Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:21][CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:23][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]1=2
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)O)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(C)(C)O)ccc3n2CC(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
To a stirred solution of 2-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl) propan-2-ol (942 mg, 3.86 mmol) in DMF (5 mL) was added sodium hydride (60%, 464 mg, 11.58 mmol). After stirring for 10 min, the reaction mixture was cooled to 0° C. and a solution of 4-(oxiran-2-yl)pyridine (700 mg, 5.8 mmol) in DMF (2 mL) was added. The reaction mixture was allowed to warm to RT and stirring was continued for 16 h. The progress of reaction was monitored by LCMS and NMR. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was crystallized from ether to yield 2-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl) propan-2-ol (500 mg) as yellow solid. 1H NMR (CDCl3, freebase) δ (ppm): 8.37 (d, 2H), 7.36 (s, 1H), 7.20 (d, 1H), 7.11 (d, 2H), 7.04 (d, 1H), 4.82 (t, 1H), 4.05 (d, 2H), 3.49 (d, 1H), 3.4 (d, 1H), 2.9 (m, 1H), 2.85 (m, 1H), 2.64 (m, 2H), 2.40 (s, 3H), 1.65 (s, 6H). Separation by chiral HPLC provided enantiomers 23a and 23b. Optical rotations: Compound 23a, (−)52.54 (c 0.55, Chloroform, 95.4% HPLC purity); Compound 23b, (+)29.08 (c 0.56, Chloroform, 98.94% HPLC purity).
Reaction SMILES: C=O.[C:3](=O)([O-])O.[Na+].[Br-].[O:9]([CH2:16][C:17]([NH:19][C@@H:20]1[C:55](=[O:56])[N:22]2[C:23]([C:47]([O:49][CH2:50][C:51]([Cl:54])([Cl:53])[Cl:52])=[O:48])=[C:24]([CH2:27][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:25][S:26][C@H:21]12)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[O:9]([CH2:16][C:17]([NH:19][C@@H:20]1[C:55](=[O:56])[N:22]2[C:23]([C:47]([O:49][CH2:50][C:51]([Cl:53])([Cl:52])[Cl:54])=[O:48])=[C:24]([CH:27]=[CH2:3])[CH2:25][S:26][C@H:21]12)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])O
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 17 %

Procedure:
40%-Aqueous formaldehyde (24 ml.) and 3%-sodium hydrogen carbonate solution (80 ml.) were added to a solution of [7β-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonyl) ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (4.93 g, 6 mmole) in methylene chloride (40 ml.). The two-phase mixture was stirred vigorously for 2 hours and the organic phase was washed with water (100 ml.), dried (MgSO4), and evaporated to an orange foam. This foam was chromatographed on Kieselgel G (Merck; 150 g) with methylene chloride and 0.5%-acetone in methylene chloride as eluants. The appropriate fractions were combined and evaporated to a colourless oil which crystallised on addition of ether. The solvent was removed to give the title ester as a white solid (0.50 g, 17%), m.p. 136° to 140° (decomp), [α]D23 - 33° (c 1.01; Me2SO), λmax. (EtOH), 296 nm (ε 12,100), νmax. (Nujol) 3300 (NH), 1764 (azetidin-2-one), 1716 (CO2R), 1668 and 1509 (CONH) and 920 cm-1 (=CH2), τ (Me2SO-d6) 0.81 (1H, d, J 8 Hz; NH), 2.67 and 2.99 (2H and 3H, 2m; C6H5O), 3.01 (1H, dd, J 11 and 18 Hz; CH=CH2), 4.19 (1H, dd, J 8 and 5 Hz; C7 -H), 4.24 (1H, d, J 18 Hz) and 4.55 (1H, d, 11 Hz) (CH=CH2), 4.71 (1H, d, J 5 Hz; C6 -H), 4.79 and 5.01 (2H, AB-q, J 12 Hz; CH2CCl3), 5.36 (2H, s; C6H5OCH2), 5.98 and 6.34 (2H, AB-q, J 18 Hz; C2 -H2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: CCOC(=O)CCc1nc(CCl)co1
Product: CCOC(=O)CCc1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 47, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with ethyl 4-chloromethyl-2-oxazole-propionate to give ethyl 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolepropionate as an oily product. The yield was 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[NH3:14].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:14])[CH3:12])[C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: N
Reactant: CC(=O)c1cc(Cl)cc2c1OCO2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(N)c1cc(Cl)cc2c1OCO2
Temperature: 0 °C
Yield: 56 %

Procedure:
1-(5-Chlorobenzo[d][1,3]dioxol-7-yl)ethanone (90.0 mg, 0.45 mmol), titanium(IV) isopropoxide (255 mL, 0.90 mmol) and 2 M solution of ammonia in ethanol (1.10 mL, 2.26 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (25.5 mg, 0.67 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 10 mL), the precipitate that formed was filtered off and washed with ethyl acetate (5 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (5 mL×2). The combined organic extracts were washed with 1 M HCl (5 mL). The acidic aqueous extracts were washed with ethyl acetate (15 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (15 mL×3). The combined organic extracts were washed with brine (5 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (50 mg, 56% yield).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: O=Cc1sccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1ccsc1C1OCCO1
Reaction time: 16 h

