Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:22]3=[C:23]4[CH:29]=[CH:28][NH:27][C:24]4=[N:25][CH:26]=[C:21]3[NH:20][N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:22]3=[C:23]4[CH:29]=[CH:28][NH:27][C:24]4=[N:25][CH:26]=[C:21]3[NH:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(CN2CCC(c3n[nH]c4cnc5[nH]ccc5c34)CC2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1cc2c(ncc3[nH]nc(C4CCNCC4)c32)[nH]1
Temperature: 65 °C
Yield: 84.4 %

Procedure:
Ammonium formate (0.50 g, 7.9 mmol) and Pearlman's catalyst (0.56 g, 0.79 mmol) were added to a solution of 1-(1-benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.26 g, 0.791 mmol, Example #24) in MeOH (20 mL). The reaction was heated at about 65° C. for about 1 h then filtered through Celite® and concentrated under reduced pressure. The filtrate was concentrated to afford 1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.161 g, 84%): LC/MS (Table 2, Method a) Rt=1.18 min; MS m/z: 242 (M+H), 240 (M−H)−. The crude product was used directly in subsequent steps without further purification.
Reaction SMILES: BrCCBr.C=C.C[Si](C)(C)Cl.I[C:13]1[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=1[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:46][O:47][C:48](=[O:66])[C@H:49]([CH2:58][C:59]1[CH:64]=[CH:63][C:62](I)=[CH:61][CH:60]=1)[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52].[Cl-].[NH4+]>C1COCC1.CC(N(C)C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:46][O:47][C:48](=[O:66])[C@H:49]([CH2:58][C:59]1[CH:60]=[CH:61][C:62]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:63][CH:64]=1)[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:52]
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1c(I)c(=O)n(C)c(=O)n1C
Agent: [Pd]
Agent: C=C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To a suspension of zinc dust (800 mmol, 52.29 g) in THF (26.0 mL) was added 1,2-dibromoethane (53.2 mmol, 4.58 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased (observed). The suspension was cooled to room temperature, trimethylchlorosilane (26.6 mmol, 3.38 mL) was added and the mixture was stirred for 15 min. A suspension of 5-iodo-1,3,6-trimethyl uracil (266 mmol, 74.6 g) in DMA (225 mL) was warmed to obtain a clear solution and was added in one portion to the reaction mixture. After addition, the mixture was heated to 70° C. The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction. The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride indicated the absence of starting material. The reaction mixture was diluted with THF (140 mL), was cooled to room temperature and the excess zinc dust was allowed to settle over 2-3 h. This solution containing the zinc compound (266 mmol) was added to a solution of Pd(dba)2 (8 mmol, 4.6 g), tri-o-tolylphosphine [P(Tol)3] (29.6 mmol, 9.0 g) and N-[(1,1-dimethylethoxy)carbonyl]-4-iodo-L-phenylalanine methyl ester (186 mmol, 75.56 g) in THF (280 mL) at room temperature and the light yellow mixture was stirred for 48 h at 50-55° C. The reaction mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×750 mL). The combined extracts were washed with brine solution (1.5 L) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel column chromatography using a Biotage (75m) column to obtain 57.88 g (72% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. EI-HRMS m/e calcd for C22H29N3O6 (M+) 431.2056, found 431.2054.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.Cl[CH2:23][C:24]#[N:25]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:24]#[N:25])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: N#CCCl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.05 h
Yield: 87.4 %

Procedure:
In an atmosphere of argon, a mixture of 26 mg (3.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 800 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 3 minutes. The mixture was further stirred for 1 hour. To the mixture was then added a mixture of 313 mg of chloroacetonitrile and 1 ml of DMF. The mixture was then stirred for 3 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 805 mg of [2-[(4-chlorophenyl)imino]-2,3-dihydro-4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetonitrile was obtained as a low polarity substance, and 70 mg of 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetonitrile was obtained as a high polarity substance.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14]CC)=[O:13].O.O.[OH-].