Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH2:24])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)(=[O:27])[CH3:26].C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC=C(C(=O)C)C=2)(=O)=O)N)=CC=CC=1)=O)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH:24][S:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:25](=[O:27])[CH3:26])[CH:29]=2)(=[O:36])=[O:35])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCc1ccccc1
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: CC(=O)c1cccc(S(=O)(=O)C(N)c2ccccc2-c2ccccc2C(=O)NCc2ccccc2)c1
Product: CC(=O)c1cccc(S(=O)(=O)NCc2ccccc2-c2ccccc2C(=O)NCc2ccccc2)c1

Procedure:
From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5b) and 3-acetylphenylsulfonyl chloride, according to the general working procedure 110 mg of 2′-(3-acetylphenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid benzylamide were obtained;
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=CC=C[CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)C(C(OCC)=O)=CC=[N+](C)C.CC[O-].[Na+].C(SCC(OCC)=O)(C)C>C(O)C>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([CH:17]([CH3:18])[CH3:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)CSC(C)C
Agent: CC[O-]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)C(C)C

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (17.5 cc) and ethyl (isopropylthio)acetate (5.7 g) in ethanol (57 cc). Diethyl 2-dimethylamino-5-isopropylthio-2,4-hexadienedioate (9.8 g) is thereby obtained in the form of an orange-coloured oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.C(#N)C.Cl[C:21](OCC)=[O:22]>O>[O:4]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:9])[NH:10][C:21]1=[O:22]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1ccccc1O
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2ccccc2o1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Following the method of Shapiro et al., JACS, 79:2811 (1957), salicylamide (59.0 g, 0.43 mol, 1.0 eq), pyridine (150 mL) and acetonitrile (125 mL) were placed in a 500 mL three-neck flask equipped with a magnetic stir bar, a thermometer, and an addition funnel. After cooling to about 5° C. in a salt ice bath, ethyl chloroformate (45.2 mL, 0.47 mol, 1.1 eq) was added dropwise over 25 minutes so that the reaction temperature did not exceed 10° C. during the addition. The reaction mixture was stirred for 30 minutes at 10° C. The addition funnel was replaced with a Dean-Stark trap and a water-cooled condenser. The mixture was heated to a distillation temperature of about 90° C. Distillation was continued until the internal temperature reached about 124° C. (200 ml. of distillate removed). The temperature was reduced so that the reaction mixture refluxed but did not distill. After one hour at reflux, the reaction mixture was cooled to about 25° C. and poured into water (400 mL). Concentrated aqueous hydrochloric acid (24 mL) was added. A white solid formed, which was collected by filtration, washed with water (200 mL), and dried under vacuum. The 2H-1,3-benzoxazine-2,4(3H)-dione was isolated as a white solid (59.3 g, 85% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 101.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 5-bromopyridine-2-carboxylic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.8 g), the title compound (9.4 g) was obtained.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCCO1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Product: O=C(Nc1nc2cccc(NCC3CCCO3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a white powder (17 mg, 16%). HPLC, Rt: 1.73 min. (purity 95.5%). LC/MS, M+(ESI): 339.1, M−(ESI): 337.1.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:41])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]([CH:52]=O)[CH:43]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:41])/[C:12](/[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33])=[CH:52]/[C:44]1[CH:43]=[N:42][C:51]2[C:46]([CH:45]=1)=[CH:47][CH:48]=[CH:49][CH:50]=2
Reactant: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (30 μL, 0.24 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 132; 55 mg, 0.11 mmol) in tetrahydrofuran (2 mL) at room temperature. After 5 min, quinoline-3-carboxaldehyde (18 mg, 0.114 mmol) was added and the solution was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and the residue was dissolved in a solvent mixture of chloroform/methanol/water/acetic acid (150:30:10:6) and evaporated to dryness. A solution of the residue in a minimum amount of chloroform/methanol/water/acetic acid (150:30:10:6) was applied to a column of three piggy-backed SepPak Plus® silica gel cartridges that had been pre-washed with chloroform. The column was eluted with chloroform, then with a mixture of chloroform/methanol/water/acetic acid (300:30:10:6). Evaporation of the appropriate fractions gave (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (32.7 mg, 55% yield) as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]1>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][N:31]4[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]4)=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1cn[nH]c1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Yield: 52.7 %

