Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=2)[C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>CO>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=2)[C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=3)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 50 °C

Procedure:
A mixture of the (+/−)-methyl 6-[(cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methyl)amino]nicotinate (486 mg, 1.03 mmol) was dissolved in methanol (2.1 ml) and tetrahydrofuran (1.0 ml) and treated with aqueous lithium hydroxide (1.0 ml, 2.1 mmol, 2.0M). The reaction was heated to 50° C. for 12 hours. The mixture was concentrated in vacuo, and the residue was diluted with water and acidified with aqueous 1.0M hydrochloric acid. The mixture was then concentrated in vacuo a second time, and the crude residue was used directly for further transformations.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.Cl[C:27]1[N:32]=[C:31]([N:33]2[CH:38]=[C:37]([CH:39]3[C:45]4[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=4[CH:43]=[CH:42][C:41]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:40]3=4)[C:36](=[O:56])[NH:35][C:34]2=[O:57])[CH:30]=[CH:29][N:28]=1>CN1CCCC1=O>[CH3:50][C:48]1[CH:47]=[CH:46][C:45]2[CH:39]([C:37]3[C:36](=[O:56])[NH:35][C:34](=[O:57])[N:33]([C:31]4[CH:30]=[CH:29][N:28]=[C:27]([NH:1][CH2:2][C:3]([NH:5][C:6]5[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=5)=[O:4])[N:32]=4)[CH:38]=3)[C:40]3[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:41]=3[CH:42]=[CH:43][C:44]=2[CH:49]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)CN)n1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)CNc2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=O)[nH]c3=O)n2)n1

Procedure:
A mixture of the product from step (i) (0.194 g), N,N-diisopropylethylamine (0.35 ml) and the product from example 8 step (ii) (0.25 g) in 1-methyl-2-pyrrolidinone (5 ml) was heated at 90° C. for 10 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 70% ethyl acetate in isohexane. Yield 0.175 g.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.C[O:22][B:23](OC)[O:24]C.Cl>C1COCC1.CCOCC.O>[F:13][C:14]1[C:19]([B:23]([OH:24])[OH:22])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: COB(OC)OC
Reactant: Fc1cccc(F)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: OB(O)c1ccc(F)nc1F
Reaction time: 0.25 h

