Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH:34]=[N:35][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[N:22][N:23]3COCC[Si](C)(C)C)=[CH:19][CH:18]=2)=[CH:5][C:4]([CH3:42])=[N:3]1.C1(N)C=CC=C(N)C=1>>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:25]=[C:24]3[C:20]([C:21]([CH:34]=[N:35][N:36]4[CH:40]=[CH:39][CH:38]=[CH:37]4)=[N:22][NH:23]3)=[CH:19][CH:18]=2)=[CH:5][C:4]([CH3:42])=[N:3]1
Reactant: Cc1cc(CNC(=O)c2ccccc2Nc2ccc3c(C=Nn4cccc4)nn(COCC[Si](C)(C)C)c3c2)n(C)n1
Agent: Nc1cccc(N)c1
Product: Cc1cc(CNC(=O)c2ccccc2Nc2ccc3c(C=Nn4cccc4)n[nH]c3c2)n(C)n1

Procedure:
Prepared in a similar manner to that described for Example 11 in U.S. Pat. No. 6,534,524, issued Mar. 18, 2003, herein incorporated by reference in its entirety for all purposes, except that N-(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-2-[3-(pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamide was used instead of N-methyl-N-{3-styryl-1-[2-trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine. 1H NMR (DMSO-d6) δ 13.27 (1H, s), 9.72 (1H, s), 9.05 (1H, t, J=5.3 Hz), 8.97 (1H, s), 8.16 (1H, d, J=8.7 Hz), 7.68 (1H, dd, J=8.3, 1.9 Hz), 7.50 (2H, t, J=2.6 Hz), 7.46–7.38 (2H, m), 7.25 (1H, s), 7.05 (1H, dd, J=8.7, 1.9 Hz), 6.91 (1H, t, J=6.80 Hz), 6.20 (2H, t, J=2.3 Hz), 5.91 (1H, s), 4.43 (2H, d, J=5.6 Hz), 3.71 (3H, s), 2.04 (3H, s).
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.O.[C:9]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:20]([C:24]1[CH:25]=[C:26](C(=O)C)[CH:27]=[C:28]([I:32])[C:29]=1[O:30][CH3:31])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CO>[C:20]([C:24]1[C:29]([O:30][CH3:31])=[C:28]([I:32])[CH:27]=[C:26]([C:1]([O:4][CH3:5])([O:6][CH3:7])[CH3:9])[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1c(I)cc(C(C)=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(I)cc(C(C)(OC)OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 935.9 %

Procedure:
Methanol (6 mL), trimethyl orthoformate (262 mg, 2.4 mmol), and p-toluenesulfonic acid monohydrate (TsOH.H2O) (38 mg, 0.2 mmol) were added to 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)ethanone (664 mg, 2 mmol), and this was stirred at room temperature for 2 hours, and then at 60° C. for 1 hour. After stirring for another 3 hours at 0° C., potassium carbonate (138 mg, 1.0 mmol) was added, and after stirring for 1.5 hours on ice, the reaction solution was concentrated to dryness. Water (5 mL) and toluene (10 mL) were added to this residue and the solution was separated. The organic layer was washed with water (5 mL) and the solvent was distilled off (50° C.) to obtain 708 mg of the subject compound as pale brown crystals (yield: 93.6%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([OH:21])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][OH:46])=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:46][CH2:45][CH2:44][CH2:43][C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:19](=[O:21])[CH2:18][CH:3]2[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]2[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:42][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)O)cc1
Reactant: Nc1ccc(CCCO)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)Nc2ccc(CCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL vial was added [3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetic acid (500 mg, 1.61 mmol), EDC (Aldrich, 464 mg, 2.42 mmol), HOBt (Aldrich, 195 mg, 1.45 mmol), CH2Cl2 (5 mL), 3-(4-amino-phenyl)-propan-1-ol (731 mg, 4.84 mmol) and (iPr)2NEt (Aldrich, 0.56 mL, 3.22 mmol). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2 (60 mL). The organic phase was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chomatography (6%-8% MeOH—CH2Cl2) to afford the title compound. MS (ESI): 444 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:18]2[C:9](=[C:10]([F:23])[C:11]3[C:16]([C:17]=2[O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=3)[C:8](CCC(O)=O)=[CH:7][CH:6]=1)(=O)C.[O-:29][CH2:30][CH3:31].[Na+].Cl.[CH2:34]([OH:36])C>>[OH:4][C:5]1[C:18]2[C:9](=[C:10]([F:23])[C:11]3[C:16]([C:17]=2[O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:34]([O:29][CH2:30][CH3:31])=[O:36])[CH:6]=1
Reactant: CCO
Reactant: COc1ccc2c(F)c3c(CCC(=O)O)ccc(OC(C)=O)c3c(OC)c2c1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cc(O)c2c(OC)c3cc(OC)ccc3c(F)c2c1
Reaction time: 0.5 h