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 100.0 mg, 0.293 mmol, 1.0 equiv.), DIEA (0.051 ml, 0.293 mmol, 1.0 equiv.), and 1-H-pyrazole-4-carbaldehyde (33.8 mg, 0.352 mmol, 1.2 equiv.) were added to acetonitrile (1.0 mL) in a microwave reaction vessel and the resulting mixture was irradiated with microwave at 180° C. for 30 minutes. The reaction mixture was cooled and concentrated and the residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile (3-8, 55.0 mg, 52.7%) as a colorless solid. LRMS m/z (M+H)+ 357.1 found, 357.1 required.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]#N)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:27][CH3:28])(=[O:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C.C(#N)C>C(Cl)(Cl)Cl.[Ag]F>[C:20]1([C:18]2([C:17]([O:27][CH3:28])=[O:26])[CH2:15][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CN(CC#N)Cc1ccccc1
Reactant: C=C(C(=O)OC)c1ccccc1
Agent: F[Ag]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A suspension of 53.4 g (0.23 mol) of N-benzyl-N-(cyanomethyl)-N-[(trimethylsilyl)methyl]amine (J. Org. Chem., 50, 4006 (1985)), 41.2 g (0.25 mol) of methyl atropate, 32.2 g (0.25 mol) of silver fluoride and 1 l of acetonitrile was stirred overnight at room temperature in the dark. The mixture was diluted with chloroform and filtered through celite. Concentration of the filtrate gave an oil which was chromatographed on silica gel, eluting with an 80:20 chloroform:ethyl acetate mixture, to give 27.9 g of methyl 3-phenyl-1-(phenylmethyl)-3-pyrrolidinecarboxylate.
Reaction SMILES: [C:1]1([N:7]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]([CH2:25][CH2:26]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([CH2:25][CH2:26][N:15]1[CH2:14][CH2:13][CH:12]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:11])[CH2:9][CH3:10])[CH2:17][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: ClCCOc1ccccc1
Product: CCC(=O)N(c1ccccc1)C1CCN(CCOc2ccccc2)CC1
Yield: 98.6 %

Procedure:
By condensing 14.7 g 4-(N'-phenyl-N'-propionylamino)-piperidine and 19.9 g phenoxyethyl chloride, they are obtained after 24 hours reflux 22 g of the title product which after recrystallization from hot cyclohexane gives a first crop weighing 13.5 g. The pure compound melts at 100°-102°. It is soluble in hydrochloric acid. The solution after distillation leads to the recovery of the hydrochloride. The hydrochloride is soluble in water.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:29].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:29])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:9]([CH:10]=1)[C:8]([OH:7])=[O:11]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccccc1C1OC(=O)c2cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)c1ccc(Br)cc1C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
This compound was prepared according to Ukita et al J. Med. Chem. 2001, 44, 2204. To a stirred mixture of 6-bromo-3-(2-methoxyphenyl)isobenzofuran-1(3H)-one (5.15 g, 16.1 mmol) in KOH (25% aqueous) (64.5 mL, 16.1 mmol) and pyridine (32.3 mL, 16.1 mmol) in a pressure tube was added powder potassium permanganate (3.83 g, 24.2 mmol). The reaction was heated at 100° C. After 4 h, LCMS showed ˜95% conversion to product. The reaction was cooled to rt. The mixture was filtered, and the solid residue was washed with water. The filtrate was acidified with concentrated HCl until pH=2. A sticky white solid was filtered off with the aid of water and dried to afford 5-bromo-2-(2-methoxybenzoyl)benzoic acid (4.2 g, 78% yield). m/z (ESI) 335.0 (M+H)+, 337.0 (M+3H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(Cl)Cl.CO>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[C:3]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:4]=2)=[O:22])=[CH:19][N:18]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1sc(N)nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1sc(NC(=O)c2ccc(Cl)nc2)nc1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a mixture of 5-methyl-4-phenyl-thiazol-2-ylamine (2.0 g, 10.5 mmol) in anhydrous tetrahydrofuran (40 mL) and methylene chloride (40 mL) in a round bottom flask under argon was carefully added sodium hydride (60% in mineral oil, 1.7 g, 42.5 mmol). The mixture was heated in a 60° C. oil bath for one hour, then chilled in an ice bath and 6-chloro-nicotinoyl chloride (2.03 g, 11.6 mmol) was added followed by diisopropylethylamine (7.32 mL, 42.1 mmol). The mixture was heated under argon in an oil bath at 60° C. for two hours and stirred at room temperature overnight. After dilution with methanol, the mixture was loaded onto silica gel and chromatographed using a mixture of ethyl acetate/hexanes to give 6-chloro-N-(5-methyl-4-phenyl-thiazol-2-yl)-nicotinamide (1.0 g, Yield: 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([N+:13]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=1>CCO>[NH2:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2cccc([N+](=O)[O-])c2n1
Solvent: CCO
Product: COc1ccc2cccc(N)c2n1
Reaction time: 1 h