Procedure:
0.6 m of n-butyllithium are added to 0.6 m of diisopropylamine in 600 ml of THF at -10°. Then the mixture is cooled to -60° to -70° and 0.6 m of 2,6-difluoropyridine are added. The mixture is stirred for further 15 minutes and 0.6 m of trimethylborate is added at -60°. The mixture is allowed to warm to -30° and is hydrolyzed by addition of 170 ml of HCl (25%) and 100 ml of H2O. Ether is added and after customary work-up 2,6-difluoropyridine-3-boronic acid is obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][CH:6]=1>C1COCC1>[CH3:3][O:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OC)c2c1OCCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c2c1OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A NaOH solution (500 ml, 2N) was added to a solution of intermediate (7) in THF (250 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated partially. The residue was extrated with DCM. The mixture was separated into its layers. The aqueous layer was acidified with a concentrated HCl solution until pH=1 to 2.The solid was filtered off, washed with water and dried, yielding 35.5 g of 9-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid (intermediate 8).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCCCCC=CC=C/C=C/C(=O)OCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCC=C/C=C/C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6 g of 3,7,11-trimethyl-2-cis/trans, 4-cis/trans-dodecatrienoic acid ethyl ester are dissolved in 75 ml of methylene chloride and treated portionwise with stirring at 0° C with 5 g of m-chloroperbenzoic acid (ca 80 percent). The mixture is subsequently stirred for a further 11/2 hours at 0° C. The reaction mixture is poured onto ice and 1-N aqueous sodium hydroxide and extracted with diethyl ether. The ether phase is washed neutral, dried and evaporated. The product is chromatographed on the 50-fold amount of Kieselgel (eluant: hexane 90 percent by volume/ethyl acetate 20 percent by volume). 10,11-Epoxy-3,7,11-trimethyl-2-cis/trans, 4-cis/trans-dodecadienoic acid ethyl ester is obtained as a colorless oil of boiling point about 135° C/0.01 mmHg (bulb:tube); nD20 = 1.4907.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH2:12]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH3:15].O>C(O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]([CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: CCCCNCC(=O)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A mixture of 4-bromo-2-fluoro-nitro benzene (34 g, 0.15 mol), N-n-butyl glycine (20 g, 0.15 mol) in ethanol (600 ml), and water (150 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with 2N sodium hydroxide, extracted with CH2Cl2 and the pH was adjusted to 5 with 1N HCl. The mixture was extracted with CH2Cl2, the CH2Cl2 solution was dried (MgSO4) and evaporated to obtain the crude product (11 g, 22%) as a brown oil, which was used without further purification. 1H-NMR (DMSO-d6) δ 0.84 (t, J=7.30 Hz, 3H), 1.23 (m, 2H), 1.45 (m, 2H), 3.18 (t, J=7.30 Hz, 2H), 3.91 (s, 2H), 7.16 (dd, J=8.68, 1.91 Hz, 1H), 7.40 (d, J=1.94 Hz, 1H), 7.69 (d, J=8.68 Hz, 1H); MS (EI) m/z 331 (M+).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[OH-].[K+].S(=O)(=O)(O)[OH:16]>O>[F:8][C:7]1[C:6]([F:9])=[CH:5][CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:16]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1O
Temperature: 40 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
1.77 kg (10 mol) of 2,3,4-trifluoronitrobenzene are added to 4 l of water. The mixture is then warmed to 40° C. and vigorously stirred. 389.4 g (22 mol) of 31.7% strength potassium hydroxide solution are then added dropwise in such a way that the temperature remains between 40° and 55° C. After about 4 h, the reaction is complete (GC checking). The reaction mixture is brought to pH 3 using 70% strength sulfuric acid at 70° C. Steam is then passed into the solution, the product passing over with it and being isolated after cooling to 10° C. 1.51 kg of 2,3-difluoro-6-nitrophenol having a purity >99.9% (GC) are obtained after drying (melting point 63.5° C.), which corresponds to a yield of 86% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[O:4].C(O[C:21](=[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=2)[NH:30][C:29]1=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:15]/[C:21](=[C:28]2\[C:29](=[O:40])[NH:30][C:31]3[C:36]\2=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: COC(=O)C1CCCN1Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN1Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared from 4-(2-methoxycarbonyl-pyrrolidin-1-ylmethyl)-aniline and 3-(1-ethoxy-1-phenylmethylidene)-5-nitro-2-indolinone in DMF.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(=O)([O-])O.[Na+]>[N:57]([CH2:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:53]=[CH:54][CH:55]=[CH:56][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCN=[N+]=[N-])cc1

Procedure:
A solution of 2.0 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 1.32 g of sodium azide in 20 ml of N,N-dimethylformamide is stirred at 65° C. over 90 minutes. The reaction mixture is diluted with semisaturated aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a colourless oil from the residue. Rf=0.43 (1:1 EtOAc-heptane); Rt=6.40.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4c(F)cccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-6-fluoro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([O:31][CH3:32])=[CH:23][C:16]=2[CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][CH:12]=[C:11]([CH3:33])[N:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[C:27]([C:25]1[C:24]([O:31][CH3:32])=[CH:23][C:16]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([C:14]2[C:9](=[O:8])[NH:10][C:11]([CH3:33])=[CH:12][CH:13]=2)[CH:26]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(CNS(C)(=O)=O)c(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CNS(C)(=O)=O)c(-c2ccc(C)[nH]c2=O)cc1C(C)(C)C
Reaction time: 1 h

Procedure:
step 3—A mixture of 74 and 10% Pd/C (5 mg) in a mixture of MeOH (8 mL) and EtOAc (4 mL) under 1 atmosphere of H2 at RT was stirred for 1 h. The catalyst was filtered off and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 4% MeOH/DCM to afford 7.3 mg (53%) of I-37.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:10][C:11]#[CH:12])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][C:11]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C#CCC1(C(=O)OCC)CCC1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Product: CCOC(=O)C1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1

Procedure:
In analogy to the procedure described in example 24E], reaction of 1-prop-2-ynyl-cyclobutanecarboxylic acid ethyl ester and 1-iodo-4-trifluoromethoxybenzene gave the title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH3:15][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CSc1ncnc2c(N(C)c3ccccc3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CSc1ncnc2c(N(C)c3ccccc3)nc(N3CCNCC3)nc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-(N-methyl-phenylamino)-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31].C(N(CC)CC)C.Cl.[CH3:43][S:44][CH2:45][CH2:46][NH2:47].ClCCl>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH2:27][NH:47][CH2:46][CH2:45][S:44][CH3:43])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: CSCCN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reaction time: 0.17 h
Yield: 56 %

