Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24].Cl>O.CC(C)=O>[CH3:21][N:22]([CH3:26])[C:23](=[S:24])[O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1ccc(S(=O)(=O)c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
2.36 g (0.0097 mol) of 4-[(4-hydroxyphenyl)sulfonyl]benzonitrile are added to a solution of 570 mg of potassium hydroxide in 35 ml of water. The solution is kept at room temperature for 15 minutes. After cooling to 0° C., a solution of 1.38 g of N,N-dimethylthiocarbamoyl chloride in 35 ml of acetone is added dropwise. After 4 hours, the reaction mixture is hydrolyzed in a 1 N solution of hydrochloric acid. The solution is extracted with ethyl acetate. The organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and concentrated to dryness. 3 g (yield: 100%) of the expected product are thus obtained.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.Cl.[O:9]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C1COCC1>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[O:7])=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Oc2ccccc2)cc1)C1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a cooled (0° C.) solution of cyclobutanecarboxylic acid (0.26 g, 2.6 mmol), 4-phenoxybenzylamine hydrochloride (0.62 g, 2.6 mmol), HOBt, (0.71 g, 5.2 mmol) and triethylamine (1.1 mL, 7.83 mmol) in THF (9 mL) was added EDCl (0.55 g, 2.6 mmol). The mixture was stirred for 18 hours at room temperature. The solvent was removed, and the residue was suspended in ether and washed with 0.1N HCl, 5% NaHCO3 and brine. The ether layer was dried (MgSO4), filtered through a plug of silica gel and concentrated in vacuo to provide 0.70 g (96%) of the title compound as a white solid. m.p. 69°-71° C. 1H NMR (CDCl3, 300 MHz) δ1.80-2.06 (m, 2H), 2.10-2.14 (m, 2H), 2.15-2.39 (m, 2H), 3.02 (pd, J=7.5, 1.2 Hz, 1H), 4.41 (d, J=6 Hz, 2H), 5.55 (br s, 1H), 6.94-7.04 (m, 4H), 7.08-7.15 (tt, J=7.5, 1.5 Hz, 1H), 7.20-7.28 (m, 2H), 7.30-7.38 (m, 2H). MS (DCl/NH3) m/e 282 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([Cl:16])[CH:9]=1)(C)(C)C.Cl.O1CCOCC1>CC(O)C>[ClH:15].[NH2:7][C:8]1[CH:9]=[C:10]([Cl:16])[C:11]([Cl:15])=[C:12]([OH:14])[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(O)c(Cl)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Nc1cc(O)c(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 189.2 %

Procedure:
tert-Butyl(3,4-dichloro-5-hydroxyphenyl)carbamate from Example 67A (960 mg, 3.45 mmol) was dissolved in 2-propanol (16 mL), and 4 M gaseous hydrogen chloride in dioxane (5.0 mL, 20 mmol) was added. The mixture was heated to 80° C. for 1.5 h. Subsequently, the solvent was removed in vacuo to yield 700 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([S:8]([N:7]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:6]2[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(N(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To a solution of 4′-Methoxy-2′-nitro-p-toluenesulfonanilide (0.32 g (1.00 mmol)) in pyridine (1,0 ml), p-toluenesulfonyl chloride (0.20 g (1.05 mmol)) was added with stirring at room temperature. After 15 hours' stirring at room temperature, the reaction mixture was poured into water and crystals separated was filtered and washed to give 0.34 g (83%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH:1]([C:23]([O:25]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:30]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:31](C(ON1C(=O)CCC1=O)=O)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[Cl:43])=[O:38]>>[NH:30]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:31]([C:23]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:20]([OH:22])=[O:21])[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:25])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[Cl:43])=[O:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1Cl)NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Yield: 63.7 %

Procedure:
