Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][C@@H:17]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[C:38]([C:43]([O:45]C(C)(C)C)=[O:44])[CH:37]=2)=[O:34])[C:16]1=[O:50])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[CH3:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:33]([NH:32][C@H:17]2[C:16](=[O:50])[N:15]([CH2:14][C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:13])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18]2)=[O:34])=[CH:37][C:38]=1[C:43]([OH:45])=[O:44]
Reactant: Cc1ccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Trifluoroacetic acid (10 ml) was added to (R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea (1.9g) in methylene chloride (10 ml), the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, the mixed solvent (100 ml) of diisopropyl ether and ethanol (40:1) was added to the residue for crystallization, collected by filtrated, to thereby obtain 1.47 g of the title compound (Yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1F
Product: O=C(Cl)Cc1ccccc1F

Procedure:
2-(2-Fluorophenyl)acetic acid, (1.7 mmol) was dissolved in thionyl chloride (0.372 ml, 5.10 mmol) and heated to reflux for 1 h. The reaction was cooled and the excess thionyl chloride was evaporated. The residue was instantly dissolved in dry THF and refridgerated until used. No purity analysis or weighing were performed.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[O:14][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:17](=[O:19])[CH:18]=2)=[CH:7][CH:6]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[O:14][C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:17](=[O:19])[CH:18]=2)=[CH:7][CH:6]=1
Reactant: O=c1cc(C=Cc2ccc([N+](=O)[O-])cc2)oc(-c2ccccc2)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C=Cc2cc(=O)cc(-c3ccccc3)o2)cc1

Procedure:
A solution of concentrated hydrochloric acid (0.2 ml) in ethanol (20 ml) was added to a stirred refluxing suspension of 2-[2-(4-nitrophenyl)-ethenyl]-6-phenyl-4H-pyran-4-one (8.5 g) and iron powder (4.5 g) in ethanol (80 ml) and water (20 ml). The stirred mixture was heated under reflux for 5 hours, adding further concentrated hydrochloric acid (0.2 ml) after 2 hours. The hot mixture was filtered and the filtrate was evaporated under vacuum. The solid residue was crystallised from chloroform-petroleum ether 60°-80° C. to give 2-[2-(4-aminophenyl)-ethenyl]-6-phenyl-4H-pyran-4-one (mp 192°-194° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: O=C(O)CCC1CCC(=O)N1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C

Procedure:
A solution of 3.0 g (0.017 mol) L-Leucine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.05 ml (0.029 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred ten minutes, filtered and concentrated at reduced pressure. The oil is dissolved in 17 ml of dichloromethane and the following is added in a single addition: 4.35 g (0.021 mol) of dicyclohexylcarbodiimide; 100 mg (0.0008 mol) of 4-dimethylaminopyridine; 2.66 g (0.017 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 20 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 93:7 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 50 ° C. yields crystalline analytically pure (as a 0.33 hydrate) N-[1-oxo-3-(5-oxo-2-pyrrolidinyl) propyl]-L-leucine, methyl ester with a melting point of 70°-74.5° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH3:16])[CH:11]=2)[O:8][C@@H:7]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[Cl:26])[C@@H:6]1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2].[NH2:32][C@@H:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34][OH:35].CCN(C(C)C)C(C)C.Cl>ClCCCl>[ClH:26].[C:1]([O:4][C@@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH3:16])[CH:11]=2)[O:8][C@@H:7]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[NH:32][C@@H:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][OH:35])[C@@H:6]1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2]
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(N[C@H](CO)Cc5ccccc5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1

Procedure:
A mixture comprising acetic acid (2R,3R,4R,5S)-4-acetoxy-2-(2,6-dichloro-purin-9-yl)-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3-yl ester (WO 99/38877) (1 g, 2.13 mmol), (S)-2-amino-3-phenyl-propan-1-ol (0.321 g, 2.13 mmol) and DIPEA (0.275 g, 2.13 mmol) in DCE (5 mL) is stirred under an inert atmosphere of argon overnight. After cooling to room temperature (RT), 1 M HCl is added, the organic portion is separated and concentrated in vacuo to afford the title compound which is used in the next step without further purification. (MH+585.1)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Na].[O:37]=[O:38]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[O:38][O:37][C:12]2([C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:13]([CH3:17])([CH3:16])[CH2:14][O:15]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C2=C(C(C)(C)COCCCCCCCCCCC(=O)O)C(C)(C)CO2)c1
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C23OCC(C)(C)C2(C(C)(C)COCCCCCCCCCCC(=O)O)OO3)c1