Procedure:
10.0 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde was dissolved in the mixture of dichloromethane/methanol (3:1). The mixture was added with 4.3 g of triethylamine, stirred for 10 min, added with 6.9 g of 2-methylthioethylamine hydrochloride, and stirred at room temperature. Upon consumption of the starting materials detected by TLC, 2.4 g of sodium borohydride was added in batches under ice-bath. Upon the end of reaction detected by TLC, dichloromethane (q.s.) was added. The mixture was washed with saturated ammonium chloride and then with saturated sodium chloride, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 6.5 g of yellow solid, yield 56%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:19])(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[Br:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][CH2:9][CH:8]([NH2:7])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of compound 3i (2.2 g, 4.3 mmol) in DCM (20 mL) was added slowly TFA (2 mL) at 0° C. The mixture was stirred at 0° C. for 2 hr. LCMS analysis indicated the total consumption of compound 3i. The solvent was removed in vacuum to give 3k as a white solid (1.68 g, 95% yield).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([N:8]([CH3:24])[C@H:9]([C:13]([N:15]1[CH2:23][CH2:22][CH2:21][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4]>CO.[Pd]>[NH2:1][C@H:2]([C:6]([N:8]([CH3:24])[C@H:9]([C:13]([N:15]1[CH2:23][CH2:22][CH2:21][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Yield: 104.4 %

Procedure:
29.3 g (61.6 mmol) of Z-Val-MeVal-Pro-OMe were dissolved in 230 ml methanol. After addition of 1.15 g 10% Palladium/charcoal, the reaction mixture was hydrogenated. Filtration and evaporation to dryness yielded 21.96 g of the product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].Br[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(Cl)cc2)C[C@H](C)N3C(C)=O)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
Ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Intermediate 16) (6.6 g, 18.73 mmol), 1-bromo-4-chlorobenzene (3.94 g, 20.60 mmol), bis(dibenzylideneacetone)palladium (0) (690 mg, 1.2 mmol) and [2′-(dicyclohexylphosphanyl)-2-biphenylyl]dimethylamine (Dave-phos) (590 mg, 1.499 mmol)) were mixed in toluene (120 mL) and the resulting mixture was treated with sodium t-butoxide (2.52 g, 26.2 mmol). The reaction was degassed under house vacuum with several quenches with nitrogen, heated at 70° C. under nitrogen for 16 h, then was allowed to cool to room temperature and filtered. The insoluble residue was washed with toluene and then Et2O. The combined filtrate and washings were washed with water (×2) then extracted with hydrochloric acid (2N, ×20, resulting in the precipitation of an orange oil which was collected with the aqueous acidic phases. The acidic extracts were washed with Et2O and the combined organic phases were washed with brine, dried (hydrophobic frit) and concentrated in vacuo. The residue was purified by chromatography on a silica cartridge (330 g), eluting with an EtOAc/cyclohexane gradient (5-45%). The appropriate fractions were combined and reduced to dryness in vacuo to give a pale yellow foam. This foam was dissolved in EtOAc (50 mL) and treated with functional thiourea silica (0.56 g, palladium scavenger). The mixture was stirred at room temperature (air atmosphere) for ˜20 min and then left at room temperature for 16 h. The mixture was filtered and the insoluble residues washed with EtOAc. The combined filtrate and washings were concentrated in vacuo to give ethyl 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoate (3.7 g, 8.0 mmol, 32%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([F:13])=[CH:4][N:3]=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:29])[CH:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]3[C:5]([F:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)[CH3:18]
Reactant: COC(=O)C(C)n1ccc2cc(O)ccc21
Reactant: OCCCNc1nc(Cl)ncc1F
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(C)n1ccc2cc(OCCCNc3nc(Cl)ncc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To a solution of 3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-propan-1-ol (Example 80, 0.66 g, 3.20 mmol) and 2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 7, 0.47 g, 2.13 mmol) in dichloromethane (10.80 mL) was added triphenylphosphine (0.85 g, 3.20 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.82 g, 3.20 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h. The desired product (0.54 g, 59%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD3OD) δ 7.85 (d, 1H), 7.27-7.06 (m, 3H), 6.82-6.79 (m, 1H), 6.40 (d, 1H), 5.24 (q, 1H), 4.11-4.07 (m, 2H), 3.70-3.67 (m, 5H), 2.15-2.09 (m, 2H), 1.77 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(F)cn1
Product: CC(C)(C)NC(=O)c1ccc(F)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 39-3), using 5-fluoro-2-pyridinecarboxylic acid and t-butyl amine.