By using 4,61 g of Boc-Leu-Ser(Bzl)-OH Japanese Patent Kokai (Laid-open) No. 61-112099 (1986) and 5.61 g of Boc-Lys(Cl-Z)-OSu, and the same procedure as in Reference Example 31 was repeated to obtain 4.92 g (yield: 64.0%) of the above-mentioned objective product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][NH:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[C:25]([O:34]N1C(=O)CCC1=O)([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=O>CC(C)=O.O>[CH3:1][O:2][C:3]([CH3:18])([CH3:17])[CH2:4][C@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:6][N:7]([CH3:8])[C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])=[O:34]
Reactant: CNC[C@H](CC(C)(C)OC)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(C)(C)C[C@@H](CN(C)C(=O)OCC[Si](C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of the above (S)-tert-butyl 4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate (˜2.99 mmol) in acetone (9 mL) and water (3 mL), there was added K2CO3 (1.24 g, 9.0 mmol), followed by Teoc-OSu (0.85 g, 3.29 mmol). The resulting mixture was stirred at rt until no starting material remained (˜1 h). Acetone was removed under vacuum, and the aqueous residue was extracted with CH2Cl2 (4×5 mL). The combined organic layers were concentrated, and crude residue was purified with flash column chromatography to give (S)-tert-butyl 4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate (0.18 g, 15%, 3 steps) as a clear oil. 1H NMR (400 MHz, CDCl3): 4.82, 4.92 (br, 1H), 4.16 (m, 2H), 3.88 (m, 1H), 3.44 (m, 1H), 3.24 (m, 1H), 3.16 (s, 3H), 2.88, 2.90 (s, 3H), 1.44 (s, 9H), 1.18, 1.20 (s, 6H), 0.98 (m, 2H), 0.02 (s, 9H); MS m/z 405 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12].CO>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccccc1N
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCC(=O)Nc1ccccc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
1128.6 g of o-toluidine were initially charged in 500 ml of toluene and heated to 90° C. 134.3 g of butyryl chloride were added dropwise within 2 hours. After completed addition, the mixture was heated to reflux and stirring continued at this temperature until the end of gas formation. The mixture was cooled to 70° C., 12 ml of methanol were added and stirring was continued for an hour. To remove the methanol, the mixture was heated and 70 ml were distilled off. 300 ml of toluene were then distilled off and 400 ml of cyclohexane were added. The mixture was cooled to 10° C. and filtration gave 199.5 g (92% yield) of the product in 98% purity after drying.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([NH2:34])[N:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:34][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)=[CH:15][CH:14]=3)[N:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:27]=2)[CH2:22][CH2:21]1
Reactant: Nc1cc(C2CC2)nn1-c1ccccc1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1cc(C2CC2)nn1-c1ccccc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-cyclopropyl-2-phenyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 435.50 [M+H]+; tR=1.34 min (System 3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][OH:21])[CH:14]=1)[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CC#N.O=[Mn]=O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=[O:21])[CH:14]=1)[CH:8]1[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CO)c1)C1CC1
Agent: O=[Mn]=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
MnO2 (1.97 g, 20.4 mmol) was added to a sol. of [2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-cyclopropyl-carbamic acid tert-butyl ester (1.33 g, 4.08 mmol) in CH3CN (41 mL). The mixture was stirred overnight at rt. The mixture was filtered over celite, and was washed with CH3CN and CH2Cl2. Evaporation of the filtrate under reduced pressure yielded the crude title compound (1.32 g, quantitative yield) that was used further without purification. LC-MS: tR=1.05 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][CH:11]([Cl:15])[C:12](Cl)=[O:13]>C(N(CC)CC)C>[Cl:10][CH:11]([Cl:15])[C:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:13]
Reactant: Nc1cccc(C=O)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: O=Cc1cccc(NC(=O)C(Cl)Cl)c1

Procedure:
3-Aminobenzaldehyde can be treated with dichloroacetyl chloride and triethylamine to yield 2,2-dichloro-N-(3-formylphenyl)acetamide.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8][C:7]1=[O:19]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:11]=2[C:10]([CH3:17])([CH3:18])[CH2:9][CH2:8][C:7]1=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)CCC(C)(C)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 72 h

