Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH2:18])[CH:5]=[CH:6][C:7]=1[F:8].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.CC(O)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:18][C:10]1[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Nc1nc2ccccc2n1-c1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1ccc(CNc2nc3ccccc3n2-c2ccc(F)c(F)c2)cc1F

Procedure:
1-(3,4-Difluorophenyl)-1H-benzoimidazol-2-ylamine, prepared as described in Procedure E (Scheme 5, Steps A-C), was dissolved in acetonitrile, added 3,4-difluorobenzaldehyde (1 eq), sodium triacetoxyborohydride (2 eq) and a catalytic amount of AcOH. The reaction mixture was heated in a sealed vial by means of MW irradiation at 100° C. for 25 min. Saturated aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative LCMS to give the title compound as the free base (solid, mp 158.5-159.5° C.). MS(ES+) m/z 372 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.50 (d, 2H), 6.85-6.92 (m, 2H), 6.99-7.15 (m, 2H), 7.20-7.46 (m, 5H), 7.68-7.74 (m, 1H), 7.78-7.83 (m, 1H).
Reaction SMILES: [Si:1](OC[C@@H](C1C=CC(B(O)O)=CC=1C)C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([CH3:32])[CH2:30][OH:31])=[C:25]([O:33][CH3:34])[CH:24]=1.C([Si](C)(C)Cl)(C)(C)C>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([CH3:32])[CH2:30][O:31][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:25]([O:33][CH3:34])[CH:24]=1
Reactant: COc1cc(Br)ccc1[C@@H](C)CO
Reactant: Cc1cc(B(O)O)ccc1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Product: COc1cc(Br)ccc1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Yield: 81 %

Procedure:
Using procedure analogous to that used to prepare Intermediate 10, Intermediate 9 (7.8 g, 158 mmol) was protected with tert-Butyldimethylchlorosilane to yield (R)-(2-(4-bromo-2-methoxyphenyl)propoxy)(tert-butyl)dimethylsilane (9.2 g, 81% yield) as a clear oil. The protected alcohol (3.00 g, 8.35 mmol) was reacted with BuLi and trimethyl borate to yield Intermediate 10 (1.87 g, 5.77 mmol, 69.1% yield) as a colorless oil. 1H NMR (400 MHz, methanol-d3) 8 ppm 7.12-7.19 (m, 2H) 7.12 (s, 1H) 3.82 (s, 3H) 3.75 (dd, J=9.89, 5.50 Hz, 1H) 3.52-3.58 (m, 0H) 3.32-3.37 (m, 0H) 1.23 (d, J=6.60 Hz, 3H) 0.84 (s, 9H) −0.04 (d, J=2.20 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]3[CH2:23][CH2:22][O:21][C:20]3=[O:24])[CH:16]=2)[NH:11][C:10]1=[O:25].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH2:32]=O.[ClH:34]>C(O)(=O)C>[ClH:34].[CH3:1][C:2]1[C:6]([CH2:32][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]3[CH2:23][CH2:22][O:21][C:20]3=[O:24])[CH:16]=2)[NH:11][C:10]1=[O:25]
Reactant: C1COCCN1
Reactant: C=O
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)[nH]1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(CN4CCOC4=O)cc32)c(C)c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step A (1.3 mmoles) in acetic acid (20 ml) there are added at 0° C. morpholine (1.43 mmoles) and formaldehyde (37% aq., 1.3 mmoles). The reaction mixture is stirred overnight at ambient temperature. The mixture is evaporated to dryness and the residue is purified on silica gel (SiO2; gradient 100% DCM to DCM/MeOH 9/1). The product obtained is converted into the hydrochloride as described in Step E of Example 19 to yield the title product. Mixture of Z/E isomers (99.5/0.5)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH3:13])=[N:4][C:3]=1[NH:14][CH2:15][CH3:16].[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][CH3:25]>CO>[CH2:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][NH:17][C:8]([C:6]1[C:5]([O:12][CH3:13])=[N:4][C:3]([NH:14][CH2:15][CH3:16])=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH3:25]
Reactant: CCN1CCCC1CN
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Solvent: CO
Product: CCNc1nc(OC)c(C(=O)NCC2CCCN2CC)nc1Cl

