Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>CN(C)C=O.[Cl-].[Li+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
1.70 g (purity 82%, 3.82 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoic acid (racemate), 631 mg (3.82 mmol) of ethyl 4-aminobenzoate, 543 mg (3.82 mmol) of Oxima and 595 μl (3.82 mmol) of DIC in 38 ml of dimethylformamide were reacted according to General Method 5B. After complete conversion, the reaction solution was diluted with 213 ml of 10% strength lithium chloride solution and 170 ml of ethyl acetate and the phases were separated. The aqueous phase was extracted twice with 170 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 100 g silica cartridge, flow rate 50 ml/min), giving the title compound. Yield: 1.1 g (purity 78%, 49% of theory)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 120 °C
Yield: 33.9 %

Procedure:
A mixture of ethyl 4,6-dichloronicotinate (500 mg, 2.272 mmol) and (4-aminophenyl)(morpholino)methanone (469 mg, 2.272 mmol) in N,N-Dimethylacetamide (5 mL) was treated with DIEA (0.794 mL, 4.54 mmol) and sealed in a large microwave vial and heated in a heating block at 120° C. overnight. The reaction mixture is removed from heating block, cooled to rt and diluted with water and extracted into CH2Cl2. Washed with water and concentrated to give dark oil which was chromatographed (ISCO Companion 40 g silica gel column and eluted with EtOAc/Hexane gradient (0-100%) to give 300 mg of ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate as a light yellow solid. LCMS: (M+H)+=390.02, 392.02 (Cl pattern). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, J=7.14 Hz, 3H) 3.74 (br. s, 8H) 4.41 (q, J=7.03 Hz, 2H) 7.00 (s, 1H) 7.30 (d, J=8.35 Hz, 2H) 7.51 (d, J=8.35 Hz, 2H) 8.80 (s, 1H) 9.99 (s, 1H).
Reaction SMILES: CS[C:3]1N=C(Cl)C([N+]([O-])=O)=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:15]=2)[N:4]=1.Cl.C(O[C:29](=O)[CH2:30][NH2:31])C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:24][N:22]([CH3:23])[C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:5]1[N:4]=[CH:3][CH:29]=[CH:30][N:31]=1)=[O:21]
Reactant: CCOC(=O)CN
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cccc(C(=O)N(C)C)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)C(=O)c1cccc(Oc2ncccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine, a compound of formula (C), (3.0 g 8.14 mmol) in 80 mL of acetonitrile at 0° C. was added glycine ethyl ester hydrochloride, a compound of formula (D), (1.14 g, 8.14 mmol), followed by the addition of cesium carbonate (6.1 g, 18.7 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred for 2 hours. The volatiles were evaporated to yield 3.6 g of 2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)-phenoxypyrimidine, a compound of formula (E).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.B(O)O.C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.[OH-].[Na+].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOCC.C1(C)C=CC=CC=1.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>[Br:8][C:4]1[CH:3]=[C:2]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccccc2)c1

Procedure:
Starting with readily available starting materials, 1,3-dibromobenzene and the appropriately substituted iodobenzene, it is possible to prepare biphenyls having 3', 4' and 5' position substitution. Referring to Flow Sheet AE 1,3-dibromobenzene AE1 is converted to boronic acid AE2 by first reacting with butyl lithium in anhydrous THF or ether at about -78° C. followed by addition of triisopropyl borate. The resultant intermediate is worked up with sodium hydroxide and acidified. Boronic acid AE2 is subsequently reacted with the appropriate iodobenzene AE3 in toluene and aqueous sodium carbonate with tetrakistriphenylphosphinepalladium as a catalyst to produce the 3-bromo biphenyl B1. This reaction to B1 is well known in art with reference made herein to N. Miyaura, T. Yanagi and A. Suzuki, Syn. Comm., 11, 513 (1981). ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)=[CH:5][C:4]=1[N+:16]([O-])=O.COC1C2[N:27]=[C:28](N)[S:29]C=2C(OC2C=CC=CC=2)=CC=1>>[O:14]1[CH2:15][CH:9]([C:6]2[C:5]3[S:29][C:28]([NH2:27])=[N:16][C:4]=3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][O:11][CH2:12][CH2:13]1
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Reactant: COc1ccc(C2COCCOC2)cc1[N+](=O)[O-]
Product: COc1ccc(C2COCCOC2)c2sc(N)nc12
Yield: 57 %

