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCC(C=C(C#N)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)CCC
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a solution of (2-trityl-2H-tetrazol-5-yl)-acetonitrile (2.0 g, 5.69 mmol) in 25 mL benzene was added 2-n-propylvaleraldehyde (0.87 g, 6.79 mmol), 25 mL 10% NaOH (aq), and tetrabutylammonium bromide (50 mg). The mixture was stirred for 1 h, then poured into EtOAc. The phases were separated, and the organic phase dried (MgSO4) and concentrated. Flash chromatography of the residue (10→15% EtOAc/hexanes) provided 1.66 g (64%) of 4-propyl-2-(2-trityl-2H-tetrazol-5-yl)-hept-2-enenitrile as a colorless solid. 1H NMR (CDCl3) δ 7.34 (m, 10H, —CHCH═C—), 7.09 (m, 6H), 2.86 (m, 1H, —CH2CH—), 1.30-1.59 (m, 8H, —CH2CH2—), 0.90 (t, J=7.1 Hz, 6H, CH3—).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCO
Product: OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as yellow solid, mp: 128-129° C., MS: 313 (M, 1 Cl).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2C(=O)O1>CC1C=CC=CC=1C>[CH2:6]([O:5][C:1]([C:2]1[CH:3]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[N:8]=1)=[O:4])[CH3:7]
Reactant: C#CC(=O)OCC
Reactant: O=C1ONN2CCCCC12
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCCC2

Procedure:
ethyl propiolate (804 mg) was added to the o-xylene (15 mL) solution of tetrahydropyridino[1,2-c][1,2,3]oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1–1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: Cc1ccccc1B(O)O
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxyphenol (1.0 g, 0.0049 mol), (2-methylphenyl)boronic acid (1.7 g, 0.012 mol), TEA (4.1 mL, 0.030 mol), cupric acetate (1.4 g, 0.0079 mol) and DCM (50 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.28 (s, 3H), 3.88 (s, 3H), 6.61 (d, J=8.59 Hz, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.99 (dd, J=8.59, 2.02 Hz, 1H), 7.04 (t, J=7.33 Hz, 1H), 7.09-7.17 (m, 2H), 7.24 (d, J=7.33 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8](Br)=[CH:7][CH:6]=1.[CH3:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[CH:31]=2)=[CH:7][CH:6]=1
Reactant: N[C@H](CNc1ccc(Br)c(-c2ccncc2)n1)Cc1ccccc1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2ccc(NC[C@@H](N)Cc3ccccc3)nc2-c2ccncc2)c1
Temperature: 25 °C

Procedure:
To a stirred, degassed mixture of 6-((S)-2-Amino-3-phenylpropylamino)-3-bromo-2-(4-pyridyl)pyridine (4.2 gm, 10.9 mmole), 3-methylbenzene boronic acid (1.8 gm, 13 mmole), in aqueous 2 M Na2CO3 (50 mL) and toluene (50 mL) at rt was added Pd(PPh3)4(400 mg, 0.35 mmole). The mixture was heated to reflux for 12 hrs, cooled to rt, and extracted with toluene. The combined organic layers were washed with brine, concentrated and purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give the title compound. MS (m/z): Calcd. C26H26N4 (M+): 394, found (M+H)+: 395.1.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:4][CH2:5][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[NH2:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1.O>[CH2:27]([O:26][C:24]([NH:7][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][C:3]([F:16])([F:2])[C:12]([F:13])([F:14])[F:15])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@@H](N)CCC(F)(F)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CCC(F)(F)C(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 141.5 g (520.99 mmol) of rac-methyl 5,5,6,6,6-pentafluoronorleucinate hydrochloride from Example 133A were taken up in 850 ml of THF and 850 ml of water, and 223.2 g (1.62 mol) of potassium carbonate were added carefully at RT. 82 ml (573.09 mmol) of benzyl chloroformate were then added dropwise, and the suspension was stirred at RT overnight. The reaction mixture was extracted twice with 500 ml of ethyl acetate and the organic phase was dried with magnesium sulphate, filtered off and concentrated. The residue was diluted with 50 ml of dichloromethane and purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient: 9/1 to 4/1). The isolated product fraction was re-purified by preparative HPLC [Daiso C18 10 μm Bio 300×100 mm, neutral; mobile phase: acetonitrile/water gradient; flow rate: 250 ml/min; temperature: RT; wave length: 210 nm). This gave 27.4 g (14% of theory) of the target compound.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[O:16][CH2:15][C@@H:10]2[CH2:11][O:12][CH2:13][CH2:14][N:9]2[CH2:8]1)(=O)=O.Cl.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:21]([F:39])[C:20]=1[Cl:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:40].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:5][CH2:6][C@@H:7]4[O:16][CH2:15][C@@H:10]5[CH2:11][O:12][CH2:13][CH2:14][N:9]5[CH2:8]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[C:21]([F:39])[C:20]=1[Cl:40]
Reactant: CS(=O)(=O)OC[C@H]1CN2CCOC[C@H]2CO1
Reactant: COc1cc2c(Nc3ccc(Br)c(Cl)c3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)c(Cl)c3F)ncnc2cc1OC[C@H]1CN2CCOC[C@H]2CO1
Reaction time: 12 h
Yield: 19.1 %