Procedure:
5-(3-acetoxyphenyl)-4-(13-carboxy-1,1-dimethyl-3-oxatridecan-1-yl)-3,3-dimethyl-2,3-dihydrofuran (compound (22)) (125 mg, 0.256 mmol) and TPP (1 mg) were added to dichloromethane (12 mL), and the mixture was irradiated with visible light by a 940 W sodium lamp in an oxygen atmosphere at 0° C. for 30 minutes. The reaction mixture was concentrated, and the concentrate was put into a silica gel column and developed with a mixed solvent of hexane and ethyl acetate (10:1 to 5:1), whereby 1-(3-acetoxyphenyl)-5-(13-carboxy-1,1-dimethyl-3-oxatridecan-1-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (compound (23)) was obtained in an amount of 133 mg in a yield of 97.6%.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cc(O)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(O)ccc1Cl
Yield: 74.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chloro-5-hydroxybenzeneboronic acid (available from Combi-Blocks Inc.; 69 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-hydroxy-biphenyl-2-carboxylic acid (71 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 9.76 (s, 1H), 8.48 (s, 2H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.78 (dd, J=8.7, 2.9 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]=O)[S:5][C:6]=1[CH3:7].Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([CH:8]=[N:11][OH:12])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(C=O)sc1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C=NO)sc1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4,5-dimethylthiazole-2-carbaldehyde (987 mg, 7.0 mmol) in 1,4-dioxane (35 mL) was added hydroxylamine hydrochloride (1.45 g, 21 mmol) and K2CO3 (3.8 g, 28 mmol). The resulting mixture was stirred at 100° C. for 2 hours and then diluted with EtOAc (150 mL), washed with H2O (30 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was used for next step without further purification. LCMS m/z (M+H) 157.1 found, 157.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of 2-chloro-N,N-dimethyl-acetamide. The crude reaction mixture was purified by preparative HPLC to afforded 10 mg of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)=[O:4]
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1C(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Trichloro-acetylchloride (0.0848 mol) was added dropwise at 5° C. to a mixture of intermediate 3 (0.0707 mol) in DCM (250 ml) under N2 flow. The mixture was stirred at 5° C. for 30 minutes. Triethylamine (0.0848 mol) was added dropwise at 5° C. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 2 hours and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from diethyl ether/DIPE. The precipitate was filtered off and dried, yielding 33.7 g (95%) of 2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(4-fluorobenzoyl)phenyl]-acetamide (intermediate 4).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:12][C:11](=[O:13])/[CH:10]=[CH:9]/[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
As in Example 115, (E)-5,5-diphenyl-2,4-pentadienoic acid (lg) and 4-nitrophenol (0.7 g) in dichloromethane (10 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.824 g). The mixture was stirred at 0°-5° C. for 10 minutes, then at room temperature for 45 minutes. After the usual work up, the ester was crystallized from 2-propanol to yield 1.1 g of (E)-5,5-diphenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 113°-115° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH:12]([OH:14])[CH3:13]>CO>[OH:14][CH2:12][CH2:13][S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(O)Br
Reactant: Oc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a solution of 10.9 g 4-hydroxythiophenol (87 mmol) in 200 ml MeOH was added at 0-5° C. 87 ml 1N NaOH (87 mmol). After the reaction mixture was stirred for 10 min 6.1 ml bromoethanol (86 mmol) dissolved in 100 ml MeOH was added. The reaction mixture was stirred for 3 h at r.t. and the methanol was partly removed under reduced pressure. The residue was poured to a 1:1 mixture of ethyl acetate and saturated NaHCO3−solution and the organic phase was separated, dried over MgSO4, filtrated and the solvent was removed under reduced pressure. The residue was purified by chromatography over silica gel (ethyl acetate/hexane 3/2 to 2/1) to give 13.4 g product (78.7 mmol, 91%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]O)[CH2:32][CH2:31]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:4][C:3]=1[F:9]
Reactant: CN1CCN(CCO)CC1
Reactant: Oc1ccc(Br)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCN(CCOc2ccc(Br)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
A flask was charged with 4-bromo-3-fluorophenol (5.00 g, 26 mmol) and triphenylphosphine (10.30 g, 39 mmol). Methylene chloride (120 mL) was added followed by 2-(4-methylpiperazin-1-yl)ethanol (4.61 g, 32 mmol) and the solution was stirred on an ice water bath to cool. After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added over 6 to 8 minutes. The reaction was left stirring on the cold bath to slowly warm to room temperature overnight. The reaction was concentrated and the residue purified by flash chromatography (25% to 100% EtOAc in hexanes) to provide the product as a colorless oil (2.62 g, 33%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][N:19]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=4)[CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(Cl)ncn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(C)ncn2)CC3)cc1
Yield: 36 %