Procedure:
2-Methoxy-8-nitroquinoline, as described above in Step D, (2.07 g, 10.14 mmol) was dissolved in EtOH (150 mL) and EtOAc (150 mL), the vessel was degassed, Pd/C (200 mg, 10 wt %) was added and the vessel was filled with H2 (1 atm). After 1 hour, the reaction was filtered through a pad of celite and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with CH2Cl2, to yield the above-titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([C:14]([CH3:16])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1.CCCCCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:15])[CH3:16])[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: CC(=O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: -70 °C
Yield: 35.9 %

Procedure:
10.5 g of tert-butyl 2-(3,4-dichlorobenzyl)acetoacetate (which was prepared by treating 3,4-dichlorobenzyl chloride and tert-butyl acetoacetate with potassium tert-butoxide in tert-butanol) was dissolved in 100 ml of tetrahydrofuran, and 45 ml of a 1M tetrahydrofuran solution of lithium tri-sec-butylborohydride was added thereto with stirring under cooling to -70° C. The mixture was stirred at the same temperature for 1 hour. Then, 20 ml of water and 15 ml of a 3N sodium hydroxide aqueous solution were added to the reaction solution, and 15 ml of a 30% hydrogen peroxide aqueous solution was dropwise added thereto with stirring under cooling to -20° C. The mixture was stirred at room temperature for 1 hour. Then, hexane was added to the reaction solution, and the organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 3.79 g (yield: 33%) of tert-butyl (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-hydroxybutanoate.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].OC(C(F)(F)F)=O.[NH2:13][C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[N:20]=2)=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[C:28]1([CH3:32])[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:17]3[S:18][C:14]([NH:13][C:1](=[O:4])[CH2:2][CH3:3])=[CH:15][CH:16]=3)[CH:24]=[CH:23][N:22]=2)[CH:27]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A solution of propionyl chloride (4.85 uL, 0.055 mmol) in DCM (100 uL) was added dropwise to a DCM solution (400 uL) of [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine TFA salt (20 mg, 0.050 mmol), followed by addition of pyridine (8.9 uL, 0.11 mmol). After 16 hours, the reaction was diluted with DMSO and prep purified to afford N-[5-(2-m-tolylamino-pyrimidin-4-yl)-thiophene-2-yl]-propionamide (6.7 mg, 39.6%). The major impurity was the TFA amide. 1H NMR (500 MHz, DMSO-d6) δ1.11 (t, J=7 Hz, 3H), 2.33 (s, 3H), 2.38 (q, J=7 Hz, 2H), 6.69 (d, J=4 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 7.12 (t, J=8 Hz, 1H), 7.18 (d, J=5.5 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.72 (d, J=4 Hz, 1H), 7.81 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 9.44 (s, 1H), 11.38 (s, 1H). MS: m/z 339 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH:18]=[C:17]([CH2:20][C:21](=[O:38])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:39]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[NH2:39][C@@H:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[C:17]([CH2:20][C:21]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:26][CH2:27]2)=[O:38])=[CH:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2C(CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)=CC[C@H]1c1cccc(F)c1F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1c2nccnc2C(CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)=CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a 50 mL round-bottomed flask was dissolved tert-butyl (5S,6S)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (58.6 mg, 0.093 mmol) in methylene chloride (1 mL). trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at rt for 1 h. LCMS showed complete conversion. Volatile components were removed in vacuo, and the residue was partitioned between ethyl acetate/0.5N sodium hydroxide/saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried and concentrated to give a tan oil. flash column chromatography up to 10% methanol (2M ammonia) in methylene chloride afforded the desired product (36 mg, 73%) as a tan solid: MS (ESI)[M+H+]=532.3; 1H NMR (400 MHz, CDCl3) δ 8.47 (ddd, J=11.4, 8.1, 2.5 Hz, 2H), 8.07 (d, J=5.1 Hz, 1H), 7.46 (t, J=6.