Procedure:
In 20 ml. of methanol were dissolved 2.0 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 2.0 g. of 2-aminomethyl-1-ethylpyrrolidine and the solution was refluxed for 24 hours. After cooling, the solvent was distilled off under reduced pressure from the reaction mixture to provide an oily residue. The residue was dissolved in 30 ml. of a dilute aqueous hydrochloric acid solution and the solution was washed three times each time with 10 ml. of chloroform. (The chloroform washings was washed with water, dried, and then the solvent was distilled off under reduced pressure, whereby 1.05 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate used as the starting material was recovered.). The aqueous layer was basified with a 3 N aqueous sodium hydroxide solution and the oily material formed was extracted with 30 ml. of chloroform. The extract was washed with water, dried, the solvent was distilled off under reduced pressure, and the oily residue formed was allowed to stand, whereby the oily residue was crystallized. After recrystallizing the crystals from toluene, 0.88 g. of N-(1-ethylpyrrolidin-2-ylmethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide melting at 167°-169° C. was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure B′ and using phenylacetyl chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 45°-47° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].S([O-])([O-])=O.[Na+:19].[Na+].Cl>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([O-:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].[Na+:19].[Na+:19].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([O-:12])=[O:11])[CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)c(S(=O)[O-])c1

Procedure:
is obtained from 186 g of 5-carboxy-2-chlorobenzenesulfinic acid, prepared by reduction of 261 g of 5-carboxy-2-chlorobenzenesulfonyl chloride with 157 g of sodium sulfite in 700 ml of water at 70° C. at pH 9-10 and subsequent acidification using HCl, by neutralization with 67.6 g of caustic soda in 2 liters of water, removal of the latter by distillation and crystallization of the residue with acetone.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[Na+:10].N[C@H:12]([C:17]([O-])=[O:18])[CH2:13][C:14](O)=[O:15].[NH4+:20]>>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+:10].[Na+:10].[C:17]1(=[O:18])[NH:20][C:14](=[O:15])[CH2:13][CH2:12]1
Reactant: [NH4+]
Reactant: N[C@@H](CC(=O)O)C(=O)[O-]
Agent: [Na+]
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Product: O=C1CCC(=O)N1

Procedure:
Thermal polymerization of the 1:1 equivalent comonomeric composition prepared from the solution of monosodium aspartate and monoammonium aspartate to produce a copolymer of sodium aspartate and succinimide by thermal treatment at 220° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:31][C@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][CH2:33][C@H:32]([NH:31][C:13]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:12][CH2:11][S:10]1)=[O:15])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: N[C@@H](CCO)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCSC1C(=O)N[C@@H](CCO)c1ccccc1
Temperature: -25 °C

Procedure:
Commercial 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid (III) (1 g, 4.29 mmol) was dissolved in dry THF (50 ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. The solution was cooled down to −25° C. and N-methyl morpholine (1.084 g, 10.72 mmol) was added in dry THF (5 ml). A solution of isobutyl-chloroformate (0.615 g, 4.5 mmol) in dry THF (10 ml) was then added dropwise over a period of 10 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of −25° C. by the use of a dry-acetone bath. After the complete addition of the chloroformate, the reaction mixture was stirred at −25° C. for 30 min after which time an amine (IV)/(IV*), e.g., (3S)-3-amino-3-phenyl-1-propanol (0.778 g, 5.14 mmol) was added drop-wise over a period of 10 min. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The solvent was removed and the residue re-dissolved in ethyl acetate (150 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). Organics then dried with magnesium sulfate and concentrated in vacuo. The product (V), e.g., tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, was finally obtained as a white foam (1.5 g, 95%). The antipodal intermediate, tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, as well as the racemic inter-mediate, tert-butyl 2-({[3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate were made according to the same protocol, starting from commercial (3R)-3-amino-3-phenylpropan-1-ol or 3-amino-3-phenylpropan-1-ol, respectively.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.C([OH:23])C.CN(C)C=O>[OH-].[Na+]>[CH2:14]([S:13][CH2:12][C:4]1[NH:3][C:2](=[O:23])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCO
Reactant: Nc1nc(CSCc2ccccc2)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(CSCc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 5.4 g (0.019 mole) of 4-amino-2-(benzylthiomethyl)pteridine in 400 ml of 5% aqueous sodium hydroxide. Reaction time: 7 hours at 85° C. Yld: 1.7 g (31%), m.p. 224°-226° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=3[CH3:31])[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.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>[ClH:12].[CH3:32][N:29]1[C:30]([CH3:31])=[C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:14]3[C:13]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:24][CH2:23]2)[C:27]([CH3:33])=[N:28]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1nn(C)c(C)c1CN1CCN(c2nccnc2Cl)CC1
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)c(C)c1CN1CCN(c2nccnc2-c2ccc(CO)cc2)CC1
Product: Cl
Temperature: 120 °C

