Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.[C:17]([CH2:19][C:20]1([N:31]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[N:32]2)[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)#[N:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([CH2:19][C:20]1([N:31]2[CH:35]=[C:34]([C:2]3[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=[C:4]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[N:3]=3)[CH:33]=[N:32]2)[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
In a 5 L 4-necked flask with an overhead mechanical stirrer was added 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J; 34.83 g, 149.1 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-Pyrazol-1-yl)azetidine-1-carboxylate (Preparation F; 86.82 g, 223.6 mmol), and K3PO4 (94.92 g, 447.2 mmol) by powder funnel. Dioxane (745.3 mL, 149.1 mmol) was added to rinse down funnel. Pd(PPh3)4 (17.23 g, 14.91 mmol) was added, followed by 74.5 mL of water. The reaction mixture was slowly heated to 70° C. as measured by an internal temperature probe. After heating for 6 hours, the reaction mixture was cooled to ambient temperature. The reaction mixture was diluted in EtOAc (500 mL) and water (100 mL), and then the resultant solids were filtered out. The solids were washed with EtOAc (2×500 mL) to afford a grey-white solid, which was re-introduced back to the 5 L 4-neck flask and diluted with 1 L of water and 300 mL of EtOAc. This was stirred for 3 hours, and then the solids were isolated by filtration. After washing with EtOAc (2×500 mL), the solids were dried to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (60.83 g, 132.4 mmol, 88.81% yield). MS (apci) m/z=460.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[CH:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:48]([O:50][C:51](=[O:65])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([SH:60])=[CH:56][C:55]=1[C:61]([F:64])([F:63])[F:62])[CH3:49]>C1COCC1>[CH2:48]([O:50][C:51](=[O:65])[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([S:60][CH2:9][CH:8]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])=[CH:56][C:55]=1[C:61]([F:62])([F:63])[F:64])[CH3:49]
Reactant: CCOC(=O)COc1ccc(S)cc1C(F)(F)F
Reactant: Cc1ccsc1C(=CCO)c1sccc1C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCC=C(c2sccc2C)c2sccc2C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 100 h

Procedure:
To a solution of 3,3-bis-(3-methyl-thiophen-2-yl)-prop-2-en-1-ol (110 mg, 0.44 mmol) and triphenylphosphine (220 mg, 0.88 mmol) in THF was added, at room temperature and under nitrogen atmosphere, DEAD (153 mg, 0.88 mmol). The reaction mixture was stirred for 5 min after which (2-trifluoromethyl-4-mercapto-phenoxy)-acetic acid ethyl ester (70 mg, 0.25 mmol) was added over 15 min. The reaction mixture was stirred at room temperature for 100 hours. The reaction mixture was evaporated and the crude residue was purified on a Horizon using a methylene chloride:heptanes gradient as eluent. The desired {4-[3,3-bis-(3-methyl-thiophen-2-yl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester was isolated in 75 mg (59%) yield.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[N:18]=[CH:17][C:16]=1C(O)=O)#[N:14].C(NC)C>CN(C=O)C>[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[N:18]=[CH:17][C:16]=1[C:1]([N:8]([CH3:9])[CH2:12][CH3:11])=[O:2])#[N:14]
Reactant: N#Cc1cccc(-n2ncc(C(=O)O)c2C#N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCNC
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1cnn(-c2cccc(C#N)c2)c1C#N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Two grams of carbonyldiimidazole was added to a solution of 2.0 g of 5-cyano-1-(3-cyanophenyl)-1H-pyrazole-4-carboxylic acid dissolved in 50 ml of DMF. The reaction mixture was stirred at room temperature for approximately 25 minutes whereupon 740 mg of N-ethyl-N-methylamine was added. The reaction mixture was allowed to stir for an additional 24 hours at which point the solution was poured into ice water. The precipitate solid was collected by filtration and dried to provide 1.2 g of 5-cyano-1-(3-cyanophenyl)-N-methyl-N-ethyl-1H-pyrazole-4-carboxamide following recrystallization from ethanol. MP=185°-187° C.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=2)[N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH:20]=[CH:19]2
Reactant: OCc1ccccc1S
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccccc1Sc1ccc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A mixture of 2-mercaptobenzyl alcohol (1.78 g, 12.7 mmol), 2,6-dichloroquinoline (2.48 g, 12.5 mmol) and potassium carbonate (1.73 g, 12.5 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature under nitrogen for 3 hours, then at 60° C. for 17 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5-10% ethyl acetate/dichloromethane, to give {2-[(6-chloroquinolin-2-yl)thio]phenyl}methanol (0.37 g, 9%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.84 (1H, d, J=8.7 Hz), 7.72-7.66 (4H, m), 7.55-7.51 (2H, m), 7.39-7.35 (1H, m), 7.19 (1H, dd, J=1.2, 8.7 Hz), 4.84 (2H, s), 3.78 (1H, s); m/z (ES+) 302, 304 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH2:22])=O)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.[Si]([N:36]=[N+:37]=[N-:38])(C)(C)C>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]4[NH:22][N:38]=[N:37][N:36]=4)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[S:8][C:7]=2[CH:31]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(N)=O)cc2)cc1
Solvent: COCCOC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnn[nH]3)cc2)cc1
Temperature: 180 °C
Yield: 88.2 %