Procedure:
The compound op was prepared following the general procedure in Example 2, substituting 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea with (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-d]azepin-2-yl)phenyl)urea and substituting 2-Chloropyrimidine with 4-Chloro-6-methylpyrimidine. The desired product op (36% yield) was obtained as white powder: 1H NMR (500 MHz, DMSO) δ 8.70 (s, 1H), 8.42 (s, 1H), 8.20 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 6.80 (s, 1H), 6.19 (t, J=5.5 Hz, 1H), 4.10-3.62 (m, 9H), 3.52 (dd, J=11.0, 3.6 Hz, 1H), 3.21-3.02 (m, 5H), 2.88 (m, 2H), 2.28 (s, 3H), 1.12 (d, J=6.4 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=503 (M+H).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][CH2:15][NH:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH2:45][CH:46]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][CH2:46][N:16]([CH2:17][CH:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH2:15][CH2:14][CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CSc2ccc(N3C[C@@H](CNCCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Product: CC(C)(C)[Si](C)(C)OCCCN(CCC1Cn2c(=O)ccc3ccc(F)c1c32)CC1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 75 %

Procedure:
Starting from the compound of Example 10 and 3-(tert-butyldimethylsilyloxy)-propionaldehyde and using procedure E, the title compound was obtained as a colourless solid (101 mg; 75% yield).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:19])[C:16](F)=[O:17].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:14][CH:15]([F:19])[C:16](=[O:17])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=CN1CCCCC1
Reactant: O=C(F)C(F)F
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initially charged in toluene (100 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced. Tributylamine (9.5 g, 51 mmol) was then added to the reaction mixture. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml) and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.7 g; purity according to GC: 82.15%; yield: 82.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH2:10][OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:11][CH2:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCc1c(Br)cc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1c(Br)cc(F)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
To a solution of 101i (20 g, 71 mmol) in CH2Cl2 (500 mL) at 0° C. was added pyridine (8.4 g, 107 mmol) and acetyl chloride (8.3 g, 107 mmol). The mixture was stirred at room temperature for 5 h. TLC showed the start material disappeared. The reaction was evaporated in vacuum and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 101j as a white solid (20 g, 87%). MS: [M−Oac]+ 267. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J=7.5, 2H), 5.38 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Br[CH:11]([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:17][CH2:16][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CS
Reactant: CCC(Br)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Methyl thioglycolate (5.0 mL, 55.0 mmol) was added dropwise to an ice cold solution of sodium methoxide (55.0 mmol) in methanol (18 mL) over 15 minutes. Methyl bromobutyrate (9.9 g, 55.0 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was filtered, concentrated, and taken up in methylene chloride and filtered again. The filtrate was concentrated and the product was distilled to give methyl 4-[(2-methoxy-2-oxoethyl)sulfanyl]butanoate (6.34 g, 55%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]2C)(=[O:15])=[O:14])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:20]1[CH2:18][CH2:17][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:30][CH3:31])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:2]=3[F:1])[N:11]=2)(=[O:15])=[O:14])[CH2:21]1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CC[C@@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R)-4-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]-3-methylpiperazine-1-carboxylate (0.75 g) in DCM (10 ml) was added TFA (10 ml) slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield: 0.27 g