Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([S:36]([NH2:39])(=[O:38])=[O:37])[S:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:31]2[CH:32]=[C:33]([S:36]([NH2:39])(=[O:38])=[O:37])[S:34][CH:35]=2)=[CH:16][CH:17]=1
Reactant: NS(=O)(=O)c1cc(Br)cs1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: CCO
Product: C[C@H](Oc1ccc(-c2csc(S(N)(=O)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
Prepared by the method outlined in Example 15g) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.200 g, example 15f)), 4-bromothiophene-2-sulfonic acid amide (0.145 g, Example 42a)), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) in ethanol (3 ml). The mixture was heated at 90° C. for 4 hours and after cooling to room temperature the mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to afford the title compound as a solid (0.134 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:23]([O-])=O)[CH:8]=2)[N:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:21])[CH3:22])=[CH:16][CH:15]=1)[CH3:13]
Reactant: Cc1nc(N(C)c2ccc(N(C)C)cc2)c2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N(C)c2ccc(N(C)C)cc2)c2cc(N)ccc2n1
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of (2-methyl-6-nitroquinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine (214 mg, 0.634 mmol) in 20 mL of ethyl acetate and methanol (1:1) with 5% Palladium on carbon was hydrogenated at 70 psi for 5 h. The reaction mixture was filtered and concentrated. The crude product was purified by chromatography (5% methanol/methylene chloride) to give the title compound (195 mg, 0.634 mmol, 100%). 1H NMR (CDCl3): 7.58 (d, J=8.7, 1H), 7.02 (m, 2H), 6.97 (dd, J=9.0, 2.7, 1H), 6.69 (m, 2H), 6.21 (d, J=2.4, 1H), 3.54 (s, 3H), 3.45 (s, broad, 2H), 2.97 (s, 6H), 2.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(O[CH:13]=[C:14]([C:20](=[O:33])[C:21]1[CH:26]=[C:25]([F:27])[C:24]([N+:28]([O-:30])=[O:29])=[C:23]([CH3:31])[C:22]=1F)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C([O-])(=O)C=C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:22]3[C:21](=[CH:26][C:25]([F:27])=[C:24]([N+:28]([O-:30])=[O:29])[C:23]=3[CH3:31])[C:20](=[O:33])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13]2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Agent: C=CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2C)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
A solution of 4-fluoro-2-methylaniline (about 1 g) in chloroform (5 ml) was added dropwise to a solution of ethyl 3-ethoxy-2-(2',5'-difluoro-3'-methyl-4'-nitrobenzoyl)acrylate (2.0 g) in chloroform (10 ml) at room temperature (while confirming the disappearance of the acrylate by tlc). After the mixture was stirred for 10 minutes, the solvent and the like were distilled off. Potassium carbonate (800 mg) was added to a solution of the whole amount of the residue in dimethylformamide (3 ml), and the mixture was stirred at 110° C. for 20 minutes. Chloroform and water were added to the reaction mixture to collect an organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Ethanol was added to the residue to disperse it therein, and filtration was conducted to obtain the title compound (1.1 g) as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2Br)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1C(=O)NN=C2COc3cc(Nc4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 13.9 %

Procedure:
A solution of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Example #1, Step B, 0.1 g, 0.21 mmol), aniline (0.06 g, 0.64 mmol), Pd2(dba)3 (0.039 g, 0.04 mmol), Xantphos (0.0496 g, 0.09 mmol), and Cs2CO3 (0.14 g, 0.43 mmol) in anhydrous dioxane (10 mL) was heated at 130° C. for 14 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo, The residue was purified by chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-7-phenylamino-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.014 g, 14%) as brown solid. LC/MS (Table 1, Method 2) Rt=1.205 min; MS m/z: 542 [M+23+41]+