Procedure:
2.0 ml of 65% nitric acid were cautiously added dropwise to 7.1 ml of acetic anhydride at 0° C. This solution was added to a solution of 3.14 g of 2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepine in 9.0 ml of acetic anhydride and 2.8 ml of glacial acetic acid. The reaction mixture was left to stand at room temperature for 3 days and then poured on ice, washed in succession with water, soda solution and water, dried and evaporated. Recrystallization from ethyl acetate/hexane yielded 3.39 g of 2,3,4,5-tetrahydro-1,5,5-trimethyl-7-nitro-2-oxo-1H-1-benzazepine, 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:8]=2)[N:3]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([NH2:27])[NH:25][N:26]=2)[CH2:21][CH2:20]1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:27][C:24]2[NH:25][N:26]=[C:22]([CH:19]3[CH2:21][CH2:20]3)[CH:23]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:8]=2)[N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1nc(Cl)c2cc(N3CCCCC3)ccc2n1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(N3CCCCC3)ccc2n1
Reaction time: 10 h
Yield: 61 %

Procedure:
To 2,4-Dichloro-6-piperidin-1-yl-quinazoline (100 mg, 0.365 mmol), in ethanol (5 omL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (88 mg 0.71 mmol). The additional resulted in the formation of a white precipitate. The partial solution was stirred for 10 hr and (2-Chloro-6-piperidin-1-yl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine was colleted by filtration to give 80 mg (61% yield). HPLC tr=4.90 min (100%), LCMS m/e 369.31 (M+H), 367.28 (M-H) tr=3.41 min, HNMR (500 MHz, dmso): 12.30-12.25 (1H, bs), 10.67 (1H, s), 7.80-7.85 (1H, s), 7.65 91H, d), 7.50 (1H, d), 6.50 (1H, bs), 3.40 (4H, m0, 2.90 (1H, m), 1.70-1.55 (6H, m), 0.95 (2H, m), 0.70 (2H, m).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](C(C)C)[C:37]=1CC(O)=O)(C)C.C1(C(C2C=CC=CC=2)C(O)=O)C=CC=CC=1>>[C:5]1([CH:13]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)=[O:15])[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: O=C(O)C(c1ccccc1)c1ccccc1
Product: CC(C)c1ccc(C(=O)C(c2ccccc2)c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with diphenylacetic acid, mp 164°-166° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][C@@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:13][C@@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCOc1ccccc1)N[C@H]1CCCc2ccccc21
Solvent: C1CCOC1
Product: c1ccc(OCCCCN[C@H]2CCCc3ccccc32)cc1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
The product from Example 52A (2.07 g) in THF (20 mL) was treated with borane-tetrahydrofuran complex (12 mL, 12 mmol) and heated at reflux for 1.5 hours. The mixture was allowed to cool to room temperature and quenched with 1N NaOH. The mixture was stirred 30 for minutes and diluted with diethyl ether. The separated organic phase was washed with brine, dried (Na2SO4), filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate/hexanes) to provide the title compound as a pale brown oil (0.48 g, 28% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=Cc1ccc(N)cc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Ethyl 4-nitro-α-methylcinnamate (11 g) was dissolved in glacial acetic acid (150 ml), and stirred at room temperature. Then, zinc powder (12 g) was added to the above-mentioned solution over a period of about 1 hour. The mixture was stirred at room temperature for 1 day. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give ethyl 4-amino-α-methylcinnamate (9 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:23][N:22]=4)=[O:20])[CH2:16]3)=[CH:11][C:10]=2[O:31][CH3:32])=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>O1CCCC1>[CH3:42][S:43]([O:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:19]([N:17]2[CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:34][CH:33]=4)=[C:10]([O:31][CH3:32])[CH:11]=3)[CH2:18]2)=[O:20])[CH:26]=1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCO)ccn4)C3)cc2OC)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of {3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-[4-(2-hydroxyethoxy)pyridin-2-yl]-methanone (8.49 g) prepared in Example 5 in THF (45 mL) were added triethylamine (2.8 mL) and methanesulfonyl chloride (1.5 mL) at 0° C. The reaction mixture was stirred at RT for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. Diisopropyl ether was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (9.5 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:6]
