Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]([C:9]1[CH:14]=[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])[N:12]=[C:11]([O:19][CH3:20])[C:10]=1[CH2:21][O:22]COC)([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O>C(O)(C(F)(F)F)=O>[CH2:7]([C@:2]1([OH:1])[C:9]2[CH:14]=[C:13]([Si:15]([CH3:16])([CH3:17])[CH3:18])[N:12]=[C:11]([O:19][CH3:20])[C:10]=2[CH2:21][O:22][C:4](=[O:6])[CH2:3]1)[CH3:8]
Reactant: CC[C@@](O)(CC(=O)O)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@]1(O)CC(=O)OCc2c1cc([Si](C)(C)C)nc2OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a round bottom flask was added 9a (0.74 g, 1.99 mmol) followed by TFA (50 mL). The mixture was stirred at rt for 16 h and then concentrated under reduced pressure. The residue was dissolved in Et2O and neutralized with sat. NaHCO3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (hexane-EtOAc 75:25) to yield 10a (0.43 g, 70%) with 90% ee as a white foam; [α]23D=+45.1 (c=0.86, CH2Cl2). Lactone 10a was analyzed for enantiomeric purity using a Chiralcel OD-H column with 92:8 hexane:iPrOH as the eluent, using the racemate as the standard.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[C:17]([O:21][C:22](=[O:25])[CH2:23][NH:16][C:10]1[CH:11]=[CH:12][C:13]([I:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccc(I)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc(I)cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 2-benzyloxy-4-iodophenylamine (2.35 g, 7.23 mmol) in DMF (15 mL) is added bromoacetic acid tert-butyl ester (1.76 g, 9.04 mmol) and K2CO3 (5.0 g, 36.2 mmol) and the mixture is heated at 50° C. for 4 h. 2N HCl solution (200 mL) is added with cooling and it is then extracted with EtOAc. The organic layer is then washed with brine, dried and concentrated. The residue is then purified by column chromatography to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Reactant: OB(O)c1ccnc(F)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccnc(F)c2)cnc1F

Procedure:
By carrying out the operation analogously to example 177, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a pink solid (yield=65%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[C:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:16]([F:17])([F:18])[F:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)c(C(F)(F)F)c1

Procedure:
Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is added to a stirred solution of 2-bromo-5-nitrobenzotrifuoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) and heated at 120° C. under an argon atmosphere for 1 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (brine), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford 4′-nitro-2′-(trifluoromethyl)-[1,1′-Biphenyl]. The biphenyl is dissolved in ethanol (200 mL) and hydrogenated at atmospheric pressure over Raney nickel (2 g) at 22° C. The calculated amount of hydrogen is taken up in 11 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel; eluent ethyl acetate) to give the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6): 5.62 (br.s, 2H), 6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H), 7.19-7.23 (m, 2H), and 7.29-7.39 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)(O)[CH3:7])C.FC1C=C(F)C=CC=1C1C=CC(C(C)=CC(O)=O)=CC=1.I.OS([O-])=O.[Na+]>C(O)(=O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH:6]([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: I
Agent: O=S([O-])O
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, or the corresponding free hydroxy acid or 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid, is heated with 2 ml. of 67% hydriodic acid and 4 ml. of acetic acid at 150° for 1 hour and the mixture is poured onto ice and decolorized with NaHSO3 solution. After the customary work up, 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°, is obtained.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[CH2:24]([O:26][C:27](=O)[C:28]#[C:29][CH2:30][O:31]C)C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:30](=[O:31])[CH:29]=[C:28]([CH2:27][O:26][CH3:24])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CCOC(=O)C#CCOC
Solvent: ClC(Cl)Cl
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and 4-methoxy-but-2-ynoic acid ethyl ester (see Example 106) employing the procedure described in Example 95. [α]D25 −14.55 (c 0.495, CHCl3).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12](OCC)=[O:13])[N:9]=[C:8]2[S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:8]2[S:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)c(Sc2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cn(-c2ccccc2)c(Sc2ccccc2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A solution (30 mL) of ethyl 1-phenyl-2-(phenylthio)-1H-imidazole-4-carboxylate (1.17 g) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (12 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The reaction mixture was stirred at 0° C. for 4 hr, water was added, and the mixture was stirred for 30 min. To the obtained gel-like substance was added tetrahydrofuran, the mixture was filtered, and the filtrate was concentrated under reduced pressure. A mixed solvent of ethyl acetate-diisopropyl ether (1:1) was added to the residue and the resulting unsoluble crystals were collected by filtration to give the title compound as pale-yellow crystals (yield 797 mg, 78%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][O:13][C:12]2=[O:22])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:23]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:23]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([O:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][N:11]4[C@H:15]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:14][O:13][C:12]4=[O:22])=[CH:8][CH:9]=3)=[O:3])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)c1ccc(CN2C(=O)OC[C@H]2c2ccccc2)cc1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CN4C(=O)OC[C@H]4c4ccccc4)cc3)cc2)cc1