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Br:18])[CH:13]=1.[NH2:20][C:21]1[C:29]2[C:25](=[CH:26][N:27]([CH3:30])[N:28]=2)[C:24]([F:31])=[CH:23][CH:22]=1>>[Br:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:20][C:21]2[C:29]3[C:25](=[CH:26][N:27]([CH3:30])[N:28]=3)[C:24]([F:31])=[CH:23][CH:22]=2)=[O:19])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Reactant: Cn1cc2c(F)ccc(N)c2n1
Product: Cn1cc2c(F)ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)c2n1

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(4-fluoro-2-methyl-2H-indazol-7-yl)-benzamide was prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester and 7-amino-4-fluoro-2-methyl-2H-indazole in analogy to the procedures detailed in Example 4A; 1H-NMR (300 MHz, d6-DMSO) 9.86 (1H, s), 8.60 (1H, s), 8.32 (1H, d), 8.13 (1H, t), 7.83 (1H, d), 7.58-7.61 (2H, m), 7.42 (1H, d), 7.30 (1H, t), 6.82 (1H, dd), 6.72 (1H, t), 6.59 (1H, d), 4.52 (2H, d), 4.22 (3H, s); m/z (ES+) 454, 456 [M+H, Br isotopes]+.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[S:6](=[O:18])(=[O:17])[N:5]=1)C.C[Si]([NH:23][Si](C)(C)C)(C)C>C(#N)C>[NH2:23][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[S:6](=[O:18])(=[O:17])[N:5]=1
Reactant: CCOC1=NS(=O)(=O)C(C(=O)N(C)C)=C1OCC
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: CCOC1=C(C(=O)N(C)C)S(=O)(=O)N=C1N

Procedure:
To a solution of 60% pure 3,4-diethoxy-5-dimethylcarbamylisothiazole-1,1-dioxide (1.3 g) from Part C in acetonitrile (7 ml), under nitrogen, was added hexamethyldisilizane (0.90%, 4.3 mmol). This solution was heated at 50° for four hours. The reaction was then quenched with methanol (0.5 ml) and the solvent evaporated. This residue was chromatographed on silica gel eluting with 40% methanol/chloroform and the collected product residue triturated with ether to give 0.61 g, of title compound (mp 221°-223°).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].CC(C[AlH]CC(C)C)C.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][C:13]([F:14])([F:16])[F:15]
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled and stirred solution of methyl 4-bromo-3-(trifluoromethoxy)benzoate (28.2, 2.60 g, 8.70 mmol) in THF (20 mL) under nitrogen, was added DIBAL-H (19.2 mL, 1.0 M in toluene) at −78° C. The reaction mixture was stirred at 0° C. for 10 minutes and 5.0 mL of water was added. The resulting mixture was stirred at room temperature for 2 hours. The solid was then filtered off. EtOAc (100 mL) was added, and the mixture was washed with brine (20 mL) and dried with Na2SO4. The solvent was removed to give 28.3. 1H NMR (CDCl3) δ 1.91 (s, 1H), 4.71 (s, 2 H), 7.18 (d, J=6.3 Hz, 1H), 7.36 (s, 1H), 7.63 (d, J=6.3 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)o1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C@@:9]2([CH:21]=[O:22])[CH2:11][C@H:10]2[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([C@@:9]2([CH2:21][OH:22])[CH2:11][C@H:10]2[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
Sodium borohydride (1.2 g, 32.2 mmol, 1 eq) was added in one portion to a mixture of (1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropanecarbaldehyde (7.8 g, 29.3 mmol, 1 eq), accessed via the method of Preparation 19B, in 100 mL ethyl alcohol at ambient temperature. The reaction was stirred at ambient temperature for 18 h, concentrated down and the residue partitioned between ethyl acetate and brine. The organics were dried over Na2SO4, filtered and concentrated to give a yellow oil. The crude material was purified by flash chromatography (SiO2, eluted successively with hexanes and EtOAc/hexanes (1:4)) to give the title product (7.8 g, 29.06 mmol, 99%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 7.31-7.15 (m, 10H), 4.61 (t, J=5.7 Hz, 1H), 4.30-4.17 (m, 2H), 3.53-3.48 (m, 1H), 3.35-3.31 (m, 1H), 3.02-2.95 (m, 2H), 1.40-1.33 (m, 1H), 0.96-0.93 (m, 1H), 0.72-0.69 (m, 1H). ES-LCMS m/z 291.2 (M+Na).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC.[I-].[Zn+2].[I-].O>[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]([OH:11])[CH2:5][NH2:6]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Solvent: O