Procedure:
4-Acetoxy-2-carboxyethyl-6,10-dimethoxy-9-fluoroanthracene (5 g) was dissolved in ethanol at room temperature and a solution of sodium ethoxide in ethanol was added. The reaction mixture was stirred for 30 minutes, then acidified with 2N HCl (aq). The solvent was removed under reduced pressure, the residue was taken up in the ethyl acetate and washed with water. The solution was dried (MgSO4) and filtered, hexane was added and a yellow solid precipitated on cooling, ethyl 4-hydroxy-6,10-dimethoxy-9-fluoroanthracene-2-carboxylate).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:15]([CH2:21][CH2:22][CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:20]
Reactant: Oc1ccccc1
Reactant: CCCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC(Oc1ccccc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Phenol (28.5 g, 0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromohexanoate (0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([C:26]([CH3:31])=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>CCCCO>[CH3:31][C:26]1[C:25]2[C:29](=[CH:30][C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[N:3]=3)=[CH:23][CH:24]=2)[NH:28][N:27]=1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(C)n[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5c(C)n[nH]c5c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 116 °C
Yield: 8.2 %

Procedure:
A mixture of 2-chloro-N-(3-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (260 mg, 0.574 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (251 mg, 1.15 mmol) and trimethylsilyl chloride (TMSCl) (0.150 mL, 1.19 mmol) in n-BuOH (5 mL) was heated at 116° C. for 48 h. It was then purified by HPLC to give 1-(4-(4-(4-(3-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]([O:10][C:11]2[N:16]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:14]([N+:27]([O-])=O)=[CH:13][N:12]=2)=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CCOC(C)=O.CCO.[Pd]>[NH2:27][C:14]1[C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[N:16][C:11]([O:10][C:7]2[N:6]=[C:5]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:4]([NH2:1])=[CH:9][N:8]=2)=[N:12][CH:13]=1
Reactant: O=[N+]([O-])c1cnc(Oc2ncc([N+](=O)[O-])c(-c3cccc4ccccc34)n2)nc1-c1cccc2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnc(Oc2ncc(N)c(-c3cccc4ccccc34)n2)nc1-c1cccc2ccccc12
Temperature: 25 °C

Procedure:
The crude nitronaphthyl-pyrimidinyl ether from above (459 mg, 1.42 mmol, 1 equiv.) was taken up in 35 mL EtOAc and 35 mL EtOH. Ammonium formate was added (537 mg, 8.52 mmol, 6 equiv.) as well as 400 mg of 10% palladium-on-carbon. The reaction mixture was heated to a gentle reflux for one h, cooled back to room temperature, filtered through diatomaceous earth and the volatiles were removed in vacuo. The crude product was purified by chromatography on SiO2, eluting with 20-40% EtOAc in hexanes. The desired aminonaphthyl-pyrimidyl ether was isolated as a yellow foam (176 mg, 0.6 mmol, 42% for 2 steps).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].[CH2:26](Br)[CH2:27][CH3:28]>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH2:26][CH2:27][CH3:28])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCCBr
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Product: CCCOc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CC(N(CCC)CCC)C2