Procedure:
505 mg (1.07 mmol) of (4R)-(-)-3-(4-carboxyphenylmethyl)-4-phenyl-2-oxazolidinone and 555 mg (1.7 mmol) of 4-decyloxy-4'-hydroxybiphenyl and 31 mg of DMAP are dissolved in 17 ml of absolute CH2Cl2, and 390 mg (1.7 mmol) of DCCI are added. The crude product is purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:7]2[C:6]3[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:28][CH:27]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Yield: 91 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 4-fluorobenzyl bromide as starting materials, the title compound was obtained in a yield of 91% as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][O:15][C:16]2[CH:47]=[CH:46][C:19]([CH2:20][N:21](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.SCC(O)=O.O.[OH-].[Li+].C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][O:15][C:16]2[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(N(Cc2ccc(OCc3cnn(C)c3-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(NCc2ccc(OCc3cnn(C)c3-c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66 %

Procedure:
To a solution of the yellow oil obtained in Example 45 and mercaptoacetic acid (100 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added lithium hydroxide monohydrate (80 mg, 1.9 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into 10% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (155 mg, yield 66%, 2 steps) as a yellow oil.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=O)(=O)[CH2:2][CH2:3][CH3:4].[NH2:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[OH:19][C:18]1[C:13]2=[N:12][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7](=[O:9])[N:14]2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ncccc1O
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1cc(=O)n2cccc(O)c2n1
Yield: 49.5 %

