Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:36]=[CH:35][N:34](C(OC(C)(C)C)=O)[CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:36]=[CH:35][NH:34][CH:33]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cc[nH]c3)c(C)sc2n1
Temperature: 100 °C
Yield: 20.4 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (100 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2.5 mL) and water (1 mL). 1,1-Dimethylethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (102 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated in a microwave at 100° C. for 10 min. The solution was then concentrated, ethyl acetate (10 mL) added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to give the title compound (19.8 mg). LCMS (A) m/z: 416 [M−1]−, Rt 1.47 min (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:21]1([NH:27][C:15]([C:14]2[CH:13]=[C:12]([CH:20]=[CH:19][CH:18]=2)[O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)O)c1
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoic acid (0.73 g, 2.98 mmol), cyclohexylamine (0.34 ml, 2.98 mmol), EDCI (0.7 g, 3.58 mmol) and HOBT (0.49 g, 3.58 mmol) in DMF was added DIPEA (1.0 ml, 5.57 mmol). The resulting mixture was stirred at room temperature for 18 h, concentrated, and partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (30 to 65% EtOAc-hexanes gradient) gave tert-butyl 2-(3-(cyclohexylcarbamoyl)phenoxy)ethylcarbamate as an orange oil. Yield (0.20 g, 20%): 1H NMR (400 MHz, CD3OD) δ 7.31-7.38 (m, 3H), 7.06-7.09 (m, 1H), 4.04 (t, J=5.6 Hz, 2H), 3.78-3.87 (m, 1H), 3.41-3.45 (m, 2H), 1.90-1.98 (m, 2H), 1.78-1.84 (m, 2H), 1.63-1.71 (m, 1H), 1.43 (s, 9H), 1.18-1.38 (m, 5H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[O:20][CH3:21]>C(Cl)Cl>[CH3:21][O:20][C:19]([NH:2][CH:3]1[CH2:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4]1)=[O:22]
Reactant: COC(=O)Cl
Reactant: NC1CCc2sccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To 3.79 g of 5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydrochloride and 4.04 g of triethylamine dissolved in 30 ml of methylene chloride was added dropwise 1.89 g of methyl chlorocarbonate under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, the organic layer was collected by separation and dried, and then the solvent was removed. The resulting crystals were recrystallized from isopropyl ether to obtain 3.80 g of 5-methoxycarbonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CCCCCCC>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[O:1]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(OCc2ccccc2)c1C=O
Reactant: CC(C)(O)C(N)=O
Solvent: O
Solvent: CCCCCCC
Product: COc1cccc(OCc2ccccc2)c1C1NC(=O)C(C)(C)O1
Temperature: 240 °C
Yield: 60.7 %

Procedure:
A mixture of commercially available 2-hydroxyisobutyramide (638.5 mg, 3 eq), 2-benzyloxy-6-methoxy-benzaldehyde (500 mg) (Katritzky A. R. et al ARKIVOC 2001, 2, 3, 3-12) is heated at 240° C. for 5 min using microwave irradiation (Lecolier S. et al Chimica Therapeutica 1969, 4,6, 437-445). The crude oil is poured into water and extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 1/1 to 1/0) gives the title compound as a yellow solid (0.41 g, 61%); LC-MS: tR=0.65 min; [M+H]+=328.22.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C([OH:17])(C)C>C(O)(=O)C.O.[O-2].[Cr+6].[O-2].[O-2]>[O:17]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4]1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2
Reactant: CC(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of chromium(VI)oxide (86 g, 0.861 mol) in acetic acid (400 mL) and water (40 mL) was added dropwise to a stirred solution of 1,1,7-trimethyl-1,2,3,4-tetrahydronaphthalene in acetic acid (70 mL) and the reaction mixture stirred 2.5 hours at room temperature. Isopropanol (5 mL) was added and the whole concentrated in vacuo. The residue was dissolved in hexane and filtered over celite. The organic was washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 40.3 g of 1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene and used without further purification in the bromination (step e). 1H NMR (300 MHz; CDCl3): 1.36 (s, 6 H), 1.98 (t, J=6.9 Hz, 2 H), 2.38 (s, 3 H), 2.68 (t, J=6.9 Hz, 2 H), 7.01 (dd, J1=0.6 Hz, J2=7.9 Hz, 1 H), 7.19 (d, J=0.6 Hz, 1 H), 7.90 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)=[O:13].[Cl-].[NH4+]>O1CCCC1>[OH:13][CH:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH2:19][CH2:18][CH2:17]2)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: O=Cc1ccc2c(c1)CCC2
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc2c(c1)CCC2
Reaction time: 0.17 h