Procedure:
A solution of (3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl methanesulfonate (0.215 g, 0.856 mmol), 4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (0.247 g, 0.570 mmol), and potassium carbonate (0.400 g, 2.90 mmol) in DMF (1.9 mL) was heated in a sealed reaction tube at 75° C. for 12 h, then 90° C. for 12 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 10% methanol in ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted (3×50 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by HPLC (reverse-phase, acetonitrile/water/0.1% TFA). Upon removal of solvent the product was taken up in methanol and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo then taken up in methanol and treated with 4.0 M hydrogen chloride in dioxane (0.10 mL). Removal of solvent in vacuo provided 32.1 mg (10%) of N-(4-bromo-3-chloro-2-fluorophenyl)-7-{[(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl]oxy}-6-(methyloxy)quinazolin-4-amine hydrochloride. MS (EI) for C23H23N4O4FClBr: 554 (M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=O.O.[NH2:13][NH2:14]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:13][NH2:14])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(Br)cn1

Procedure:
5-Bromo-pyridine-2-carboxylic acid methyl ester (J. Org. Chem., 2001, 66(2), 605-608, compound 4) (18.10 g, 83 mmol) and hydrazine monohydrate (12.5 mL, 250 mmol) were dissolved in methanol (400 mL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title product, 15.40 g.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32](=[N:34]O)[NH2:33]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[N:34]=[C:20]([CH:8]2[CH2:9][CH:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=3)[CH2:11][N:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:23])=[O:5])[CH2:7]2)[O:22][N:33]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Reactant: NC(=NO)c1c(F)cccc1F
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 23 mg (26% of theory)
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][C:6]1=NCCC2.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[C:11]([N:1]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C1CN=C2CCCN2C1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)n1cccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound ◯3 (10.43 g, 20 mmol.) in dichloromethane (100 ml) at 0° C. was added DBN (1,5-diazabicyclo[4,3,0]non-5-ene) (4.96 g, 40 mmol.) followed by a solution of ethyl chloroformate (3.42 g, 32 mmol.) in dichloromethane (20 ml). After completion of the transformation to the N-carboethoxy derivative 4 (approximately 1 hour), an additional equivalent of DBN (2.48 g, 20 mmol.) was added and the reaction mixture was stirred at 25° C. for 20 hours and evaporated to dryness. Chromatographic purification of the residue on silica gel (chloroform/ethyl acetate; 9/1) afforded the N-carboethoxy pyrrole ◯5 (α, β-anomeric mixture) as a white foam (10 g, 84% from ◯3 ). The structure was confirmed by CHN elemental analysis and NMR spectroscopy.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH2:9][CH2:8][O:7]2)[CH2:3][CH2:2]1.C(=O)(OC(C)(C)C)[O:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.[Cl-].[Na+]>CC1CCCO1>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:2][CH2:3][C:4]2([C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH2:9][CH2:8][O:7]2)[CH2:5][CH2:6]1
Reactant: c1cc2c(s1)C1(CCNCC1)OCC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OCCc1ccsc12
Reaction time: 12 h
Yield: 99 %

Procedure:
Spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine] (60 g, 286.6 mmol) in 2-methyltetrahydrofuran (600 mL) is stirred at 22° C. for 10 min. Then, tert-butoxycarbonyl tert-butyl carbonate (65.6 g, 301 mmol) in 2-methyltetrahydrofuran (300 mL) is added dropwise. After 12 hr., an aqueous solution of sodium chloride (250 mL) is added and the organic layer is separated. The aqueous layer is washed twice with 2-methyltetrahydrofuran (2×50 mL) and the organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound in 99% yield. MS (m/z): 310 (M+1).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:14]([CH2:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:36]=3[N:35]=2)=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[N:18](S(C1C=CC(C)=CC=1)(=O)=O)[CH:17]=[CH:16]2.O.NN.[OH-].[K+]>CCO.C(Cl)Cl.FC(F)(F)CO>[NH2:3][CH2:12][C:13]1[C:14]([CH2:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:36]=3[N:35]=2)=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[NH:18][CH:17]=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(CN4C(=O)c5ccccc5C4=O)cc(C)c32)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CN)c(Cc2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-((5-((1,3-dioxoisoindolin-2-yl)methyl)-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (60 mg, 0.100 mmol) and hydrazine hydrate (5.01 mg, 0.100 mmol) in EtOH (2 mL) was stirred at 100° C. under microwave irradiation for 0.5 hr. To the mixture was added KOH (56.1 mg, 1.001 mmol), and then the mixture was stirred at 100° C. under the microwave irradiation for 1.75 h. The reaction mixture was diluted with CH2Cl2/2,2,2-trifluoroethanol (c.a. 9/1). The layers were separated and the organic layer was washed successively by H2O and brine, dried over Na2SO4, and filtered. After concentration, the residue was purified by silica gel flash column chromatography (CH2Cl2/2M NH3 in MeOH=94/6) to give the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.28 (br. s., 1H), 8.53 (br. s., 3H), 8.09 (s, 1H), 7.68 (d, J=8.34 Hz, 1H), 7.55 (dd, J=1.00, 8.30 Hz, 1H), 7.38 (t, J=2.80 Hz, 1H), 7.06 (s, 1H), 6.76-6.84 (m, 1H), 4.61 (s, 2H), 4.27-4.42 (m, 2H), 2.45 (s, 3H). HRMS calcd. for C19H17N6 (M+H)+ 316.1557. found 316.1559.