Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[I:14][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1nccc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1ncc(I)c(-c2ccccc2)n1
Yield: 16 %

Procedure:
To a stirred solution of 500 mg (2.9 mmol) 2-amino-4-phenylpyrimidine in 38 ml acetic acid was added 689 mg (3.1 mmol) N-iodosuccinimide and stirring continued in the dark at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between ether and water. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Trituration in ether/ethyl acetate then afforded 138 mg (16%) 5-iodo-4-phenyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 297 (M+, 100), 170 ([M—I]+, 38).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]([OH:25])=[O:24])=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27].[C:32](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]([O:25][CH3:32])=[O:24])=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (5 drops) was added to a suspension of 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (12.5 g, 27.6 mmol) in dichloromethane (120 mL). Oxalyl chloride (3.62 mL, 41.4 mmol) was added slowly. The mixture was stirred at room temperature for 1 h. Methanol (30 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to provide methyl 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 468.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[C:10]1([CH3:17])[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Mg]Br)C>CCOCC>[CH3:17][C:10]1[C:15]([OH:16])=[C:14]([CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[OH:1])[CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1O
Reactant: Cc1ccccc1O
Agent: CC[Mg]Br
Solvent: CCOCC
Product: Cc1cccc(Cc2ccccc2O)c1O
Yield: 23.6 %

Procedure:
2-Hydroxybenzyl alcohol (18.6 g, 0.15 mol) and o-cresol (16.2 g, 0.15 mol) were dissolved in 150 ml of ether in a flask and a dry nitrogen atmosphere established. Ethyl magnesium bromide (100 ml of 3M solution in ether, 0.30 mol) was added dropwise with stirring. The ether was removed by evaporation under reduced pressure and 450 ml of benzene added. The resulting mixture was heated at reflux with stirring for 20 hours and then allowed to cool. Saturated aqueous ammonium chloride solution was added and the mixture extracted with 2-500 ml portions of ether. The combined ether extracts were dried over magnesium sulfate and the ether then removed by evaporation. The residue was chromatographed on a silica gel column eluting with an 80:20 mixture of hexane and ethyl acetate and dried in a vacuum oven at 100° C. to obtain 7.6 g (24 percent of theory) of (3-methyl-2-hydroxyphenyl) (2-hydroxyphenyl)methane as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:28])[CH2:17][C:18]3([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:28])[CH2:17][C:18]3([C:24]([O:26][CH3:27])=[O:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1(CC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)CCOCC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)C1(CC(=O)c2ccc(-c3ccc(N)cc3)cc2)CCOCC1
Yield: 91.4 %

Procedure:
To a solution of methyl 4-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (1.24 g, 3.25 mmol) in 85% ethanol (50 mL) was added iron powder (1.81 g), followed by 2 N aqueous HCl (1.62 mL), and the resulting mixture was refluxed for 2.5 h. The mixture was then filtered through a pad of Celite® and the filtrate was extracted with dichloromethane. The combined organic phases were then dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 4-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (1.05 g, 91%). LC-MS ret. time 2.20; m/z 354.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.57-1.66 (m, 2H), 2.09 (m, 2H), 3.28 (s, 2H), 3.61 (s, 3H), 3.64-3.71 (m, 4H), 6.76 (d, 2H), 7.42 (d, 2H), 7.54 (d, 2H), 7.88 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[OH:11].Cl.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1>>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([O:11][CH2:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:21]#[N:22])[C:4]([CH3:10])=[N:5][CH:6]=1
Reactant: Cc1ncc(CO)c(C)c1O
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Product: Cc1ncc(CO)c(C)c1OCc1cccc(C#N)c1
Yield: 53 %

Procedure:
The coupling of 4-deoxypyridoxine hydrochloride (5.0 g, 0.026 mol) and α-bromo-m-tolunitrile (5.2 g, 0.026 mol), as described in Example 3, gave 3-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (26) (3.7 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[OH-].[Na+]>O1CCOCC1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:7]=1
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Reactant: CS(N)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Temperature: 50 °C
Yield: 5.8 %