[Li+]>C1COCC1.CO>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1sc2nc[nH]c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (1.0 g, 4.5 mmol) in THF (14 mL), MeOH (3 mL), and H2O (3 mL) was added lithium hydroxide monohydrate (0.68 g, 16 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated, diluted with H2O (20 mL) and washed with DCM (25 mL). The aqueous layer was acidified (pH˜2) with 1M HCl and the resultant precipitate was filtered and dried to give 0.9 g of pure 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, (yield: 94%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].N#N.[N:9]1([CH:15]([CH3:20])[C:16](OC)=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[OH-].[Na+]>O.C1COCC1>[N:9]1([CH:15]([CH3:20])[CH2:16][OH:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COC(=O)C(C)N1CCOCC1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
LAH powder (1.6 g) was added to a flask while under N2 atmosphere, immediately followed by THF (50 mL). The mixture was chilled to 0° C., methyl 2-morpholin-4-yl-propionate (5 g) was added dropwise to the reaction mixture and stirred at 0° C. After 1 h, the mixture was worked up by adding H2O (44 mL), 2N NaOH (44 mL), then H2O (44 mL, 3×). After 30 min of stirring, the mixture was filtered through Celite® and the organic portion was concentrated in vacuo providing 2-morpholin-4-yl-propanol as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([C:22]#[N:23])[CH:17]=[C:18]([CH:21]=1)[C:19]#[N:20])=[O:13])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([CH2:31]OS(C)(=O)=O)[CH:28]=[C:27]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:26]=1.[I-].[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:24][C:25]1[CH:30]=[C:29]([CH2:31][N:6]2[C:5]([C:12]([C:14]3[CH:15]=[C:16]([C:22]#[N:23])[CH:17]=[C:18]([CH:21]=3)[C:19]#[N:20])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])[CH:28]=[C:27]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:26]=1
Reactant: COc1ccc(CNc2cc(COS(C)(=O)=O)cc(F)n2)cc1
Reactant: CC(C)c1c(C(=O)c2cc(C#N)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C#N)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
A solution 5-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-isophthalonitrile (0.016 g, 0.0535 mmol), methanesulfonic acid 2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl ester (0.017 g, 0.0535 mmol), lithium iodide (0.0036 g, 0.0268 mmol) and potassium carbonate (0.0074 g, 0.0535 mmol) in DMF (0.5 mL) was stirred at 0° C. for 4 h, then warmed to rt overnight. Reaction mixture was diluted with ethyl acetate, washed with water (2×), dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexane), then by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give an yellow solid (0.0091 g, 31%). 1H NMR (300 MHz, CD3OD): δ 8.31 (s, 2H), 8.13 (s, 1H), 7.25 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.79 (s, 1H), 5.74 (s, 1H), 5.17 (d, J=16.8 Hz, 1H), 4.20 (s, 2H), 4.13 (d, J=16.8 Hz, 1H), 3.75 (s, 3H), 2.2-2.0 (m, 1H), 1.12 (d, J=6.6 Hz, 3H), 1.07 (d, J=6.6 Hz, 3H). Mass spectrum: 553.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][N:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.Cl.[NH2:55][CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59].CCN=C=NCCCN(C)C.Cl>CO>[F:33][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:55][CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])=[O:28])=[CH:25][N:24]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Methyl 6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (18 mg, 0.037 mmol) was dissolved in 1 mL methanol. 500 μL 1N aqueous sodium hydroxide was added. The resulting solution was stirred overnight at room temperature then at 50° C. for 1 h. The solution was concentrated under reduced pressure and the residue partitioned between dichloromethane and 1N aqueous HCl. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in 2 mL dichloromethane. Triethylamine (20 μL, 0.14 mmol), HOAt (10 mg, 0.073 mmol), and methyl 3-aminopropionate hydrochloride (10 mg, 0.072 mmol) were added. EDCl (10 mg, 0.052 mmol) was added and the resulting solution stirred 72 h at room temperature. The reaction solution was washed with water and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give a pale yellow oil. Purification by silica gel chromatography provided methyl 3-(6-(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoate (13 mg, 63%) as a colorless film. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.6 Hz, 2.4 Hz, 1H), 7.61-7.69 (m, 4H), 7.54-7.59 (m, 2H), 7.39-7.43 (m, 2H), 6.56-6.63 (m, 1H), 6.30 (d, J=8.6 Hz, 1H), 5.14 (d, J=7.8 Hz, 1H), 4.91-4.99 (m, 1H), 3.62-3.70 (m, 5H), 2.57-2.63 (m, 2H), 2.07-2.32 (m, 4H).