Procedure:
The title compound was prepared from 6-(4-methoxy-3-nitro-phenyl)-1,4-dioxepane in exact the same manner as described in WO01/97786 for 4-methoxy-7-phenoxy-benzothiazol-2-yl-amine in 57% yield (3.7 g). MS: m/e=281(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:22]([N:29]1[C:33](=[O:34])[C:32](=[C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[C:42]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:43]=[CH:44][C:37]=3[S:36]2)[S:31][CH2+:30]1SC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:8]([C:4]1[CH:3]=[C:2]([N:1]=[C:30]2[N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:33](=[O:34])[C:32](=[C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[C:42]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:43]=[CH:44][C:37]=4[S:36]3)[S:31]2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COCCOc1ccc2c(c1)N(C)C(=C1S[CH2+](SC)N(Cc3ccccc3)C1=O)S2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: COCCOc1ccc2c(c1)N(C)C(=C1SC(=Nc3cccc(C(C)=O)c3)N(Cc3ccccc3)C1=O)S2

Procedure:
The title compound was synthesized in a manner similar to that described in Example 146 by condensing 3′-aminoacetophenone with 3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate. 1H-NMR (CDCl3): δ 7.75 (1H, d), 7.60-7.64 (3H, m), 7.28-7.50 (6H, m), 7.24 (1H, d), 6.85 (1H, m), 5.21 (2H, s), 4.18 (2H, m), 3.80 (2H, m), 3.70 (3H, s), 3.48 (3H, s), 2.65 (3H, s); MS(ESI): 546 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(Cl)cccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(Cl)cccc1Br
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
To a solution 2-bromo-6-chlorobenzoic acid (9.5 g, 0.041 mol) and potassium carbonate (8.6 g, 0.061 mol) in N,N-dimethylformamide (50 mL) was added methyl iodide (11.2 g, 0.081 mol) dropwise over a 10 minute period. The reaction mixture was stirred at RT for 3.5 hours and was subsequently diluted with water (500 mL). The aqueous phase was back-extracted with EtOAc (3×300 mL). The organic layers were combined, washed with 1M HCl aq (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (10.0 g, 99.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.413 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.137 (t, J=8 Hz, 1H), 3.9 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([N:5]1[C:9]([CH2:16][CH2:17][NH:18][S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][C:7]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)=[O:4].[CH2:33]([NH2:35])[CH3:34]>C(#N)C>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([N:5]1[C:9]([CH2:16][CH2:17][NH:18][S:19]([CH2:22][CH2:23][NH:35][CH2:33][CH3:34])(=[O:21])=[O:20])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][C:7]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:6]1)=[O:4]
Reactant: CCN
Reactant: C=CS(=O)(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Solvent: CC#N
Product: CCNCCS(=O)(=O)NCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-[4-(2,2-Dimethylpropionyl)-5-(2-ethenesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (0.16 g, 0.33 mmol) obtained in Step 4 mentioned above was dissolved in acetonitrile (10 mL), and 70% aqueous ethylamine (1.0 mL, 12 mmol) was added, then the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (chloroform/methanol/concentrated aqueous ammonia=100/10/1) to give Compound 21 {N-{4-(2,2-dimethylpropionyl)-5-[2-(2-ethylaminoethanesulfonyl-amino)ethyl]-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl}-2,2-dimethylpropanamide} (0.15 g, 86%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:15]=[C:16]([C:29](=[O:31])[CH3:30])[CH:17]=[C:18]([N:22]2[CH2:26][C@@H:25]([OH:27])[C@H:24]([OH:28])[CH2:23]2)[C:19]=1[O:20][CH3:21])([CH3:13])([CH3:12])[CH3:11].[CH2:32](Cl)[O:33][CH3:34].C(OCC)(=O)C>C(Cl)Cl.O>[C:10]([C:14]1[CH:15]=[C:16]([C:29](=[O:31])[CH3:30])[CH:17]=[C:18]([N:22]2[CH2:26][C@@H:25]([O:27][CH2:32][O:33][CH3:34])[C@H:24]([OH:28])[CH2:23]2)[C:19]=1[O:20][CH3:21])([CH3:13])([CH3:11])[CH3:12]
Reactant: COCCl
Reactant: COc1c(N2C[C@@H](O)[C@H](O)C2)cc(C(C)=O)cc1C(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1O
Reaction time: 0.17 h
Yield: 32.9 %