Procedure:
A mixture of Example 61a (0.130 g, 0.322 mmol), methanesulfonamide (0.046 g, 0.482 mmol), cesium carbonate (0.136 g, 0.418 mmol), palladium acetate (3.61 mg, 0.016 mmol), and Xantphos (0.014 g, 0.024 mmol) in dioxane (3 mL) and DMF (0.1 mL) was heated at 160° C. for 30 minutes in a Biotage microwave reactor. The mixture was concentrated. The residue was treated with EtOAc and washed with 20% brine. The emulsion of the organic layer was concentrated. The solid was suspended in dioxane (4 mL), treated with 20% sodium hydroxide (0.15 mL, 0.322 mmol), and heated at 50° C. for 3 hours. The reaction mixture was concentrated. The residue was treated with DMSO/MeOH and purified by reverse-phase HPLC as described in Example 56 to give the title compound (6.0 mg) as trifluoroacetic acid salts. 1H NMR (300 MHz, DMSO-d6) ppm 3.36 (s, 3H), 7.26 (dd, J=7.93, 4.76 Hz, 1H), 7.41 (d, J=0.79 Hz, 1H), 7.55 (d, J=1.19 Hz, 1H), 8.27-8.40 (m, 3H), 10.76 (s, 1H), 12.36 (s, 1H). MS (ESI+) m/z 322.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](O)(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12][CH3:13].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CSc1cc(S(=O)(=O)O)ccc1Cl
Solvent: Cc1ccccc1
Product: CSc1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 85 °C
Reaction time: 18 h
Yield: 7.6 %

Procedure:
To a mixture of 4-chloro-3-methylsulfanyl-benzenesulfonic acid (24 mmol) in anhydrous toluene (100 mL) at 0° C. was added thionyl chloride (2.62 mL, 36 mmol). The ice bath was removed and the reaction heated to 85° C. for 5 h, then 70° C. for 18 h. Unreacted starting material was still present by LC-MS and thionyl chloride (5 mL) was added and the reaction stirred for 18 hours at 70° C. The solvent was removed to give a black oil (470 mg, 8%) that was used as is in the next reaction.
Reaction SMILES: [Li].[C:2]([NH:5][CH:6]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1)[C:7](OC)=[O:8])(=[O:4])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[C:2]([NH:5][CH:6]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1)[CH2:7][OH:8])(=[O:4])[CH3:3]
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)C(=O)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Li]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(CO)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a suspension of lithium abluminum hydride (1.2 g) in tetrahydrofuran (100 ml), a solution of methyl 2-acetamido-4-(4-octylphenyl)butyrate (11 g) in tetrahydrofuran (200 ml) was added and the suspension was stirred at room temperature for 30 minutes. An aqueous tetrahydrofuran (70%, 10 ml) was added to the solution and the mixture was left standing overnight. Magnesium sulfate was added to the mixture, the precipitate was filtered off and the solvent was distilled away under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order and dried over sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (6.6 g). MS: 319(M+).
Reaction SMILES: BrCC1C=CC(CBr)=CC=1[F:11].[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][C:15]=1Cl>>[NH2:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][C:15]=1[F:11]
Reactant: Fc1cc(CBr)ccc1CBr
Reactant: NCc1ccc(CN)c(Cl)c1
Product: NCc1ccc(CN)c(F)c1

Procedure:
The starting material 4-aminomethyl-3-fluoro-benzylamine was prepared from 1,4-bis-bromomethyl-2-fluoro-benzene as described for 4-aminomethyl-3-chloro-benzylamine in example 59a
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10]O)[CH:3]=1>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[C:4]2[CH:3]=1
Reactant: ON=C(Cc1cc(Br)ccn1)c1ccc(F)cc1
Solvent: ClCCCl
Product: Fc1ccc(-c2cc3cc(Br)ccn3n2)cc1