Procedure:
To a microwave vial, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (75 mg, 0.174 mmol) and Bu2SnO (4.33 mg, 0.02 mmol) were suspended in DME (3 mL). The vial was charged with TMSN3 (0.023 mL, 0.17 mmol) and the reaction was heated for 60 min at 180° C. under microwave irradiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO2, 1-20% MeOH/DCM) to afford (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole (66 mg, 0.15 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.45-7.61 (m, 5H), 7.32 (d, J=2.02 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 6.98 (d, J=16.67 Hz, 1H), 6.86-6.93 (m, 2H), 6.78-6.86 (m, 3H), 3.78 (s, 3H), 3.69 (s, 3H). LC/MS (m/z, MH+): 457.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccccc1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzyl bromide.
Reaction SMILES: [Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([C:46](=O)[CH3:47])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:58][C:59]([NH2:61])=[S:60].C(=O)([O-])O.[Na+]>O1CCCC1.C(O)C.O>[NH2:61][C:59]1[S:60][CH:47]=[C:46]([C:38]2[CH:37]=[C:36]([C:35]([F:50])([F:49])[F:34])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=2)[N:58]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
Phenyltrimethylammonium tribromide (753 mg, 2 mmol) was added to a solution of 3′,5′-bis(trifluoromethyl)acetophenone (0.51 g, 2.0 mmol) in tetrahydrofuran (5 mL) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, ethanol (5 mL) and thiourea (152 mg, 2 mmol) were added to the residue obtained by evaporation of the solvent under reduced pressure, and the mixture was refluxed for 30 minutes. After the reaction mixture was cooled to room temperature, it was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) and washed with n-hexane under suspension to give the title compound (520.1 mg, 83.3%) as a light yellow white crystal.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.COS(OC)(=O)=O.[C-:16]#[N:17].[K+]>C(O)C.O>[C:16]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[CH3:7])#[N:17]
Reactant: [C-]#N
Reactant: Cc1ccc[n+]([O-])c1
Agent: [K+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cnccc1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
To a cooled (0° C.) round bottom flask charged with 3-picoline-N-oxide (4.53 g, 42 mmol) was added dimethylsulfate (5.8 g, 47 mmol). The mixture was stirred for 18 hours and allowed to warm to room temperature. To this mixture was added potassium cyanide (3.25 g, 50 mmol) dissolved in ethyl alcohol/water (75 mL, 1:1). The reaction was stirred at room temperature for 18 hours, concentrated to half the volume and diluted with chloroform (100 mL). The organic layer was separated and washed with sodium chloride (sat. 25 mL) and dried over Na2SO4. The solvent was removed and the residual material was chromatographed (SiO2, hexanes/ethyl acetate) to give the title compound as off-white crystals (2.01 g, 41%). 1H NMR (300 MHz, DMSO-d6): δ 2.55 (s, 3H); 7.47 (d, 1H); J=5.1 Hz); 8.60 (d, 1H, J=5.1 Hz); 8.68 (s, 1H).
Reaction SMILES: [CH2:1]([NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:7]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCCCCCN[C@H]1CC[C@H](c2ccccc2)CC1
Product: CCCCCCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-hexyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 105° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].[C:22]([O:26][CH3:27])(=[O:25])[C:23]#[CH:24]>C1C=CC=CC=1>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:24]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[N:3]=[N:2]1
Reactant: C#CC(=O)OC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Solvent: c1ccccc1
Product: COC(=O)c1cn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)nn1
Yield: 68.6 %