Procedure:
Diisopropylethylamine (2.3 ml, 13 mmol) was added to a solution of the 1-{3-(tert-butyl)-5-[(3R,4R)-3,4-dihydroxytetrahydro-1H-1-pyrrolyl]-4-methoxyphenyl}-1-ethanone (1.32 g, 4.29 mmol) in methylene chloride (10 ml) while cooling on ice, and then MOMCl (0.49 ml, 6.5 mmol) was added dropwise and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 2.5 hours. After completion of the reaction, it was diluted with water and extraction was performed with ethyl acetate. After washing with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (496 mg, 33%) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].Cl.Cl.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][NH:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([NH:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])[CH:31]=2)[CH2:27][CH2:28]1
Reactant: Nc1ccc2c(c1)NCC2
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)NCC4)c2cc1OCC
Temperature: 100 °C
Yield: 106.3 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 258 mg (1.88 mM) of 6-Aminoindoline dihydrochloride salt in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The solid was dissolved in 50/50 methanol/chloroform and dried onto silica gel and purified by chromatography using a gradient of 20% to 50% acetone in hexane to yield 496 mg of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 375.1, mp=121-124° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[C:9]1([CH:7]([CH3:8])[CH2:6][C:5]([C:15]([F:16])([F:17])[F:18])([OH:19])[CH2:4][OH:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(O)(CC(C)c1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CC(O)(CO)C(F)(F)F)c1ccccc1
Reaction time: 1 h
Yield: 110.2 %

Procedure:
4.35 g of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester is dissolved in 100 ml of diethyl ether and stirred at 0° C. with 1.3 g of lithium aluminum hydride for one hour at 0° C. and for 16 hours at room temperature. A little water is added while being cooled, and it is stirred for one hour. The diethyl ether phase is separated, dried (Na2SO4) and concentrated by evaporation and distilled on a bulb tube. 4.1 g of 4-phenyl-2-trifluoromethyl-1,2-pentanediol, boiling point 120° C./0.04 hPa, is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[OH:18])[CH2:30][CH2:29]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: Oc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2O)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-hydroxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-hydroxy-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=399.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[N:38][CH:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[N:38][CH:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (900 mg, 2.90 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K14) (1.16 g, 2.90 mmol) according to the general procedure M. Obtained as a light yellow foam (790 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([Cl:57])[CH:51]=1>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:51][C:52]=1[Cl:57]
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NCc1ccc(O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)NCc2ccc(O)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-2-chloro-phenol hydrochloride (104 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-chloro-benzylamide (114 mg) as a colourless oil. LC-MS: tR=1.00 min, [M+1]+=362.14.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:52]=[N:51]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Cn1nccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.010 g of product in 44% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH:37]C(OC(C)(C)C)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[CH3:19][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][C@@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[NH2:8]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)N[C@H](C)C(=O)NC[C@@H](N)Cc1ccccc1
Yield: 98.6 %

Procedure:
N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide (6.1 g, 9.1 mmol) was dissolved in 25 mL dichloromethane and 25 mL TFA and stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was evaporated under reduced pressure to give a yellow gum. The gum was dissolved in 20 mL methanol and split into 4 equal portions. Each was loaded onto a separate 10 g SCX-2 cartridge, pre-wetted with methanol. Each cartridge was flushed with 50 mL of methanol to remove non-basic impurities, and then with 80 mL of 2N ammonia solution in methanol to elute the desired product. Fractions containing product were concentrated in vacuo to give a pale yellow gum. This was heated with a hot air gun and placed under vacuum (15 mm Hg) overnight to give 3.7 g (100%) of the title compound as a stiff white foam.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:20])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20][CH:13]([CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:23])[CH3:22]
Reactant: OC(COc1cccc2c1CC=CC2)CN1CCCC1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(COc1cccc2c1CC=CC2)CN1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g. of 1-(5,8-dihydro-1-naphthyloxy)-3-(pyrrolidino)-2-propanol, 1.5 g. of fused acetate and 15 ml. of acetic anhydride is heated on a steam bath with occasional shaking for one hour. At the end of this time, the warm solution is poured with vigorous stirring into 100 ml. of ice water. The mixture is stirred for 10-15 minutes and the crystals of 1-(5,8-dihydro-1-naphthyloxy)-3-(pyrrolidino)-2-propyl acetate are collected, washed thoroughly with water, and purified by crystallization from alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:20]1[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3ccc4ccccc4c3)cc2sc1=O
Yield: 46.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added naphthalen-2-yl-boronic acid (144 mg, 0.84 mmol), Pd(PPh3)4 solid (64 mg, 0.06 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 3 h. After cooling, the reaction mixture was diluted with water (100 mL) and acidified using 1 N HCl to pH 3-4. The precipitate was collected by filtration, rinsed with CH2Cl2 and the solid dried to provide 4-hydroxy-7-naphthalen-2-yl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (119 mg). MS ESI(+) m/e: 363.19 (M+1).