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.1 Hz, 1H), 7.08 (dt, J=14.8, 7.7 Hz, 2H), 6.99 (td, J=8.2, 5.3 Hz, 2H), 6.41 (dt, J=22.6, 7.2 Hz, 1H), 4.90-4.68 (m, 2H), 4.56 (dd, J=17.3, 12.7 Hz, 1H), 4.15 (ddd, J=24.9, 20.2, 15.2 Hz, 2H), 3.83 (dt, J=7.2, 6.4 Hz, 1H), 3.64 (dd, J=33.2, 16.2 Hz, 1H), 3.26 (t, J=13.1 Hz, 1H), 2.69 (dd, J=28.5, 13.4 Hz, 1H), 2.39 (d, J=6.8 Hz, 2H), 2.33-2.05 (m, 3H), 2.03-1.69 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −137.26-−138.00 (m), −142.22 (dd, J=96.1, 21.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1F.[CH3:37][N:38]([CH3:44])[CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[N:41]1[CH2:42][CH2:43][CH:39]([N:38]([CH3:44])[CH3:37])[CH2:40]1
Reactant: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3F)c2)ccn1
Reactant: CN(C)C1CCNC1
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3N3CCC(N(C)C)C3)c2)ccn1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
N-[2-Chloro-5-(2′-methylamino-[3,4′]bipyridinyl-2-yloxy)-phenyl]-2-fluoro-5-trifluoromethyl-benzamide (65 mg, 0.13 mmol) and dimethyl-pyrrolidin-3-yl-amine (22 mg, 0.189 mmol) were dissolved in 0.3 mL DMSO. The solution was heated to 80° C. and stirred for 22 h. The reaction was then cooled to RT, quenched with water, extracted into EtOAc, washed twice with water, once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield a crude mixture that was purified by preparative TLC (10% MeOH/CH2Cl2) to give the title compound as an off-white solid. MS m/z (M+H)+=611; Calc'd 611.06 for C31H30ClF3N6O2.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[C:14]2=[N:15][CH:16]=[C:17]([C:31]3[CH2:38][C:34]4([CH2:37][CH2:36][CH2:35]4)[O:33][N:32]=3)[C:18]([NH:19][CH:20]3[CH2:23][CH:22]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:21]3)=[C:13]2[CH:12]=[N:11]1)[CH3:9]>ClC(Cl)C.C(OCC)(=O)C>[CH2:8]([N:10]1[C:14]2=[N:15][CH:16]=[C:17]([C:31]3[CH2:38][C:34]4([CH2:35][CH2:36][CH2:37]4)[O:33][N:32]=3)[C:18]([NH:19][CH:20]3[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[CH2:23]3)=[C:13]2[CH:12]=[N:11]1)[CH3:9]
Reactant: CCn1ncc2c(NC3CC(C(=O)OC(C)(C)C)C3)c(C3=NOC4(CCC4)C3)cnc21
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCn1ncc2c(NC3CC(C(=O)O)C3)c(C3=NOC4(CCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 equivalent) is added to the solution of tert-butyl 3-{[1-ethyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}cyclobutanecarboxylate (1 equivalent) (example 9) in dichloroethane and the reaction mixture is stirred at room temperature for about 2 hours under inert atmosphere. It is cooled and diluted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C(C(O)=O)N)C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.[CH3:41][NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:43]([N:42]([CH3:41])[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: CNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(C(=O)O)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 24 h

Procedure:
In another example of a process for preparing a compound of formula C, where R6 is methyl and R7 is benzyl, (RS)-N-tert-butoxycarbonyl-2-phenylglycine, commercially available or prepared from (RS)-2-phenylglycine using methods well known in the art, is combined with 1-hydroxybenzotriazole hydrate, commercially available N-methylbenzylamine and N-[3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride in dichloromethane and the resulting mixture stirred for about 24 hours. The resulting mixture is subjected to an aqueous work-up similar to that described above, providing (tert-butyl (RS)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate, which may be treated with trifluorocaetic acid and triethylsilane in dichloromethane, followed by aqueous workup to yield (RS)-N-benzyl-N-methyl-2-phenylglycinamide.