Procedure:
A solution of 2.8 ml (32 mmol) of methyl propiolate in 60 ml of tetrahydrofuran was treated at -78° under argon with 20 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 4.7 g (32 mmol) of 5-formylindane in 80 ml of tetrahydrofuran was added within 15 minutes. The reaction mixture was stirred at -78° for a further 10 minutes, then brought to room temperature and treated with 60 ml of saturated ammonium chloride solution. The aqeuous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(5-indanyl)-2-butynoate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2c1CC(=O)c1ccc(F)cc1S2
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2c1CC(=NN)c1ccc(F)cc1S2

Procedure:
The mixture of 1.0g of 9-cyano-3-fluoro-10,11-dihydrodibenzo-[b,f]thiepin-11-one, 1.1g of 100% hydrazine hydrate and 16ml of ethanol was heated under reflux for 4.5 hours. The reaction mixture was concentrated to about one-fifth. After cooling, crystals was collected by filtration, there was obtained 9-cyano-3-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone having a melting point of 178°-179° C in quantitative yield.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=2[N:36]=[CH:37][N:38]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:27])([F:29])[F:28]
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 259 mg (0.52 mmol) of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxy-methyl-amide, 213 mg (0.52 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.26 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 2 mL methanol and 2 mL 6N hydrochloric acid mixture to give after purification 40 mg of the final product as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:66])[C@H:41]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:68]([O:70][CH3:71])=[O:69].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([C@H:8]([NH:39][C:40](=[O:66])[C@H:41]([CH2:43][C:44]([NH:46][C:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:45])[NH:42][C:68]([O:70][CH3:71])=[O:69])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:34])([CH3:35])[CH3:36])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)C
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 108.3 %

Procedure:
A solution of Example 168B (24 mg, 0.027 mmol) in dioxane (0.25 mL) was treated with methyl chloroformate (3.2 μL, 0.041 mmol) and triethylamine (7.5 μL, 0.054 mmol) at 25° C. for 0.5 h. The solvents were evaporated to give the crude title compound (27.7 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:15][CH:16]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2ccc(Br)cn2)cc1F

Procedure:
A mixture of 6.2 g of 3,4-difluorophenylboric acid, 8.5 g of 2,5-dibromopyridine, 0.31 g of tetrakistriphenylphosphine palladium, 60 ml of ethanol, 120 ml of benzene and 120 ml of 2N sodium carbonate solution is heated to boiling (66° C.) for 7 hours while stirring. After cooling the mixture is extracted with diethyl ether. The organic phase is washed with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water, dried over sodium sulphite, filtered and concentrated. Purification of the residue by chromatography on silica gel with hexane/ethyl acetate 19:1 yields pure 5-bromo-2-(3,4-difluorophenyl)pyridine.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C(O)(=O)C>O>[C:18]([O:21][CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4])(=[O:20])[CH3:19]
Reactant: CC(Br)C(=O)c1ccc2c(c1)CN(C)C(=O)N2
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C)C(=O)c1ccc2c(c1)CN(C)C(=O)N2

Procedure:
A mixture of 6-(2-bromopropionyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone (2 g) prepared in Step 1, potassium acetate (2.64 g) and glacial acetic acid (20 ml) is refluxed for three hours. The reaction mixture is diluted with water and extracted with methylene chloride (3×50 ml) and the combined organic layers are washed with saturated aqueous sodium bicarbonate, dried, filtered and concentrated to obtain 6-(2-acetoxypropionyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone which is used in the next step.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[Cl:13][C:14]1[CH:22]=C2[C:17]([CH2:18][NH:19]C2=O)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:11]([O:8][C:9]1[C:10]2[C:17](=[CH:16][CH:15]=[C:14]([Cl:13])[CH:22]=2)[CH2:18][N:19]=1)[CH3:12]
Reactant: O=C1NCc2ccc(Cl)cc21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 151 g of triethyloxonium tetrafluoroborate in 3200 ml of methylene chloride was stirred under argon at room temperature for 3.5 hours after the addition of 106.6 g of 6-chloro-2,3-dihydro-1H-isoindole-1-one. The mixture was then treated within 40 minutes with 1.28 1 of saturated sodium hydrogen carbonate solution, the organic phase was separated and washed with 1.28 1 of water. After drying over sodium sulphate the organic phase was filtered and evaporated. The residue was taken up in 1.3 1 of diethyl ether, whereupon it was stirred at room temperature for about 30 minutes. After removing insoluble material by filtration the filtrate was evaporated. There was obtained 110.5 g of 1-ethoxy-6-chloro-3H-isoindole with a m.p. of 64°-66°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:27][CH3:28])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:8]2[CH:29]=[CH:30][CH:31]=[C:6]([Cl:5])[C:7]=2[F:32])[CH2:22]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
Acetyl chloride (27 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-3-yloxy)-7-methoxyquinazoline (starting material described in Example 22; 134 mg) and diisopropylethylamine (65 mg) in methylene chloride (5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated to give the title product (0.07 g); 1H NMR Spectrum: (DMSO d6 at 373K) 1.52-1.62 (m, 1H), 1.80-1.94 (m, 2H), 2.00 (s, 3H), 2.06-2.15 (m, 1H), 3.43-3.64 (m, 3H), 3.82-4.04 (m, 4H), 4.58 (m, 1H), 7.20-7.29 (m, 2H), 7.42 (t, 1H), 7.59 (t, 1H), 7.93 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:34]2)=[O:29]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COC(=O)c1cccc2c1CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 26.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 4-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 65 mg of the target compound.
Reaction SMILES: Br[C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:10])[C:4]=2[CH:3]=1.[O:12]1C[CH2:15][CH2:14][CH2:13]1.C(O)C#C.C(N(CC)C(C)C)(C)C>[Cu]I.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.O>[Cl:10][C:9]1[C:4]2[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:12])[NH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: C1CCOC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1cc2c(Cl)ncnc2[nH]1
Yield: 31 %