Procedure:
Stir together 4-(hydroxymethyl)benzeneboronic acid (182 mg, 1.2 mmol), 3′-chloro-4-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (321 mg, 1.0 mmol), potassium carbonate (332 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 5 μmol) in dry N,N-dimethylacetamide (4 mL) and water (2 mL) at room temperature. Heat to 120° C. for 6 hr. under nitrogen. Cool to room temperature, purify using SCX chromatography and further purify using silica gel chromatography eluting with (5:95 to 20:80 methanol:DCM). Dissolve in acetonitrile, and add 2 M aq. HCl and water then lyophilize to give the title compound as a peach coloured powder (405 mg, 94%). MS (ES): m/z=393 [M+H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9](N)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1ccccc1
Reactant: NCCCCCCN
Product: NCCCCCCNC(=O)c1ccccc1
Yield: 62 %

Procedure:
Using the general method of Example 9 Part A, hexamethylenediamine (348.63 g, 3 mol) was reacted with benzamide (121.14 g, 1 mole) to provide 136.5 g of N-(6-aminohexyl)benzamide.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:17]Cl.CO.C[Si](C=[N+]=[N-])(C)C>O.C(O)=O>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:5]=1[NH:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(F)c(F)cc1NC1CC1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: COC(=O)c1cc(F)c(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropylamino-4,5-difluorobenzoic acid (Example 5a) (6.0 g, 28.1 mmol), dichloromethane (100 mL), and methanol (20 mL) is added (trimethylsilyl)diazomethane (2.9 M solution in hexane) dropwise until the evolution of gas stops. The solution is stirred at room temperature for 0.5 hour and 88% formic acid is added dropwise until the evolution of gas again stops. Water is added, and the solution is extracted with dichloromethane, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue is purified by silica gel column chromatography using hexane/EtOAc (9:1) as the eluent afford a 5.4 g of the title compound as a clear oil. MS CI: m/z 228 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[CH3:16][OH:17]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:1](=[O:5])[C:2]([C:9]1[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[N:7][CH:8]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CO
Reactant: c1ccn2ccnc2c1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)c1cnc2ccccn12

Procedure:
Add oxalyl chloride (2.13g, 1.46 ml, 16.8 mmol) to a solution of imidazo[1,2-a]pyridine (1.0 g, 8.47 mmol) in toluene (75 ml). Heat the mixture at reflux for 15 hours. Cool the reaction and gently add methanol. Concentrate the resulting mixture under reduced pressure and partition between hot ethyl acetate and saturated aqueous sodium bicarbonate. Wash organic phase with saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure. Triturate in ethyl acetate to give the title compound as an off-white solid (0.75 gm).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2Cl)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2Cl)ccn1)NO
Reaction time: 22 h
Yield: 44 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (19 mg, 0.043 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a pale blue oil (8 mg, 44%).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21](=[O:35])[N:22]([CH3:34])[CH2:23][C:24]3[O:25][C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]=3[CH3:29])[CH:17]=[N:18][C:12]=2[NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][N:22]([CH2:23][C:24]1[O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]=1[CH3:29])[C:21](=[O:35])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[N:18][C:12]2[NH:11][CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[CH:15]=1
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C(=O)OC(C)(C)C)CCN3)oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCN3)oc2ccccc12
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A solution of (E)-7-{2-[methyl-(3-methylbenzofuran-2-ylmethyl)carbamoyl]vinyl}-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid tert-butyl ester (0.38 g, 0.80 mmol) in CH2Cl2 (4 mL) was cooled in an ice bath and then treated with TFA (4 mL). After stirring for 2 h, the mixture was concentrated under vacuum. The residue was treated with saturated NaHCO3 (25 mL) and extracted with CH2Cl2/MeOH (4×═mL of a 98:2 mixture). The combined organic layers were dried over Na2SO4, filtered and concentrated to a light yellow solid. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 92:8) gave the title compound (0.21 g, 70%) as a white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ8.14 (br s, 1H), 7.68-7.63 (m, 1H), 7.50-7.40 (m, 3H), 7.26-7.20 (m, 2H), 7.04-6.72 (m, 1H), 5.10 (s, 1H), 4.83-4.72 (m, 2H), 3.89 (s, 2H), 3.30-3.26 (m, 2H), 3.22-3.04 (m, 5H), 2.31 (s, 3H), 1.70 (br s, 1H); MS (ESI) m/e 377 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:5][C:6]([OH:24])([CH2:11][C:12]([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13])[C:7]([F:10])([F:9])[F:8].[N+:33]([O-])([OH:35])=[O:34].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:5][C:6]([OH:24])([CH2:11][C:12]([CH3:14])([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([N+:33]([O-:35])=[O:34])[CH:16]=1)[CH3:13])[C:7]([F:9])([F:8])[F:10]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cccc2c1OCC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cc1cc(C(F)(F)F)cc(Cl)c1F)C(F)(F)F)c1cc([N+](=O)[O-])cc2c1OCC2
Reaction time: 0.08 h