Procedure:
3-bromo-2-formylthiophene (3.89 parts, 0.02M) was heated at reflux with dry ethyleneglycol (1.6 parts) toluene (25 parts) and p-toluene sulphonic acid (0.1 parts) in a vessel equipped with a Dean and Stark separator for 16 hours. The reactants were then cooled and evaporated into silica. The silica was formed into a column which was then developed by elution with hexane containing increasing amounts of dichloromethane. The product was obtained from fractions containing 10-60% dichloromethane as a pale straw-coloured oil (4.42 parts).
Reaction SMILES: N#CBr.C[N:5]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[C@@H:6]1[CH2:7][C:8]1[C:9]3[C:22]([NH:23][CH:24]=1)=[CH:21][CH:20]=[CH:19][C:10]=32.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:19]1[C:10]2[C@H:11]3[C@H:6]([CH2:7][C:8]4[C:9]=2[C:22]([NH:23][CH:24]=4)=[CH:21][CH:20]=1)[NH:5][CH2:18][C:17]1[C:12]3=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN1Cc2ccccc2[C@H]2c3cccc4[nH]cc(c34)C[C@@H]21
Agent: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CN[C@H]1Cc3c[nH]c4cccc(c34)[C@H]21

Procedure:
38.6 g of cyanogen bromide are dissolved in 400 ml of chloroform. 20 g of trans-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridine are added to the solution whilst stirring, followed by 10 g of potassium carbonate. The resultant suspension is stirred overnight at room temperature, then filtered and the filtrate concentrated. The residue of evaporation is dissolved whilst heating in 400 ml of concentrated acetic acid, and then 55 ml of water, followed by 47.5 g of zinc powder, are added. The resultant suspension is stirred for 18 hours at 90°. The reaction solution is then filtered, the residue of filtration washed with methylene chloride/methanol, and the combined filtrates evaporated. The residue of evaporation is taken up in methylene chloride/methanol=9/1, and extracted with 1n aqueous sodium carbonate solution. The combined organic phases are washed with sodium chloride solution, dried over magnesium sulphate, filtered, concentrated and the residue chromatographed on silica gel, using methylene chloride/methanol=95/5 (CH2Cl2 10% saturated with NH3). The title compound is obtained. When crystallised from methanol, its hydrochloride melts at 301°-303°.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH2:27][CH3:28])=[C:20]([C:22](OCC)=[O:23])[CH3:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:23])[C:20]([CH3:21])=[C:19]([CH2:27][CH3:28])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=C(CC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-ethyl-1-propenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 192°-194° C.,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][NH2:11])[CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=1
Reactant: Cc1ccnc(NCCN)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(NCCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a cooled (0° C.) solution of N-(4-methyl-2-pyridyl)ethane-1,2-diamine (683 mg, 4.52 mmol) in dichloromethane (25 ml) were added triethyl amine (1.26 ml, 9.06 mmol) followed by methanesulfonyl chloride (370 μl, 4.78 mmol). The mixture was stirred at room temperature for two hours and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated to give 1.04 g of a yellow oil (4.57 mmol, 95%) MS(ESI) m/z=230.1 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C@@H:18]([OH:27])[C:19]2([S:25][CH3:26])[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:30])[C@:7]1([CH3:29])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].CS(C)=O.C(OC(=O)C)(=O)C.C(O)(=O)C>O>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][C:18](=[O:27])[C:19]2([S:23][CH3:24])[S:25][CH3:26])[C@H:15]2[C@@:6]1([F:30])[C@:7]1([CH3:29])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:28])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CSC1(SC)[C@H](O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CSC1(SC)C(=O)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Yield: 97.1 %

Procedure:
A solution of 3.0 g (6.6 mmole) of 11β-(acetyloxy)-9-fluoro-16α-hydroxy-17,17-bis(methylthio)androsta-1,4-dien-3-one in a solution of dry dimethylsulfoxide (30 ml), acetic anhydride (20 ml) and glacial acetic acid (10 ml) was stirred at room temperature under nitrogen overnight. The resulting solution was poured into cold water and extracted with dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate solution and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give 2.9 g of solid, melting point 225°-227° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:15][C:16]#[C:17][CH2:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CCC#CCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 522 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 231 mg of 2-pentyn-1-ol, to which 110 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 470 mg of 4-(2-fluorophenyl)-6-(2-pentynyloxy)pyrimidine (the present compound (86)).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>C(O)(C)C>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)coc2cc(OCC3CO3)ccc12

Procedure:
7-Hydroxy-3-phenylchromone and epichlorohydrin were reacted according to general procedure A, and the product obtained was white prisms, m.p. 151°-152° (83% crude yield) from isopropyl alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[N+]([C:13]1C=CC(OC)=CC=1C(F)(F)F)([O-])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Product: COc1ccc(Br)cc1Cl
Yield: 93 %