Reaction SMILES: O.[N+:2]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc(CCC(=O)O)cc1
Reaction time: 2 h

Procedure:
15 g of palladium on carbon (10% and 30 ml of water are added to a mixture of 155 g of 4-nitrocinnamic acid in 1 l of methanol, and hydrogenation is carried out at room temperature under 3 bar until no further hydrogen is taken up, after about 2 hours. After filtration and evaporation of the solvent in a rotary evaporator, residual water is removed by twice adding 300 ml portions of toluene and distilling off the solvent in a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)=[CH:5]2.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH2:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([CH3:51])[C:45]([CH3:53])([CH3:52])[CH2:44]1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:42][CH:43]3[CH2:44][C:45]([CH3:52])([CH3:53])[N:46]([CH3:51])[C:47]([CH3:50])([CH3:49])[CH2:48]3)=[O:17])=[CH:14][CH:13]=1)=[CH:5]2
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: O=C(O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
A mixture of) of 4-(5,6-dichloro-1H-indol-2-yl) benzoic acid (0.25 g, 0.82 mmol), WSC (0.156 g, 0.82 mmol), HOAT (0.11 g, 0.82 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (0.209 g, 1.2 mmol), DIEA (0.212 g, 1.2 mmol) in DMF (3 ml) was stirred at room temperature for 16 h. The mixture was then poured on water, made basic by NaOH N and extracted with ethyl acetate. The organic solution was washed with water, dried over MgSO4, concentrated in vacuo, and the residue was purified by column chromatography (SiO2, CH2Cl2/CH3OH/NH4OH; 9/1/0.1), affording 0.35 g (0.76 mmol, yield 93%) of the title compound as white crystals, mp=325° C.
Reaction SMILES: [OH-].[NH4+:2].C1(=O)OC(=O)C=C1.[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].N>O>[NH2:2][C@H:11]([C:10]([OH:17])=[O:16])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: [NH4+]
Reactant: O=C(O)/C=C\C(=O)O
Agent: N
Agent: O=C1C=CC(=O)O1
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
In a 250 ml reagent bottle, an amount of 69 ml (0.11 mole) of a 10% solution of concentrated ammonium hydroxide (15.9 M) was slowly added with smooth stirring to 9.8 g (0.1 mole) of maleic anhydride in 18 ml (1 mole) of water at 60° C. The bottle was capped and the solution allowed to react for 2 hours. The anhydride converted to maleic acid in the presence of the water, and the ammonia added across the double bond of maleic acid to form aspartic acid.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(OC(C)C)OC(C)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)OB(OC(C)C)c1cccs1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4cccs4)cc23)cc1Cl
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 3 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 2-thienylboronate to give 4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline in 36% yield, m.p. 205-208° C.; NMR Spectrum: 7.2 (m, 1H), 7.4 (t, 1H), 7.7 (m, 2H), 7.8 (m, 2H), 8.15 (m, 2H), 8.55 (s, 1H), 8.75 (d, 1H), 10.0 (broad s, 1H); Elemental Analysis: Found C, 58.6; H, 3.1; N, 11.3; C18H11ClFN3S 0.75H2O requires C, 53.5; H, 3.4; N, 11.4%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[C:52]([CH3:55])([CH3:54])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:51]([C:52]([CH3:54])([CH3:53])[CH3:55])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 294 mg of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113.5 mg (0.60 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF at 0° C. and the mixture is stirred at room temperature for 16 hours. Ice-water and ethyl acetate are added; the aqueous phase is separated off and extracted with ethyl acetate. The organic phases are washed 2× with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate) and crystallisation from ethyl acetate/ether/hexane yield the title compound: Anal. (C36H50N6O7S (1.4% H2O)) calc. C 59.97, H 7.15, N 11.66, S 4.45: found C 59.99, H 7.18, N 11.35, S 4.59; TLC: Rf =0.51 (methylene chloride/THF 3:1); HPLC20-100 : tRet =15.2; FAB MS (M+H)+ =711.