Procedure:
7.82 g (25.50 mmol) of 2-(4-bromopyridin-2-yl)-1-(4-fluorophenyl)ethanone oxime are placed in a round-bottomed flask and dissolved in 400 mL of 1,2-dichloroethane. An O-(mesitylenesulfonyl)hydroxylamine solution (0.27 M in 1,2-dichloroethane—compound obtained according to the protocol described in step 1.3) is added dropwise to the medium cooled to about 0° C. After the addition, the medium is stirred at room temperature for 1 hour 30 minutes. The medium is then diluted with 200 mL of water and 200 mL of sodium hydroxide solution (1N). The two-phase medium is stirred and the phases are then separated by settling. The organic phase is separated out and the aqueous phase is then extracted 4 times with 200 mL of dichloromethane. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, and the resulting mixture is then concentrated under reduced pressure. The powder obtained is used as solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1/1). 5.06 g (68%) of compound are obtained in the form of a fleecy white powder.
Reaction SMILES: S1C2NC(C(OCC)=O)=CC=2C=C1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C(=O)N([Br:39])C(=O)C1.[Br:40][C:41]1[C:42]2[CH:53]=[CH:52][S:51][C:43]=2[NH:44][C:45]=1[C:46]([O:48][CH2:49][CH3:50])=[O:47]>C(Cl)Cl.CCOC(C)=O>[Br:40][C:41]1[C:42]2[CH:53]=[CH:52][S:51][C:43]=2[NH:44][C:45]=1[C:46]([O:48][CH2:49][CH3:50])=[O:47].[Br:39][C:52]1[S:51][C:43]2[NH:44][C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:41]([Br:40])[C:42]=2[CH:53]=1
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(=O)c1[nH]c2sccc2c1Br
Agent: CCOC(=O)c1cc2ccsc2[nH]1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2sc(Br)cc2c1Br
Temperature: 23 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of ethyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (0.55 g, 2.82 mmol) in DCM (10 mL) was added TBAF (1.0 M THF, 4.2 mL) followed by NBS (0.55 g, 3.1 mmol). The resulting mixture was allowed to stir at 23° C. for 1 h in the dark at which time the entire reaction mixture was placed on a silica gel column. Flash column chromatography (0-100% EtOAc in hexanes) affords one major peak containing a mixture of starting material, ethyl 4-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate, and 2,4-dibromo products. Separation of the desired products from the byproduct by RP-HPLC (10-100% gradient 0.1% formic acid in H2O to CH3CN over 10 min) afforded ethyl 4-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.30 g, 39% yield) and ethyl 2,4-dibromo-6H-thieno[2,3-b]pyrrole-5-carboxylate (183 mg, 18%). Ethyl 2,4-dibromo-6H-thieno[2,3-b]pyrrole-5-carboxylate: 1H NMR (400 MHz, CD3OD) δ (ppm) 6.95 (s, 1H), 4.32 (q, J=4.6 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H). LCMS m/e=351 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=[O:2].Cl>C(OCC)(=O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:25][CH:24]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 141.9 %

Procedure:
5 g (14.6 mmole) tert-butyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate was deprotected in ethyl acetate saturated with hydrochloric acid at room temperature over night. The product precipitated and filtration yielded 5 g (100%) of 4-[2-(4-aminophenyl)ethoxy]benzaldehyde x HCl. The product contained some solvent, but was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]([CH2:12][CH3:13])[C:10]2[CH:14]=[CH:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[CH:18][C:9]=2[C:8](=[O:23])[CH:7]=1)=[O:5])C.Cl>>[O:23]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]([CH2:12][CH3:13])[C:10]2[CH:14]=[CH:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[CH:18][C:9]1=2
Reactant: CCOC(=O)c1cc(=O)c2cc(OCC)c(=O)ccc2n1CC
Agent: Cl
Product: CCOc1cc2c(=O)cc(C(=O)O)n(CC)c2ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-6-ethoxy-1-ethyl-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (8.2 g, described in Example 7) and 19% hydrochloric acid (246 ml) is refluxed for 30 min and cooled to room temperature. The crystalline precipitate is collected and washed with water to give the title compound, mp 227°-228° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCCl)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (78 mg, 0.19 mmol) and TEA (0.52 mL, 3.78 mmol) in DCM (10 mL) was added 3-chloropropane-1-sulfonyl chloride (63 mg, 0.36 mmol, in 1 mL DCM). After stirring at rt for one hour, EtOAc (100 mL) was added. The mixture was sequentially washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-100% EtOAc in hexanes gradient) to give 5-chloro-N2-(4-(1-(3-chloropropylsulfonyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; ESMS m/z 552.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](OC([O-])=O)(=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C:14]([N:12]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][C:11]1=[O:13])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1CCC(c2ccc(F)cc2)N1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CCC1c1ccc(F)cc1
Yield: 61.9 %