Procedure:
A solution 1.0 g(3.4 mmol) of the azide of Example 17 in 50 mL benzene was treated with 573 mg(6.8 mmol) of methyl propiolate followed by warming at reflux for 24 h. The mixture was cooled and the product isolated by filtration of the reaction mixture. These procedures afforded 880 mg of the title compound as a white solid. High Resolution Mass Spectrum (EI): calcd for C16H16FN5O5 : 377.1135. found: 377.1131.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:26][NH:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]=3[N:22]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1.C(N)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([N:25]1[CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[N:22]=[C:17]([NH:16][C:6]3[CH:7]=[CH:8][C:9]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:4]([O:3][CH3:2])[CH:5]=3)[N:18]=[CH:19][C:20]=2[CH2:26]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CNC3)ccc1-n1cnc(C)c1
Agent: CCN
Agent: Cl
Solvent: ClCCl
Product: COc1cc(Nc2ncc3c(n2)C(c2ccccc2)CN(S(C)(=O)=O)C3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
To a suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(8-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-amine hydrochloride (75 mg, 0.17 mmol) in methylen chloride (2 mL) was added at room temperature NN,-diisoprpyl ethyl amine (33 mg, 0.25 mmol) and methanesulfonyl chloride (21.3 mg, 0.18 mmol). The reaction was stirred at room temperature over night. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (13 mg, 16%) as a yellow solid. MS ISP (m/e): 491.0 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.33 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.26-7.35 (m, 3H), 7.17 (d, 2H), 7.05 (d, 1H), 6.82 (s, 1H), 6.77 (d, 1H), 4.56 (d, 1H), 4.46 (d, 1H), 4.32 (t, 1H), 3.97 (dd, 1H), 3.43 (dd, 1H), 3.38 (s, 3H), 2.80 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([NH2:27])=[C:22]([NH2:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[CH3:37][O:38][C:39](OC)(OC)OC.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]4[NH:27][C:37]([O:38][CH3:39])=[N:28][C:22]=4[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
A solution of 1.00 g (2.02 mmol) (R)-2-(3,4-diamino-5-methyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2.00 mL (15.01 mmol) tetramethoxymethane in 20 mL MeOH was refluxed for 1 h in the presence of 40 mg (0.21 mmol) toluenesulphonic acid hydrate. The mixture was evaporated down i.vac. and the residue was purified by chromatography (Alox, activity grade II-III, DCM/MeOH 20:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24]([NH:13][C:11]1[S:10][CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([F:14])=[C:2]([CH3:1])[CH:7]=2)[N:12]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Product: Cc1cc(-c2csc(NS(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (50.9 mg) with purity >90%: MS (pos) m/z 451.0, 453.0, 455.0; HRMS m/z 449.9218 (calc. of monoisotopic mass for C16H10Cl3FN2O2S2 gives 449.9233).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([O:35][CH3:36])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: COC(=O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 49.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.1 g, 2.2 mmol) was reacted with methyl morpholine-3-carboxylate (0.4 g, 2.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.62 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:11][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Yield: 99 %

Procedure:
The title compound was prepared from the product of step 3 (0.5 g, 1.8 mmol) and BBr3 (1.34 g, 5.4 mmol) using the procedure of Example 159, step 4 with 99% yield (0.48 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](O)=[O:18].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([F:23])=[C:14]([Cl:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-chloro-4-fluorobenzoic acid (319 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) at room temperature was stirred for 2 hours. 3M aqueous LiOH (3 mL) was then added, and the mixture was stirred for 10 minutes. Next, water (10 mL) and DCM (10 mL) were added, and the resulting precipitate was filtered. The solid isolated was triturated with 10:1 CH2Cl2:MeOH and filtered to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (240 mg, 71% yield) as a solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:16]=1>CN(C)C=O.[Cu]I>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=1
Reactant: Clc1cccc(OCc2cccs2)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cccc(OCc3cccs3)n2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (3.62 g, 0.0045×5.0 mol), sodium hydride (0.36 g, (Ca.60% in mineral oil), 0.0045×2.0 mol) and CuI (0.42 g, 0.0045×0.5 mol) in dimethylformamide, 2-chloro-6-(2-thienylmethyloxy)pyridine (1.0 g, 0.0045 mol) was added and the resultant solution was refluxed for about 3 hours. Additional sodium hydride (0.36 g, (60% in mineral oil), 0.0045×2.0 mol) was added thereto and the resultant solution was refluxed for another about 1 hour, thereafter the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on a silica gel column to obtain the end product.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([F:12])[C:5]=1[CH:13]([C:19]([O:21]CC)=[O:20])[C:14]([O:16]CC)=[O:15].Cl>CCOCC>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([F:12])[C:5]=1[CH:13]([C:19]([OH:21])=[O:20])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1cc(F)c(C(C(=O)O)C(=O)O)c(F)c1
Yield: 88 %

Procedure:
3M aq. NaOH (80 mL) was added to a solution of diethyl 2-(2,6-difluoro-4-methoxyphenyl)malonate, 6.30 g, 20.85 mmol) in Et2O (5 mL). The reaction mixture was heated at reflux until all the solid had dissolved. After cooling, the mixture was acidified with 3M aq. HCl and the product was extracted with EtOAc (2×100 ml). The combined organic layers were dried (MgSO4) and solvent was removed in vacuo to give the title compound as a tan coloured solid (4.50 g, 88%); mp 157° C. (dec); 1H NMR (270 MHz, DMSO-d6) 3.78 (3H, s, CH3), 4.72 (1H, s, CH), 6.70-6.79 (2H, m, ArH).