Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:4][C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([NH:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[N:6][C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:4][C:3]=1[N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)(=[O:34])[CH3:33]
Reactant: Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Yield: 43 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A solution of 5-amino-2-(4-phenylpiperazin-1-yl)-4,6-dimorpholinopyrimidine (700 mg, 1.64 mmol), acetic anhydride (5 ml), and pyridine (a few drops) was agitated for 1 hour at 60 degrees Celsius. The deposited solid was captured by filtering, washed with ether, and 330 mg of 5-acetylamino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (43% yield). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 77 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.O.[NH2:31][NH2:32].O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:6]([C:7]([NH:31][NH2:32])=[O:27])[CH:28]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.88 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.19 ml of hydrazine monohydrate and 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.94 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH2:9])[N:3]=[CH:2]1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>CC(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][NH:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCCc1c[nH]cn1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(NCCCc2c[nH]cn2)nc1

Procedure:
A solution of 0.158 g (0.97 mmol) of 3-(1H-imidazol-4-yl)propylamine and of 0.154 g (0.97 mmol) of 2-chloro-5-nitropyridine in 10 ml of 2-propanol is brought to reflux for 21 h while stirring and evaporated under reduced pressure. The resulting residue is chromatographed on a column of silica gel, using a chloroform/methanol (1/1) mixture, to give the title compound in the form of a yellow oil. The latter is treated with oxalic acid in heated absolute ethanol to provide the oxalate salt which, after crystallization from 2-propanol, melts at 181°-182° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12](Cl)=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].[ClH:24].[NH2:25][OH:26].C(N(CC)CC)C>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:24])=[CH:11][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:20])[NH:25][OH:26])[C:3]=1[S:21]([CH3:23])=[O:22]
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Cl
Reactant: NO
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)c1c(C(=N)NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a suspension of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinylpyrazole (20 g) in methanol (120 ml) was added hydroxylamine hydrochloride (3.99 g), followed by addition of triethylamine (8.0 ml). The mixture was stirred at room temperature overnight then evaporated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, followed by wash with brine. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated by evaporation of solvent. A precipitate was formed and collected by filtration. The solid was washed with small amount of ethyl acetate to give Compound 44 (16.1 g), m.p. 225-226° C.
Reaction SMILES: [Li+].[OH-].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24].C(O)(=O)C(O)=O>C1COCC1.O>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCO
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCCCCCCCCO
Reaction time: 10 h
Yield: 91.3 %

Procedure:
LiOH (45 μL of a 1 M aqueous soln) was added to a stirring, room temperature solution of the above ester (5.2 mg, 0.015 mmol) in THF/H2O (5:1, 1.5 mL). After 10 hours, the pH was adjusted to 4 using 1 M oxalic acid and the reaction mixture was extracted with EtOAc (3×4 mL). The combined organic extracts were evaporated in vacuo to give 20-hydroxyeicosanoic acid (55) (4.5 mg, 92%) as a solid, mp 86° C. 1H NMR (250 MHz, CD3OD): δ 1.20-1.45 (m, 30H), 1.45-1.63 (m, 4H), 2.28 (t, J˜7.4 Hz, 2H), 3.55 (t, J˜6.5 Hz, 2H); TLC: EtOAc/hexanes (3:7), Rf˜0.08. 19-Hydroxynonadecanoic Acid (56) was prepared in an analogous manner from ester 8a.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][C@@H:33]([CH3:36])[C:34]#[N:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:34]([C@@H:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:36])#[N:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: C[C@H](N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 32.8 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Vb, 25 mg, 0.058 mmol), (S)-2-aminopropanenitrile (Int-X, 6.09 mg, 0.087 mmol), HATU (28.7 mg, 0.075 mmol), and 4-methylmorpholine (23.45 mg, 0.232 mmol) were dissolved in DMF (1 mL). The reaction mixture was stirred for 1 h, and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm gradient elution with Method 2—CH3CN/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 20 mL/min, 220 nM, product retention=25.5 min) to provide single enantiomer N—((S)-1-cyanoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.019 mmol, 32.1% yield): LCMS=484.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.26 (2 H, m), 7.50-7.78 (7 H, m), 5.17 (1 H, s), 4.85-4.94 (1 H, m), 1.56 (3 H, d, J=7.26 Hz); HPLC peak RT=9.9 min (Method A).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:17][CH:16]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:31]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Yield: 30.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.582 g, 1.38 mmol) was dissolved in acetonitrile (15.0 mL), and the solution was treated with pyrrolidine (2.30 mL, 27.8 mmol), acetic acid (1.60 mL, 27.8 mmol) and sodium triacetoxyborohydride (0.876 g, 4.13 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-hydroxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.200 g, 30%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][NH2:19])=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:20](Cl)(=O)[CH2:21][CH2:22][CH3:23].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>N1C=CC=CC=1.C1COCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[S:35][C:20]([CH2:21][CH2:22][CH3:23])=[N:19][N:18]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)NN)CC2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCc1nnc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.25 mol of trans-4-(trans-4-n-propylcyclohexyl)cyclohexanecarbohydrazide is dissolved in 300 ml of pyridine. At room temperature, 0.25 mol of butyryl chloride is added dropwise, and the mixture is stirred for a further 11/2 hours. The mixture is then poured into 1.5 1 of ice/water, and the crystals are filtered off with suction and washed with water. The product obtained is recrystallized from toluene. 0.1 mol of this compound and 0.1 mol of Lawesson's reagent are refluxed for 10 hours in 200 ml of THF. 2/3 of the solvent are removed by distillation, the residue is poured into 500 ml of water and 50 ml of 32% sodium hydroxide solution, and the precipitate is filtered off with suction and recrystallized from ethanol/activated charcoal to give 2-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-5-propyl-1,3,4-thiadiazole.
Reaction SMILES: C(NCC)C.[C:6]([O:10][C:11](=[O:41])[CH2:12][C@H:13]([NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([O:10][C:11](=[O:41])[CH2:12][C@H:13]([NH2:23])[C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC(O)CC1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)N1CCC(O)CC1
Reaction time: 1 h