Reaction SMILES: Br[C:2]1[S:12][C:5]2[C:6]3[S:11][CH:10]=[CH:9][C:7]=3[S:8][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(N(CC)CC)C.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.[Cu]I>[CH2:13]([C:3]1[C:4]2[S:8][C:7]3[CH:9]=[C:10]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:11][C:6]=3[C:5]=2[S:12][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Reactant: C#CCCCCCCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1cc2sc3c(CCCCCCCCCC)csc3c2s1
Temperature: 130 °C
Yield: 81.9 %

Procedure:
2-bromo-3-decanyldithieno[3,2-b:2′,3′-d]thiophene (92)(4.16 g, 0.01 mol) was mixed with 1-decyne (3.6 g, 0.026 mol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) and copper(I) iodide (0.19 g, 1.0 mmol) in triethylamine (80 mL). This mixture was bubbled with nitrogen for 5 minutes and then heated up to 130° C. under argon for 16 hours. Triethylamine was evaporated and hexane (150 mL) was added. This mixture was filtered to remove solid salts. The organic layer was washed with 1 M hydrochloric acid (50 mL) and brine (50 mL) then dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel eluting with hexane to yield the target compound (3.87 g, 93.0%). 1H NMR, solvent CD2Cl2. δ 7.36 (d, 1H), 7.30 (d, 1H), 2.82 (t, 2H), 2.49 (t, 2H), 1.63-1.27 (m, 28H), 0.88 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[Br:22][CH2:23][C:24]([N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:25]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CN[C@@H](C)CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)CBr)[C@@H](C)CO)cc1
Temperature: -21 °C

Procedure:
Into a 20000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (S)-2-(4-methoxybenzylamino)propan-1-ol (300 g, 1.54 mol) in dichloromethane (12000 mL) and triethylamine (155.8 g, 1.54 mol). 2-Bromoacetyl bromide (310.8 g, 1.54 mol) was added dropwise, while cooling to a temperature of −17 to −25° C. and maintained at this temperature for 4 hours. The reaction mixture was warmed to room temperature and washed three times with 2000 mL of water, dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Si:22]([C:29]#[CH:30])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(NC(C)C)(C)C.N>C(#N)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.ClCCl>[Si:22]([C:29]#[C:30][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:21])=[CH:8][CH:9]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(=O)NC(C)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)NC(C)Cc1ccc(C#C[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2.40 g (7.38 mmol) trifluoromethanesulfonic acid 4-(2-acetylamino-propyl)-phenyl ester (I53.1), 1.52 mL (8.12 mmol) (tert-butyldimethylsilyl)acetylene and 2.56 mL (18.4 mmol) diisopropylamine in 25 mL ACN are added 72.3 mg (0.089 mmol) [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane and 17.2 mg (0.09 mmol) CuI, and the mixture is stirred at r.t. for 24 h. Again 0.69 mL (3.69 mmol) (tert-butyldimethyl-silyl)acetylene are added and stirring is continued for additional 24 h. The mixture is poured onto aq. ammonia solution (5%), diluted with EtOAc and the organic layer is separated. The organic layer is washed with diluted aq. ammonia solution (1×) and water (1×), dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; PE/EtOAc 2/8).