Product: NCC(O)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trimethylsilyl cyanide (8.5 g) was added to a stirred mixture of 2-fluorobenzaldehyde (10.6 g) and zinc iodide (500 mg) in dry ether (150 ml). The mixture was stirred at ambient temperature for 24 hours and was then added dropwise to a stirred suspension of lithium aluminium hydride (3.2 g) in dry ether (50 ml) under nitrogen. The mixture was refluxed for 2 hours, cooled and water (3.2 ml), 2 N sodium hydroxide solution (3.2 ml) and water (9.6 ml) slowly added. The precipitate was filtered off, the filtrate was dried (MgSO4) and evaporated to a yellow oil (13.0 g) which crystallised slowly on standing.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:26][C:25]4([CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[O:24][CH2:23][CH2:22]3)=[O:20])[N:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[C:8]1([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:26][C:25]4([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[O:24][CH2:23][CH2:22]3)=[O:20])[N:18]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1csc(-c3ccccc3)n1)CCO2
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3.8 mL) was added to a solution of tert-butyl 4-(2-phenylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 112, step a) (0.85 mg) in DCM (15.2 mL). The resulting mixture was stirred at RT for 1 h. Toluene (30 mL) was added and the mixture was evaporated in vacuo. The yellow residue was dissolved in MeOH and applied to a SCX cartridge pre-wetted with MeOH. The cartridge was washed with MeOH and eluted with 2M ammonia in MeOH. The eluent was evaporated in vacuo to give the subtitled compound as a brown oil. Yield 0.629 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.O.ClCCl.Br[CH2:14][C:15](OCC)=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:14][C:15](=[O:16])[N:8]=2)[CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: ClCCl
Product: O=C1CN2C=C(Br)C=CC2=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.0 g of 5-bromopyridin-2-ylamine in 5.8 ml of ethyl 2-bromoacetate are placed in a round-bottomed flask and stirred at ambient temperature for 48 h. A precipitate forms, and is recovered by filtration, washed with diethyl ether and oven-dried under reduced pressure. The solid is then taken up in 50 ml of ethanol, and 2.18 g of sodium hydrogencarbonate are added thereto. The reaction mixture is heated at the reflux of the solvent for 5 h, cooled to ambient temperature, and then concentrated under reduced pressure. The residue obtained is taken up between water and dichloromethane and the organic phase is separated, dried and concentrated under reduced pressure. 1.46 g of compound, used as it is in the subsequent stages, are obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]=2[CH2:11][O:10][CH2:9]1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)(Cl)Cl.CO.O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:4][C@@H:3]1[N:8]1[C:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]=2[CH2:11][O:10][CH2:9]1
Reactant: N#CCC(=O)O
Reactant: C[C@@H]1CCNC[C@@H]1N1COCc2cnc3[nH]ccc3c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N1COCc2cnc3[nH]ccc3c21
Yield: 11.4 %

Procedure:
rac-1-[(3R,4R)-4-Methylpiperidin-3-yl]-1,2,4,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[4,3-d][1,3]oxazine (21.2 mg, 0.0777 mmol) in N,N-dimethylformamide was stirred with cyanoacetic acid (15 mg, 0.18 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67 mg, 0.18 mmol), N,N-diisopropylethylamine (44.9 μL, 0.264 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: chloroform/methanol=20/1 (v/v)) to give the title compound as a yellow oil (3 mg, yield 10%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cc(F)cc(F)c2)s1
Yield: 34.3 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 3,5-difluorophenylboronic acid (9 mg, 0.06 mmol) giving 7.2 mg (34%) of the title compound. MS (ESI+) calcd for C17H11F2N5O2S2 419.032222, found 419.032222.