Procedure:
Diethylamine (1.0 mmol) was added to (S)-3-(9H-fluoren-9-ylmethoxycarbonyl-amino)-4-(4-hydroxy-piperidin-1-yl)-4-oxo-butyric acid tert-butyl ester in dimethyl-formamide (5 ml) at 25° C. After 1 hour, the reaction mixture was concentrated, the residue suspended in 1:1 ether/dichloromethane, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 1-50% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 217 mg, 80%.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][C@H:5]1[S:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].OC1C=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][S:22][C@H:5]1[O:4][C:3]1[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[CH:31][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C(C)=O)cc1
Yield: 47 %

Procedure:
If the procedure described in Preparation LXXXI is followed starting from 380 mg (0.882.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 100 mg (73.5.10-3 mol) of 1-(4-hydroxyphenyl)ethanone and 1.47 ml of a 0.1M solution of boron trifluoride etherate in methylene chloride, 140 mg (yield: 47%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2([CH3:30])[CH2:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21]([CH3:29])=[CH:22][C:23]=3[CH3:28])[O:18]2)=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:31][C:32](N)=[S:33].S1(CCCC1)(=O)=[O:36].Cl>COCCO>[CH3:30][C:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:2]3[S:33][C:32](=[O:36])[NH:31][C:3]3=[O:4])=[CH:14][CH:13]=2)[CH2:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([CH3:29])=[CH:22][C:23]=2[CH3:28])[O:18]1
Reactant: O=S1(=O)CCCC1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)cc(C)cc3O2)cc1
Agent: Cl
Solvent: COCCO
Product: Cc1cc(C)c2c(c1)OC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)CC2=O

Procedure:
Following a procedure similar to that described in Example 1, but using 1.5 g of ethyl 2-chloro-3-[4-(2,5,7-trimethyl-4-oxochroman-2-ylmethoxy)phenyl]propionate (prepared as described in Preparation 29), 0.4 g of thiourea, 1.5 ml of sulfolane, 10 ml of ethylene glycol monomethyl ether and 5 ml of 2N aqueous hydrochloric acid, 1.13 g of the title compound were obtained as a pale yellow powder.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][S:48]([CH3:50])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([O:32][CH2:47][S:48][CH3:50])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
To a solution of the compound of Example 3 (3.0 g, 4.8 mmol), DMSO (18 mL), and acetic acid (3.6 mL) at room temperature was added acetic anhydride (23 mL), and the reaction was stirred for 48 hours at room temperature. The reaction was quenched with ice and 10% Na2CO3 was added to adjust the pH to 7. The mixture was extracted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over Na2SO4, filtered and evaporated to give the crude product, which was chromatographed on silica gel eluting first with 25-100% ethyl acetate in dichloromethane to give the title compound (2.1 g, 64% yield).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].N1C=CN=C1.[C:18]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[C:23]([CH3:32])([CH3:31])[CH2:22]1)(=[O:20])[CH3:19].Cl.[CH3:34][C:35]([C:38]([O:40]C)=O)([CH3:37])[NH2:36]>O1CCCC1.O.C(N(CC)CC)C>[C:18]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[C:38](=[O:40])[C:35]([CH3:34])([CH3:37])[NH:36][C:1]3=[O:2])[CH:28]=2)[C:23]([CH3:32])([CH3:31])[CH2:22]1)(=[O:20])[CH3:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)NC(C)(C)C3=O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 6.6 g of 1,1′-carbonylbis(1H-imidazole) and 460 mg of 1H-imidazole in 50 mL of tetrahydrofuran is stirred under argon and cooled in an ice bath at 0° C. To this solution is added a suspension of 6.9 g of 1-acetyl-3,3-dimethylindolin-6-amine obtained in stage f) below in 50 mL of tetrahydrofuran. After stirring for one hour, 9.5 mL of triethylamine and 5.2 g of methyl 2-methylalaninate hydrochloride are added and the mixture is stirred for two hours at room temperature and then refluxed for 17 hours. After cooling to room temperature, the mixture is diluted with 800 mL of water and the precipitate formed is filtered off, washed with four times 25 mL of water and with three times 15 mL of diethyl ether and then dried to give 8 g of 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.C1COCC1.O.[Na+].[Cl-].C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:8][CH2:9][C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)c1ccccc1
Yield: 94.2 %