Procedure:
Using procedure 38, 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 1.9 g, 5 mmol) was treated with propylbromide (2.5 g, 20 mmol). Chromatographic purification yielded pure product 72 as a oil which was converted into the HCl salt and crystallized from EtOAc/hexane to give a white solid (mp 169-170° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[NH:17][S:18](=[O:20])(=[O:19])[C:13]=3[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>CN(C)C=O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH2:40][C:39]4[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=4)[S:18](=[O:19])(=[O:20])[C:13]=3[CH:12]=2)=[O:10])=[CH:25][CH:26]=1
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)NC(=O)N3C)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)N(Cc2ccc([N+](=O)[O-])cc2)C(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide (1.0 g), and cesium carbonate (0.87 g) were mixed in 50 mL of N,N-dimethylformamide. 4-Nitrobenzylbromide (0.58 g) was added, and the resulting mixture was stirred for 16 hours at room temperature. The reaction was diluted with IM HCl and filtered to give a gummy solid. Recrystallization from ethyl alcohol gave the title compound as a white solid (0.77 g). 1H-NMR (CDCl3); δ 8.48 (s, 1H), 8.26 (d, 1H), 8.10 (m, 3H), 7.54 (d, 2H), 7.25 (m, 4H), 6.82 (t, 2H), 5.05 (s, 2H), 4.50 (d, 2H), 3.73 (d, 3H), and 3.48 (s, 3H) ppm. Anal. (C24H22N407S-1.01H2O) C,H,N. MS: M++1=511.2 Da
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]3[CH:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:13]1.[F:39][C:40]([F:46])([F:45])[CH2:41][C:42](O)=[O:43].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>C(Cl)Cl>[F:39][C:40]([F:46])([F:45])[CH2:41][C:42]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]3[CH:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25]3=[N:26][CH:27]=2)=[O:20])[CH2:13]1)=[O:43]
Reactant: O=C(O)CC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(C(=O)CC(F)(F)F)C3)cnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
DIPEA (0.082 mL, 0.47 mmol) was added at RT to a mixture of 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.066 g, 0.142 mmol), 3,3,3-trifluoropropionic acid (0.015 mL, 0.171 mmol), EDCI (0.033 g, 0.171 mmol), HOBt monohydrate (0.026 g, 0.171 mmol) in 1 mL of DCM. The resulting mixture was stirred at RT for 24 hours before being partitioned between H2O and DCM. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (DCM/(DCM:MeOH:NH4OH 60:10:1] 80% DCM) to give 0.04 g of 1-[1-(3,3,3-trifluoro-propionyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (56% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:9]2[CH3:19])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[Cl-].[CH:26]1([Zn+])[CH2:28][CH2:27]1>C1COCC1>[CH:26]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:9]3[CH3:19])=[CH:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(Cl)nc1
Reactant: [Zn+]C1CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(C2CC2)nc1