Reaction SMILES: [Br:1]CCCC#CC1C=C(NC(C2C=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=CC=2)=O)C=CC=1.O[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([N:66]([CH3:101])[C:67]([C:69]2[CH:70]=[C:71]([S:75]([C:78]3[CH:79]=[C:80]4[C:85](=[C:86]([CH3:88])[CH:87]=3)[N:84]=[CH:83][C:82]([C:89]([NH2:91])=[O:90])=[C:81]4[NH:92][C:93]3[CH:98]=[CH:97][CH:96]=[C:95]([O:99][CH3:100])[CH:94]=3)(=[O:77])=[O:76])[CH:72]=[CH:73][CH:74]=2)=[O:68])=[CH:62][CH:61]=1>>[Br:1][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([N:66]([CH3:101])[C:67]([C:69]2[CH:70]=[C:71]([S:75]([C:78]3[CH:79]=[C:80]4[C:85](=[C:86]([CH3:88])[CH:87]=3)[N:84]=[CH:83][C:82]([C:89]([NH2:91])=[O:90])=[C:81]4[NH:92][C:93]3[CH:98]=[CH:97][CH:96]=[C:95]([O:99][CH3:100])[CH:94]=3)(=[O:77])=[O:76])[CH:72]=[CH:73][CH:74]=2)=[O:68])=[CH:62][CH:61]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCO)cc5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCBr)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 98, using Intermediate 79 in place of Intermediate 77. ES/MS calcd. for C42H48BrN4O6S+ 815.3. Found m/z=815.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6](/[CH:8]=[CH:9]/[C:10](=[O:25])[CH2:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH:7]=1.CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[OH:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([CH2:14][CH2:13][C:12](=[O:24])[CH2:11][C:10](=[O:25])[CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=2[O:26][CH3:27])[CH:20]=1
Reactant: COc1ccc(O)cc1/C=C/C(=O)CC(=O)/C=C/c1cc(O)ccc1OC
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: COc1ccc(O)cc1CCC(=O)CC(=O)CCc1cc(O)ccc1OC

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1,7-bis(5-hydroxy-2-methoxyphenyl)hepta-1,6-diene-3,5-dione (19 mg, 52 μmol, synthesized in Example 255) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=60/40 to 50/50. The product was obtained as a solid (14.0 mg, 73%) having the following characteristics.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[C:10]([CH2:36][CH:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)[CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(CC2CCCCC2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.54 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (0.4 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)-ethoxy]-2-cyclohexylmethyl-phenoxy}-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ8.23 (s, 1H), 7.95 (dd, 1H, J=7.8 Hz, J=1.0 Hz) 7.64-7.69 (m, 3H), 7.50-7.54 (m, 1H), 7.46 (t, 2H, J=7.6 Hz), 7.37-7.39 (m, 1H), 6.77 (d, 1H, J=8.3 Hz), 6.66 (d, 1H, J=3.4 Hz), 6.62 (dd, 1H, J=8.8 Hz, J=2.9 Hz), 4.17 (t, 2H, J=6.4 Hz), 3.03 (t, 2H, J=6.4 Hz), 2.41 (s, 3H), 1.62-1.65 (m, 5H), 1.52 (s, 6H), 1.44 (s, 2H), 1.15-1.19 (m, 4H), 0.85-0.91 (m, 2H), MS (ES) m/e 554.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[F:1][C:2]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Cc1cccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F
Product: Cc1cccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.29 g, 0.0059 mol), N-[3-(2-fluoro-3-methylbenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (2.0g, 0.0049 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.59g, (84.5%), m.p. 179°-181 ° C.