Procedure:
(R)-tert-butyl 3-(tert-butyldimethylsilyloxy)-1-oxo-1-phenylpropan-2-ylcarbamate (23) (1.5 g, 4.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by a 1:1 mixture of THF/H2O (20 mL). The mixture was stirred and glacial acetic acid (30 mL) was added to the reaction flask. The reaction stirred for 22 h at rt. The reaction was transferred to a 500 mL separatory funnel with sat. NaCl (75 mL) and sat. NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (3×75 mL) and the combined organic layers were dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 1.3 g of crude material. The residue was purified by flash column chromatography (40% EtOAc/hexanes) to give 1.0 g (95%) of 24 as a colorless oil which crystallized to a white solid. Rf=0.27 (40% EtOAc/hexanes); mp=60-62° C.; [α]D23.5=+12.4 (c 1.01, MeOH); IR (KBr) 3420, 2976, 2931, 1683, 1503, 1366, 1165, 1061 cm−; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=7.5 Hz, 2H, Ph-H), 7.62 (t, J=7.5 Hz, 1H, Ph-H), 7.51 (t, J=7.5 Hz, 2H, Ph-H), 5.88 (br s, 1H, carbamate-NH), 5.35 (br s, 1H, Boc-NH—CH), 4.02 (m, 1H, CH—CH2), 3.86 (m, 1H, CH—CH2), 2.91 (br s, 1H, CH2—OH), 1.47 (s, 9H, t-butyl-CH3); 13C (125 MHz, CDCl3) δ 197.4, 156.3, 134.6, 134.1, 129.0, 128.9, 80.5, 64.7, 58.1, 28.4; LRMS (ESI-MS m/z): Mass calcd for C14H19NNaO4 [M+Na]+, 288.29. Found 288.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 25.9 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (73 mg, 0.232 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (57 mg, 0.279 mmol), DL-10-Camphorsulfonic acid (67 mg, 0.288 mmol) and isopropanol (4 mL) in a microwave tube. Microwaved reaction at 120° C. for 70 minutes. Evaporated off solvent and purified with normal phase chromatography to yield a yellow solid, 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (29 mg, 26%). mp 153° C.; LCMS: m/z=483.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 7.53 (d, 1H, J=8.6 Hz), 7.27 (m, 3H), 6.70 (m, 2H), 6.40 (m, 1H), 2.92 (d, 3H, J=4.8 Hz), 2.32 (m, 2H), 2.04 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.C(O)=[O:27]>[Ni]>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH:14]=[O:27])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)cc1
Agent: [Ni]
Product: CCOc1ccc(Cc2nc3cc(C=O)ccc3n2CC2CC2)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-carbonitrile (0.049 g, 0.149 mmol) in 50% aqueous formic acid (1 mL) was added a catalytic amount of Raney nickel (50% suspension in water) and the resulting mixture was heated at 90° C. for 6 hours. The mixture was filtered through a short pad of diatomaceous earth and washed with EtOAc. The solvent was evaporated in vacuo and the residue was taken up into EtOAc (5 mL). The organic phase was washed with 1 N NaOH (2×2 mL) and brine (2 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (40% EtOAc/hexanes) to provide the title compound (0.041 g, 82%) as a white solid. 1H NMR (acetone-d6): δ 10.16 (s, 1H), 8.29 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 4.24 (d, J=6.4 Hz, 2H) 4.07 (q, J=6.8 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H), 1.27–1.14 (m, 1H), 0.58–0.49 (m, 2H), 0.48–0.38 (m, 2H). MS (ESI) (M+H)+=335.