Procedure:
To a solution of 42 mg (0.087 mmol) of 2-(3-chloro-2-fluoro-5-trifluoromethylbenzyl)-4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol in 2 mL of acetic acid was added a mixture of 15 μL of fuming nitric acid (90%) and 22 μL of sulfuric acid in 250 μL of acetic acid in several portions. The mixture eventually turned from clear to green to deep blue. After 5 minutes, the reaction was cautiously made basic with saturated aqueous sodium bicarbonate and extracted with four 6 mL portions of EtOAc. The combined organic layers were washed with three 5 mL portions of saturated aqueous sodium bicarbonate, two 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The yellow residue was purified by preparative chromatography (silica gel, EtOAc-hexanes, (2:8)) to afford 34 mg of partially purified product, a second preparative chromatography (silica gel, toluene-hexanes (6:4)) afforded 24 mg of the title compound.
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@:18]12[CH2:27][O:26][C@@H:25]([CH:28]([OH:34])[CH2:29][CH2:30][C:31]([CH3:33])=[CH2:32])[CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N:19]2>ClCCl.O>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@:18]12[CH2:27][O:26][C@@H:25]([CH:28]3[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[O:34]3)[CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N:19]2
Reactant: C=C(C)CCC(O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Boron trifluoride diethyl etherate (21 μL, 0.98 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1-hydroxy-4-methylpent-4-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C77) (106 mg, 0.22 mmol) in dichloromethane (7 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes, then allowed to warm to room temperature and stirred for a further 5 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated to afford a yellow oil. Purification via silica gel chromatography (Gradient: 0% to 90% ethyl acetate in heptane) afforded the product as a white solid. By 1H NMR analysis, this was isolated as a single diastereomer. Yield: 30.1 mg, 28%. LCMS m/z 487.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.24 (br d, 7.0 Hz, 2H), 7.37-7.53 (m, 4H), 6.85-6.95 (m, 2H), 4.15 (d, J=12.1 Hz, 1H), 3.90 (ap. q, J=6.8 Hz, 1H), 3.79 (d, J=12.1 Hz, 1H), 3.53 (ddd, J=10.1, 6.6, 3.3 Hz, 1H), 3.10-3.15 (m, 1H), 3.01 (dd, J=12.8, 4.2 Hz, 1H), 2.66 (dd, J=12.7, 2.7 Hz, 1H), 2.03-2.12 (m, 1H), 1.86-1.99 (m, 3H), 1.68-1.78 (m, 2H), 1.27 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)(C)C.Cl>[ClH:1].[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH3:13])[CH:15]=1
Reactant: Fc1ccc2ncnc(Cl)c2c1
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(Nc2ncnc3ccc(F)cc23)c1
Yield: 43 %

Procedure:
4-Chloro-6-fluoroquinazoline (1.1 g) was suspended in isopropanol (20 ml) and 3-methylaniline (0.65 ml) was added. The mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool and the precipitate was filtered off. The solid so obtained was suspended in 2N aqueous hydrochloric acid and stirred for several minutes. The mixture was filtered to give 6-fluoro-4-(3-methylanilino)quinazoline hydrochloride salt in 43% yield, m.p. 255-260° C.;