Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=2)[CH2:24]1)=[O:12]
Reactant: FC(F)(F)c1ccc(C2CCCNC2)cc1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (44 mg, 0.22 mmol) was dissolved in DCM (4 ml). 3-(4-Trifluoromethylphenyl)piperidine HCl (51 mg, 0.19 mmol) and triethylamine were added. The mixture was stirred for 1 h, 1 M HCl (2 ml) was added, and the phases were separated. The organic phase was absorbed on silica and the mixture purified by flash chromatography using heptane/EtOAc as eluent. The fractions containing the first eluting diastereomer were collected to yield 21 mg of A11.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[OH:19][C:20]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:19][C:20]1[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C(F)(F)F)c1O
Yield: 39.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 978 mg of 2-hydroxy-3-(trifluoromethyl)aniline and 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 6 ml of pyridine and 8 ml of N,N-dimethylformamide. 600 mg of N-[2-hydroxy-3-(trifluoromethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10].[CH:12](OCC)(OCC)OCC>>[NH2:8][C:6]1[N:5]=[CH:4][C:3]2[C:9](=[O:10])[NH:11][CH:12]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1cnc(N)cc1N
Product: Nc1cc2nc[nH]c(=O)c2cn1

Procedure:
Crude 4,6-diamino-3-pyridylcarboxamide (9.2 g) is heated in purified (EtO)3CH (distilled from Na, 60 mL) at 170° C. for 1.5 d. After removing the solvent, the residue is dissolved in hot 2 M NaOH, filtered, neutralized (conc. HCl) and cooled to give 7-amino-4-oxo-3H-pyrido[4,3-d]pyrimidine (3.57 g, 69% from the nitrile) as a light brown solid 1H NMR (DMSO) δ 11.79 (1H, brs), 8.74 (1H, s), 7.97 (1H, s), 6.76 (2H, brs), 6.38 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27](OC)[O:28]C)[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27]=[O:28])[CH:19]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 42 h

Procedure:
Cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.0027 mol) was dissolved in THF (12 mL). Water (6 mL) and 12 N HCl (3 mL) were added and the reaction mixture was stirred for 42 hours at room temperature. Water was added. This mixture was extracted with diisopropyl ether. The organic layer was separated, washed with a 10% aqueous NaHCO3 solution and then with water, dried (MgSO4) and filtered. The solvent was then evaporated to yield a residue that was used in the next reaction step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].[Cl-].[Zn+2:9].[Cl-]>[OH-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][Zn:9][S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: [Zn+2]
Reactant: Sc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(S[Zn]Sc2ccccn2)nc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
In a mixture of 525 ml of 1N aqueous sodium hydroxide solution and 400 ml of water was dissolved 61.00 g of 2-pyridinethiol. To this solution was added dropwise 300 ml of water containing 39.36 g of zinc chloride, and the resulting mixture was stirred at 20° C for 3 hours. The reaction mixture was then filtered off, washed with one liter of water and dried. There was obtained 74.25 g of bis(2-pyridylthio)zinc as slightly yellowish colorless crystals. The crystals gradually decomposed at about 240° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[C:24]12([C:34]3[N:35]=[C:36]([NH2:39])[S:37][CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>>[C:24]12([C:34]3[N:35]=[C:36]([NH:39][C:1]([C:4]45[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]6[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]6[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]4)[CH2:6][CH2:5]5)=[O:2])[S:37][CH:38]=3)[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nc(C23CC4CC(CC(C4)C2)C3)cs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(C45CC6CC(CC(C6)C4)C5)cs3)(CC1)CC2
Yield: 35.3 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-adamantyl-2-aminothiazole (79.7 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-adamantylthiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.5 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]1COCC1>C[Mg+].[Br-].CCOCC>[OH:1][C:2]1[C:11]2[CH2:10][C:9]([OH:12])([CH3:18])[CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnc2c(c1O)CC(=O)CC2
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCOC(=O)c1cnc2c(c1O)CC(C)(O)CC2
Reaction time: 1 h