Reactant: NCC(F)(F)F
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cccc1C(=O)NCC(F)(F)F
Yield: 81 %

Procedure:
2-Amino-3-bromo-N-(2,2,2-trifluoroethyl)benzamide (501a) (1.67 g, 81%) was prepared according to the procedures described for 720 using (2-amino-3-bromo-benzoic acid (1.5 g, 6.94 mmol, Sigma Aldrich), 2,2,2-trifluoroethylamine hydrochloride (1.1 g, 8.33 mmol, TCI), and DIEA (2.9 mL, 16.66 mmol, Sigma Aldrich) as the reagents. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H, t, J=6.16 Hz) 7.52-7.63 (2H, m) 6.57 (1H, t, J=7.82 Hz) 6.48 (1H, s) 4.05 (2H, qd, J=9.75, 6.36 Hz). m/z (ESI, +ve) 298.9/300.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2nc3ccccc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
tert-Butyl 4-{[(2-aminoanilino)carbothioyl]amino}benzylcarbamate (4.3 g; 11.54 mmol) was refluxed in analogy to 21c with 5 g of HgO (yellow) and 0.05 g of sulfur in 150 ml of ethanol. Filtration of the reaction mixture through Celite and concentration afforded 2.1 g of a dark solid (ESI-MS [M+H+]=339.15). The tert-butyl 4-(1H-benzimidazol-2-ylamino)benzylcarbamate obtained in this way was treated without further purification with 15 ml of TFA at RT for 2 h, and concentration afforded 4.7 g of a dark oil which was reacted further without further purification (ESI-MS [M+H+]=239.05).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH2:3][CH:4]=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:6][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:1])[CH2:3][CH2:4][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CC=O)cn1
Reactant: C1CCNC1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CCN2CCCC2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-3-oxo-propyl)-1H-imidazol-4-yl]-amide was reacted with pyrrolidine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 23.6, 28.4, 28.7, 36.0, 42.1, 43.2, 51.3, 53.1, 54.4, 57.5, 103.0, 105.3, 112.4, 112.6, 131.2, 137.8, 169.0, 169.2. MS m/z 476.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[NH:8]2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH:28](I)([CH3:30])[CH3:29]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:14][CH2:13]3)[N:8]2[CH:28]([CH3:30])[CH3:29])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3[nH]2)CC1
Reactant: CC(C)I
Product: CC(C)n1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(1-((2-Chloro-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g) was reacted with isopropyl iodide via General Procedure C to give 2-(1-((2-chloro-9-isopropyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol which was subsequently reacted with 2-methylbenzimidazole via General Procedure I for Buchwald coupling to give 43.3 g 247 following reverse phase purification. MS (Q1) 533.3 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:59]=[N:60][C:61]([NH:64][C:65]3[CH:66]=[C:67]([NH2:72])[C:68]([CH3:71])=[N:69][CH:70]=3)=[N:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:72][C:67]1[C:68]([CH3:71])=[N:69][CH:70]=[C:65]([NH:64][C:61]2[N:60]=[CH:59][C:58]([C:55]3[CH:54]=[CH:53][C:52]([O:51][CH3:50])=[CH:57][CH:56]=3)=[CH:63][N:62]=2)[CH:66]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(N)c3)nc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)C4CCCCN4C(=O)OC(C)(C)C)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.04 mmol) in DMF (1 mL) is added HATU (0.05 mmol) and DIEA (20.12 mmol). The resulting mixture is stirred for 2 min at rt and then N5-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-2-methyl-pyridine-3,5-diamine 12 (0.032 mmol) is added. The reaction mixture is stirred at 45° C. for 12 h. The mixture is cooled down and directly purified by preparative LCMS to afford 2-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-ylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester 20. MS (m/z) (M+1)+: 519.1.