Procedure:
A mixture of 31.5 g of ethyl butyrylacetate, 11.0 g of 2-amino-3-pyridinol, 125 ml of ethyleneglycol monomethyl ether, and 1.0 g of p-toluenesulfonic acid is stirred and heated under reflux for 21 hours and then allowed to cool. The product that crystallizes is filtered and dried to give 10.1 g of 9-hydroxy-2-propyl-4H-pyrido[1,2-a]pyrimidin-4-one, m.p. 95°-96°. The filtrate is concentrated to one-half volume to give 5.8 g of solid, m.p. 92°-94°. This is extracted with two 50 ml portions of boiling diisopropyl ether to leave behind 1.0 g of an insoluble solid. From the diisopropyl ether extracts there is obtained 3.8 g of additional product, m.p. 95°-96°. The 1.0 g of solid insoluble in diisopropyl ether is recrystallized from acetonitrile to give 0.60 g of 9-hydroxy-2-propyl-4 H-pyrido[1,2-a]pyrimidin-4-one, salt with p-toluenesulfonic acid, m.p. 202° -204°. The same salt is prepared by mixing rapidly hot solutions of 1.40 g of the product, m.p. 95°-96° in 15 ml of acetonitrile and 1.30 g of p-toluenesulfonic acid in 15 ml of acetonitrile. A clear solution forms briefly and then the salt crystallizes. The yield of salt, m.p. 202°-204°, is 2.16 g.
Reaction SMILES: CC1C=CC([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=CC=1.C(Cl)(=O)C(Cl)=O.C[N:29](C)C=O>ClCCl>[O:17]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:21][C:12]=2[CH:13]=[C:14]([C:18]([NH2:29])=[O:19])[CH2:15][CH2:16]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)C1=Cc2ccccc2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15g) in dichloromethane (6ml) were added oxalyl chloride (0.14ml) and dimethylformamide (catalytic amount) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in tetrahydrofuran. The mixture was dropwise added to a solution of 4-((N-(3,5-dimethylcyclohexyl)-N-methyl)-aminomethyl)aniline (0.13g) and triethylamine (0.23ml) in tetrahydrofuran (10ml), under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from diethyl ether-hexane to give N-(4-((N-methyl-N-(3,5-dimethylcyclohexyl))aminomethyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 133) (0.22g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 42 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 μl (0.935 m mol) of triethyl amine and 20 ml of dichloromethane were added 98 μl (0.935 m mol) of isobutyryl chloride with stirring at the room temperature, followed by further stirring for four hours. After the completion of the reaction, the mixture was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 109 mg (yield: 42%) of the pure intended compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:10]=2[N:11]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[N:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(F)nc12
Product: Fc1ccc2ncnc(Cl)c2n1
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 6-fluoro-3H-pyrido[3,2-d]pyrimid-4-one (0.20 g, 1.21 mmol) in POCl3 (30 mL) is heated under reflux with stirring until homogeneous (2 h), and then for a further 1 h. Excess POCl3 is removed under reduced pressure, and the residue is partitioned between CH2Cl2 and saturated aqueous NaHCO3. Workup of the organic portion gives crude 4-chloro-6-fluoropyrido[3,2-d]pyrimidine (100%) as an unstable white solid which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41]CC)=[O:40].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (30 mg, 0.075 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (48 mg, 65 μL, 0.375 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (27.6 mg, 19 μL, 0.165 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. After 2 h, a 5 M solution of sodium hydroxide (0.5 mL, 2.5 mmol, 33 equiv; [CAS RN 1310-73-2]) was added and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.5 mg (22%) of the title compound as a light yellow powder. MS (ISP): 458.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH:18]2[O:22][CH2:21][CH2:20][O:19]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH:18]1[O:19][CH2:20][CH2:21][O:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 101.4 %

Procedure:
Methanesulphonyl chloride (5.5 g) was added over 10 minutes to an ice-cooled solution of 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-ol (12 g) (see Preparation 15) and triethylamine (5.7 g) in dichioromethane (100 ml). The mixture was stirred for 30 minutes before further addition of dichioromethane (50 ml). The solution was then washed sequentially with water (3×50 ml) and brine (50 ml) before drying over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane as a yellow oil (15.6 g) which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:41])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[O:15])[O:10][C:11]=1[CH2:12][CH3:13].NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:9]1[O:10][C:11]([CH2:12][CH3:13])=[C:7]([C:6]2[N:5]([CH3:41])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]
Reactant: CCc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCc1oc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 69.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.43 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at 25° C. was added hydrazine (0.13 ml, 4.27 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide (166 mg, 0.30 mmol, 70% yield) as a yellow solid: LCMS (ES) m/z=455, 457 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (br. s., 1H) 8.06 (br. s., 3H) 7.67 (s, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.59 (d, J=4.29 Hz, 2H) 7.44 (d, J=4.04 Hz, 1H) 7.31 (d, J=5.81 Hz, 1H) 4.50-4.57 (m, 1H) 3.72 (s, 3H) 2.99-3.12 (m, 4H) 2.63 (q, J=7.33 Hz, 2H) 1.21 (t, J=7.45 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[NH2:1][C:2]1([C:14]([O:16][CH3:21])=[O:15])[CH2:6][CH2:5][C@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: NC1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 70 °C

Procedure:
To a heterogeneous mixture of (3S)-1-amino-3-(4-bromophenyl)cyclopentanecarboxylic acid (I-1C, 14 g, 49.3 mmol) in MeOH (250 mL) was added thionyl chloride (36.0 mL, 493 mmol) dropwise over a period of 20 minutes at room temperature via an additional funnel (exothermic). The reaction mixture was placed in an oil bath and heated to 70° C. for 4 hours. The solvent was removed under vacuum, with the residue being dissolved in ethyl acetate (200 mL) and washed twice with 1N NaOH. The organic layer was then dried over Na2SO4 and concentrated to give 10.8 g of (3S)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate. HPLC retention time=0.68 min (Condition G); LC/MS M+1=298/300.