Procedure:
To a stirred suspension of ethyl 4-hydroxy-6-oxo-5,6,7,8-tetrahydroquinoline 3-carboxylate (12 g) in 250 mL of THF, 35 mL of 3N MeMgBr in Et2O is added dropwise under cooling maintaining the temperature at 0° to 5°. The mixture is stirred for another 1 hour at the same temperature, then quenched and evaporated. The dried residue is taken up in CHCl3, washed with aqueous NaCl, dried (MgSO4) and evaporated to obtain ethyl 4,6-dihydroxy-6-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[N:13]([CH:27]=[CH:28][N:29]=3)[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[NH:21][CH2:20]4)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.ClC1N2C=CN=C2C(NC2C=CC(N3CCN(C(C)C)CC3)=CC=2)=CC=1.O.[OH-].[Li+]>CCO.CCOC(C)=O>[O:26]=[C:22]1[C:23]2[C:19](=[CH:18][C:17]([C:14]3[N:13]4[CH:27]=[CH:28][N:29]=[C:12]4[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=4)=[CH:16][CH:15]=3)=[CH:25][CH:24]=2)[CH2:20][NH:21]1
Reactant: COC(=O)c1ccc(Nc2ccc(-c3ccc4c(c3)CNC4=O)n3ccnc23)cc1
Agent: CC(C)N1CCN(c2ccc(Nc3ccc(Cl)n4ccnc34)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Nc2ccc(-c3ccc4c(c3)CNC4=O)n3ccnc23)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Crude 4-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-imidazo[1,2-a]pyridin-8-ylamino]-benzoic acid methyl ester (500 mg, 1.256 mmol), prepared using methods similar to those described for compound 12, and lithium hydroxide hydrate (263.5 mg, 6.281 mmol) in solution in THF/water (1/1: 10 mL) is stirred at room temperature for 36 hours then heated 4 hours at 60° C. The mixture is concentrated and then acidified to pH 1 with aqueous 2N HCl. The resulting precipitate is filtrated to yield the title compound, which is used as such for the next step.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1.O>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:5][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A solution of 1-butanol (0.16 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-butoxy-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.40 g, 70%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:25][C:26]1([CH3:32])[O:30][C:29](=[O:31])[N:28]=[CH:27]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:27][C:26]([CH3:32])([CH3:25])[O:30][C:29]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC1(C)C=NC(=O)O1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3)CC2)c(C)c1
Yield: 51.2 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (871 mg) described in Preparation Example 177 and 5,5-dimethyloxazolin-2-one (276 mg) described in Preparation Example 43, the title compound (433 mg) was obtained.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([CH2:7][C:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[N:4]1([C:5]([CH2:7][C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)N1CC1

Procedure:
1(N-[2-Hydroxyethyl]carbamoyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g), triphenylphosphine (1.09 g) and diethyl azodicarboxylate (0.72 g) were stirred at room temperature for 20 hours in dry tetrahydrofuran (20 ml). The reaction mixture was then diluted with water (70 ml) and extracted with ethyl acetate (3×5 ml). The combined organic extracts were washed with saturated sodium chloride solution (2×20 ml), dried (MgSO4), and evaporated to a brown gum. This material was chromatographed on Merck "Kieselgel 60" silica, eluting with 5% by volume ethanol in ether increasing to 10% ethanol in ether. The eluted material, which was one compound as judged by thin-layer chromatography, was crystallized from ethyl acetate/n-pentane to give colorless crystals of the title compound, 441 mg, m.p. 151°-153° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[O:22]1[C:18]2([CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)=[O:34])[CH2:24][CH2:23]2)[O:19][CH2:20][CH2:21]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)N1CCC2(CC1)OCCO2)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCC3(CC2)OCCO3)c2ccccc2)c1
Yield: 42.9 %

Procedure:
Following a procedure analogous to that described in Example 106, but using 1.0 g of 2-amino-N-[2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-2-oxoethyl]-N-phenylacetamide and 0.4 g of 3-methylphenyl isocyanate as the starting material, 0.6 g of N-[2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 130° C is obtained after recrystallization from a cyclohexane/ethyl acetate mixture (50/50 by volume).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[C:12]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:27]([Si:31]([CH3:37])([CH3:36])[O:32][CH2:33][C:34]#[CH:35])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.C(OCC)(=O)C>[Si:31]([O:32][CH2:33][C:34]#[C:35][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:36])[CH3:37]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(I)cc23)cc1Cl
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC#Cc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A suspension of N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (1.00 g, 2.10 mmol), tert-butyldimethyl(2-propynyloxy)silane (0.85 ml, 4.20 mmol), copper(I) iodide (4.0 mg, 0.021 mmol), dichlorobis(triphenylphosphine) palladium (II) (Pd(PPh3)2Cl2) (29 mg, 0.042 mmol), and triethylamine (1.17 ml, 8.39 mmol) in DMF (15 mL) was stirred overnight at room temperature under argon atmosphere. Water (30 mL) and ethyl acetate (30 mL) were added to the mixture. The resultant precipitate was removed by filtration. The filtrate was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (1×100 mL) and brine (1×100 mL) and was dried over Na2SO4. After filtration and evaporation, the crude product was obtained, which was purified by column chromatography on silica gel (eluted with hexane/ethyl acetate 6:1 to 1:3) to give 0.73 g of 6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine as light brown solid (67%). LCMS m/z=519 (M+1) (Method D) (retention time=3.22 min). 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.35 (s, 1H), 8.62-8.44 (m, 3H), 8.11 (dd, J=6.8, 2.6 Hz, 1H), 7.76-7.66 (m, 3H), 7.45-7.30 (m, 2H), 4.48 (s, 2H), 0.75 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][OH:27]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[O:27][CH2:26][CH2:25][CH2:24][O:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: OCCCO
Reactant: O=Cc1cc(Br)cc2ccoc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(C2OCCCO2)c2occc2c1