Procedure:
A mixture comprising 3.00 g (12.9 mmol) 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No: 784150-41-0), 90 mL tetrahydrofuran, 3.0 mL prop-2-yn-1-ol, 246 mg copper(I) iodide, 746 mg tetrakis(triphenylphosphine)palladium(0) and 3.93 mL N,N-diisopropylethylamine was heated at 80° C. for 4 hours. Water was added and the mixture extracted with ethylacetate/methanol (8:2). The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvents the residue was purified by chromatography to give 833 mg (31%) of the title compound.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[Br:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:38][CH3:39])[CH:34]=2)[CH:29]=1>C(O)C>[C:5]12([C:32]3[CH:31]=[C:30]4[C:35]([CH:36]=[CH:37][C:28]([Br:27])=[CH:29]4)=[CH:34][C:33]=3[O:38][CH3:39])[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h
Yield: 20.9 %

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, are placed 1 g of 1-acetoxyadamantane and 30 ml of n-heptane, and 0.25 g of concentrated sulfuric acid is introduced. At a temperature of about 20° C., 1.22 g of 2-bromo-6-methoxynaphthalene are poured in slowly and the mixture is left in vigorous agitation for 48 hours. Next, 20 ml of denatured ethanol are introduced and the mixture is evaporated to dryness under reduced pressure. The product is taken up in denatured ethanol and the precipitate is filtered with sintered glass. After drying of the raw product in a vacuum oven for 24 hours at 30° C., one purifies using silica column chromatography. There were obtained 0.4 g of the desired raw product (Melting point: 164°-168° C.).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[O:22]([CH2:29][CH2:30][NH2:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[N+:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:19]=[C:20]([NH:31][CH2:30][CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:8][CH2:9][C:10]=2[CH:15]=1)([O-:18])=[O:17]
Reactant: NCCOc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Yield: 95.8 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (1.95 g, 6.0 mmol; HPLC: 4.446 min) and 2-phenoxyethylamine (CAS 1758-46-9) (807 mg, 6.0 mmol; HPLC: 0.381 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (1.80 g, 96%, HPLC 1.789 min), MS (ISP) m/e=314.0 [(M+H)+].
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:56]([O:58]C(C)(C)C)=[O:57])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44]C(C)(C)C)=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=O)C1C=CC=CC=1.Cl>C(OCC)(=O)C.O>[C:56]([C@H:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:49]([OH:51])=[O:50])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:58])=[O:57]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NS(C)(=O)=O)CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@@H](CCCCN)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a cooled (10° C.) solution of tert-butyl (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-(tert-butoxycarbonyl)propyl]-1-cyclopentylcarbonyl)-O4-tert-butyltyrosinate (13.3 g, 15.0 mmol) in ethyl acetate (27 ml) was added a 5.1M solution of hydrogen chloride in ethyl acetate (70 ml) (357 mmol of HCl). After 30 minutes the initially clear solution deposited a tar. The mixture was stirred at room temperature for 18 hours. The clear solution was decanted off from the tar and the tar triturated with ethyl acetate (75 ml) to give a sticky solid. The decantation and trituration were repeated 5 times to give a hygroscopic solid which was dissolved in water (12 ml). The resulting aqueous solution was washed twice with ethyl acetate, basified with aqueous sodium hydroxide solution to pH 4.0, seeded with the compound of Example 1 and stirred at 45-50° C. for 42 hours. The off-white solids were collected by filtration, washed with water and acetone and dried to give the title compound (1.95 g), m.p. 237-238° C.