Procedure:
22.6 g (0.126 mol) of 5-(4-fluorophenyl)-pyrrolidin-2-one in 200 ml of toluene are boiled at reflux with 55 g (0.25 mol) of tert-butyl pyrocarbonate for 5 hours. After cooling the mixture, is washed repeatedly with water and the organic phase, is dried and concentrated under reduced pressure using a rotary evaporator. The residue is stirred with petroleum ether and the crystals are filtered off with suction. This gives 21.8 g (62% yield of theory) of 1-(tert-butyloxycarbonyl)-5-(4-fluorophenyl)-pyrrolidin-2-one of m.p. 117°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[N:25]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:23][N:24]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[N:25]4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccn(CCl)n1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc[nH]1
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Yield: 30.5 %

Procedure:
4-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (426 mg, 1.18 mmol) synthesized in Reference Synthesis Example 14 and 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole (219 mg, 1.18 mmol) were used to obtain the title compound (158 mg, yield 30%) by synthesis in a similar manner to Reference Synthesis Example 8.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11])=O)(C)(C)C.Cl.CCOCC>ClCCl>[NH2:8][C@H:9]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@H](N)CCCCN)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-{[(2R)-2,6-di(tertbutoxycarbonylamino)hexanoyl]amino}propanoate (1) (0.123 g; 0.162 mmol) in dichloromethane (10 ml) was treated with a 4.8M solution of hydrogen chloride in ether (170 μl; 0.81 mmol). The mixture was stirred at ambient temperature for 1 hour and the resulting precipitate was filtered, washed with ether and dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-{[(2R)-2,6-diaminohexanoyl]amino}propanoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:27]([NH:34][C:11](=[O:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: NCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)NCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a solution of 10.80 g (0.060 mole) of 3-(4-methoxyphenyl) propanoic acid and 6.57 g (0.065 mole of triethylamine in 25 ml dichloromethane at about 0.5° C., 6.84 g (0.063 mole) of ethyl chloroformate was added dropwise. The mixture was stirred for about 15 minutes at a temperature of about 5° to 10° C., then 6.96 g (0.065 mole) of benzylamine were added. The resulting mixture was stirred for about thirty minutes, and the solvent was evaporated. The residue was slurried in 5% aqueous sodium hydroxide. The solid was collected by filtration and rinsed with water until neutral. The washing process was repeated using 5% hydrochloric acid. The residue was dried under vacuum to give 11.0 g of the above-identified product, melting point 92°-94° C., which was suitable for use in step (b).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)[CH3:5]>C(Cl)Cl>[CH2:4]([C:6]1[S:7][C:8]([C:11]([O:13][CH3:3])=[O:12])=[CH:9][N:10]=1)[CH3:5]
Reactant: CCc1ncc(C(=O)O)s1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: CCc1ncc(C(=O)OC)s1

Procedure:
A solution of diazomethane in methylene chloride was added to a suspension of 10.45 g of 2-ethyl-thiazole-5-carboxylic acid in 30 ml of methylene chloride until efferversence stopped and the methylene chloride was distilled. The oily residue was chromatographed over silica and was eluted with a 1:1 mixture of benzene-ethyl acetate to obtain 11.3g of methyl 2-ethyl-thiazole-5-carboxylate.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:26][CH3:27])=[CH:7][C:8]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[OH:4][C:5]1[C:6]([O:26][CH3:27])=[CH:7][C:8]([CH2:17][O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])=[C:9]([CH:16]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCc1cc(OC(C)=O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CCc1cc(O)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
A mixture of methyl 5-acetoxy-2-tert-butyldimethylsilyloxymethyl-4-methoxyhydrocinnamate (4.64 g) and potassium carbonate (0.16 g) in anhydrous methanol (50 ml) is stirred at 0°-5° C. for about 18 hours, diluted with water, and the pH adjusted to 5 with dilute HCl. The mixture is extracted with ether and the ether solution is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by HPLC, eluting with 20% ethyl acetate in hexanes to give the desired product.