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (400 mg), 4-methylphenylsulphonic acid (0.38 g) and 1,3-propanediol (10 ml) in toluene (15 ml) was heated at reflux for 19 h, with azeotropic removal of water by Dean-Stark Apparatus. The reaction mixture was cooled, diluted with water (80 ml) and extracted with toluene (30 ml). The organic phase was dried, filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluted with hexane:ethyl acetate (7:1→3:1) gave the title compound as a yellow solid (427 mg).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>[Pd]>[F:32][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[CH2:27][CH2:28]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)N1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: CC(C)N1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-(1-isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.79 (t, J=5.92 Hz, 1H), 8.01 (d, J=8.71 Hz, 1H), 7.97 (dd, J=0.5, 9.02 Hz, 1H), 7.76 (d, J=9.02 Hz, 1H), 7.60 (d, J=8.81 Hz, 1H), 3.27 (t, J=6.23 Hz, 2H), 2.91 (d, J=7.61 Hz, 3H), 2.82 (s, 1H), 2.25 (s, 2H), 2.03 (d, J=9.4 Hz, 2H), 1.86-1.74 (m, 9H), 1.30-1.24 (m, 2H), 1.00 (d, J=5.8 Hz, 6H). m/z: 464.20 [M+H]+
Reaction SMILES: O[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:19])=O>ClCCl>[Cl:19][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: Cc1ccccc1-c1cc(O)ncc1C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cl)ncc1C#N
Temperature: 50 °C
Yield: 106.7 %

Procedure:
A mixture of 2.5 g (11.89 mmol) 6-hydroxy-4-o-tolyl-nicotinonitrile, 3.64 g (23.78 mmol) phosphorus oxychloride in 10.0 ml dichloromethane was heated at 50° C. for 80 minutes. The mixture was cooled down to 20-25° C., poured on water by keeping the internal temperature between 20-30° C. and extracted by adding additional 80.0 ml dichloromethane. Evaporation of the organic phase in vacuo gave 2.9 g of crude product of 6-chloro-4-o-tolyl-nicotinonitrile which was purified by chromatography over silica gel (ethylacetate:hexane=4:1) to afford 2.4 g of, m.p. 112.4° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN1CCOCC1.[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56](ON1C(=O)CCC1=O)=[O:57]>Cl.CCOC(C)=O>[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56]([NH:1][C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:57]
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NCC(N)=O)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 1.0 g of Boc-Ser(Bzl)-Pro-Arg(NO2)-Gly-NH2, 10 ml of 4N HCl-AcOEt, 0.34 ml of NMM and 0.54 g of Z-Pro-OSu in the same manner as in Example 26-(4).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].[O:21]=[C:22]1[N:26]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:25](=[O:35])[CH:24]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[S:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[CH2:27][N:26]1[C:25](=[O:35])[CH:24]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:44][CH2:45][CH:46]([NH:5][CH2:6][C@H:7]([OH:8])[C:9]4[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=4)[CH2:47][CH2:48]3)=[CH:39][CH:38]=2)[S:23][C:22]1=[O:21])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)C1=O
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
Acetic acid (0.12 mL, 2.16 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (266 mg, 1.08 mmol) (which was obtained in Example 10), tert-butyl 2-{2,4-dioxo-5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidin-3-yl}acetate (450 mg, 1.08 mmol) (which was obtained in Example 49), and DMF (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (276 mg, 1.3 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 5/1) to produce a yellow solid (480 mg, 68% yield); mp 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20-1.50 (m, 11H), 1.81-1.85 (m, 2H), 2.60-2.80 (m, 4H), 2.85-2.9 (m, 4H), 3.40 (m, 1H), 3.60 (m, 1H), 4.20 (s, 2H), 4.50 (m, 1H), 5.04 (m, 1H), 6.80-6.87 (m, 3H), 7.02 (m, 1H), 7.08 (m, 2H), 7.20 (m, 1H); Anal. Calcd. for C30H40N4O8S2: C, 55.54; H, 6.21; N, 8.64. Found: C, 53.86; H, 6.11; N, 7.65.