Procedure:
Starting from 4-bromo-2-chlorophenol (22 g, 110 mmol) in place of 4-nitro-3-trifluoromethylphenol, the title compound (22 g, 93%, m.p. 69-71° C.) was synthesized in essentially the same manner as described above for 4-nitro-3-trifluoromethylanisole in Step 1, Scheme 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(N4CCOCC4)nc4c3CCC4)cc2)CCC1
Yield: 83.1 %

Procedure:
A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (2 g, 5.594 mmol), morpholine (0.64 mL, 7.27 mmol) and diisopropylethylamine (1.46 mL, 8.392 mmol) in isopropanol (25 mL) was heated at reflux for 50 hours. After cooling to a temperature in the range of 15° C. to 40° C., the precipitated solid was filtered, washed with hexane and dried. The solid was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (1.9 g, 83% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22](=[N:42]O)[C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[CH:25][CH:24]=1>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:16][N:21]=[C:22]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)=[CH:25][CH:24]=3)[N:42]=2)=[CH:10][C:9]=1[C:17]([F:20])([F:18])[F:19]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 3 starting from Intermediate 24 (168 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellow oil. LC/MS (method B): 565.2 (M+H)+. HPLC (Method A) Rt 5.00 min (Purity: 95.4%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(O)C.Br[C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][C:18]2=[O:21])=[CH:13][CH:12]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>CCCCCC.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.C(OC(=O)C)C.C1(C)C=CC=CC=1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][NH:17][C:18]3=[O:21])=[CH:13][CH:12]=2)=[CH:25][CH:24]=1
Reactant: O=C1NCCc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)cc1
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: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCCc2ccc(-c3ccc(F)cc3)cc21
Temperature: 110 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
1M Na2CO3 (211.8 mg, 2.0175 mmol) was added to a mixture of ethanol (10 mL) and toluene (10 mL) previously degassed with argon for 30 minutes. The reaction mixture was degassed with argon for a further 20 minutes. This was followed by the addition of 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (I-3e: 200 mg, 0.877191=4 (4-fluoro-phenyl)-dihydroxy-borane (245 mg, 1.7543 mmol) and Pd(PPh3)4 (20.2 mg, 0.01754 mmol). The resulting mixture was stirred at 110° C. for 5 hours. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 200 mg of the product (94.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:29])[CH3:28])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:28])[CH3:29])[N:11]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
10.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester are dissolved in 150 ml of chloroform and treated with 8.2 ml of diisopropylethylamine at 0°. 2.4 ml of ethyl chloroformate are added and the mixture is heated to reflux for 3 hours. The reaction mixture is washed with 0.1M hydrochloric acid and brine, dried and concentrated. Amorphous product. TLC (system N3) Rf : 0.45.
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]1[C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=1[F:24])(=[O:3])[CH3:2].CO.[CH2:27](OCC)C.C[Si](C=[N+]=[N-])(C)C>ClCCl>[C:1]([N:4]1[C:8](=[O:9])[CH:7]=[C:6]([O:10][CH3:27])[N:5]1[C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:20])([F:21])[F:22])[C:14]([CH3:23])=[CH:13][C:12]=1[F:24])(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)N1C(=O)CC(=O)N1c1cc(SCC(F)(F)F)c(C)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(=O)n(C(C)=O)n1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Then, 1.50 g of 1-acetyl-2-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazolidine-3,5-dione was dissolved in 50 mL of dichloromethane, 5 mL of methanol was added, and 2.1 mL of a diethyl ether solution (2.0 mol/L) of trimethylsilyldiazomethane was added under cooling with ice, followed by stirring at room temperature for 5 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.69 g of 2-acetyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methoxypyrazol-3-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C([Li])CCC.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>O>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:20](=[NH:21])[C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)[CH3:2]
Reactant: Cc1ccc(C#N)cc1
Reactant: CCc1ccccc1N
Agent: [Li]CCCC
Solvent: O
Product: CCc1ccccc1NC(=N)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
Procedure as described for Amidine I using the following amounts: 6.18 mL of 2-ethylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was dark brown. Addition of water yielded a yellow solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 75 mL of pentane, stirred overnight, and filtered yielding 10.51 g (88%) of light yellow solid. 1H NMR (400 MHz, CDCl3): 7.79 (d, 2H), 7.25 (d, 3H), 7.17 (t, 1H), 7.02 (t, 1H), 6.86 (d, 1 H), 4.68 (s, 2H), 2.57 (q, 2H), 2.41 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: COC(=O)Cn1c(=O)oc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(=O)oc2cc(N)ccc21
Yield: 99 %

Procedure:
A mixture of methyl 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.570 g, 2.260 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH (30 ml) and ethyl acetate (30 ml) was hydrogenated in a Parr apparatus at 20 psi for 1 hour. The catalyst was filtered off and the solvent was removed affording methyl 2-(6-amino-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (0.497 g, 2.237 mmol, 99% yield). MS/ESI+ 222.9 [MH]+.