Procedure:
2-Chloro-5-(2-methyl-4-trimethylsilanylethynyl-imidazol-1-yl)-pyridine (425 mg, 1.47 mmol) were dissolved in 0.4M cyclopropylzinc chloride in THF (7.33 mL, 0.4M in THF) and tetrakis(triphenylphosphin)palladium (34 mg, 0.03 mmol) were added. The reaction mixture was refluxed for 16 hrs and poured into 50 mL sat. sodium bicarbonate solution. The mixture and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→1:1 gradient) and the desired product was obtained as a light yellow solid (395 mg, 91%), MS: m/e=296.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5](C)=[CH:4][N:3]=1.[ClH:10].ClCl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[Cl:10][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:13]([Cl:17])([Cl:15])[Cl:14])=[CH:4][N:3]=1
Reactant: Cl
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cnc(Br)c(Cl)c1
Agent: ClCl
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
The product from paragraph (i) (2.9 g) in dry carbon tetrachloride (25 ml) was treated with dry hydrogen chloride to convert it to the hydrochloride. Chlorine was passed through the suspension which was kept at 80° C. and illuminated by an ultra-violet lamp inside the reaction flask. After three hours the solvent was removed, leaving a residue of 2,3-dichloro-5-trichloromethylpyridine.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28]SC)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1.[CH3:34]O>O.C(Cl)Cl>[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][S:3]([CH3:34])(=[O:5])=[O:2])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCSC
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A solution of OXONE, (trade mark of E.I du Pont de Nemours & Co., Inc), (800 mg) in water (4.5 ml) was added to a solution of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline (300 mg, 0.66 mmol), (prepared as described in Example 31), in methanol (15 ml) and the mixture was stirred for 4 hours at ambient temperature. The mixture was diluted with methylene chloride, was washed with aqueous sodium hydrogen carbonate solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ethyl acetaie/hexane, collected by filtration and dried to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (235 mg, 73%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[CH2:1]([NH:4][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[F:14])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Reactant: C=CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCNCCc1ccccc1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
0.89 ml of allylamine (11.9 mmol) and 0.311 ml of diisopropyl ethylamine (1.78 mM) were added to the reaction solution (1.2 mmol) containing 350 mg of toluen-4-sulfonate-2-(2-fluoro-phenyl)-ethyl ester (u) prepared by above Step 1 dissolved in acetonitrile solution with stirring for 6 hrs at 80° C. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 141 mg of allyl-[2-(2-fluoro-phenyl)-ethyl]-amine (v) (yield: 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].CN(C)[CH:13]=[O:14].[NH4+].[Cl-]>O1CCCC1>[Br:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([CH:13]=[O:14])=[C:3]([F:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at −40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise. After 1 h at −40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at −40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (800 mg, 1.54 mmol; Example 4) and morpholine (1.5 eq., 201 mg, 2.31 mmol) were initially charged in dry THF (25 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 89 mg, 0.077 mmol) was added, and the reaction mixture was stirred at RT for 90 min (HPLC control). The reaction mixture was then concentrated and the residue was taken up in ethyl acetate (500 ml). The organic phase was washed with saturated ammonium chloride solution (50 ml), with water (50 ml) and with conc. sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (696 mg, purity 86%, 81% of theory).
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]#[N:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:25]O.[CH2:27]([OH:29])[CH3:28]>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16]2[N:25]=[C:27]([CH3:28])[O:29][N:17]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(C#N)cc2c1OCC2(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(-c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)no1
Temperature: 25 °C
Yield: 43 %

Procedure:
7-tert-butyl-5-cyano-2,3-dihydro-3,3-dimethylbenzo[b]furan (6.39 g, 27.9 mmol), potassium carbonate (15.80 g, 114.0 mmol), hydroxylamine hydrochloride (7.93 g, 114.0 mmol), and 135 mL of ethanol is heated at reflux for 20 h. The reaction mixture is cooled to room temperature, filtered, and concentrated in vacuo to give a solid residue. Purification by flash column chromatography on silica gel (20% ethyl acetate-hexane→5% methanol-dichloromethane) furnishes about 3.13 g (43%) of the title compound as a colorless foamy solid: mp 109-110° C.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[CH2:32]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:5]
Reactant: CC(C)CNCC(C)C
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CC(C)C)CC(C)C

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diisobutylamine.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:15])(=[O:14])[C:12]3[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=[CH:19][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:23]=1)=[O:3].C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:11]2[CH:10]=[CH:9][C:8]3[CH:23]=[C:4]([S:2]([CH3:1])=[O:3])[CH:5]=[CH:6][C:7]=3[S:13](=[O:14])(=[O:15])[C:12]=2[CH:16]=1
Reactant: CS(=O)c1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2(=O)=O
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: CS(=O)c1ccc2c(c1)C=Cc1ccc(CO)cc1S2(=O)=O

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-methylsulfinyldibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.