Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7].CO>O>[NH2:3][C:4]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)cc1C(O)c1ccccc1F
Reaction time: 16 h

Procedure:
A solution of 18.5 g of sodium borohydride in 125 ml of water is added dropwise at 20° to 25° within 20 minutes to a solution of 124.8 g of 2-amino-5-chloro-2'-fluorobenzophenone. The mixture is stirred for a further 16 hours. 250 ml of methanol are then added thereto and the mixture is heated to boiling under reflux for 15 minutes. After evaporation of the organic solvent, the residue is diluted with water, whereupon the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solutions are washed, dried, concentrated to 100 ml in vacuo and subsequently treated with 300 ml of petroleum ether. There is obtained crystalline 2-amino-5-chloro-2'-fluorobenzhydrol of melting point 97°-99°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>C(Cl)CCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][CH:35]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Solvent: ClCCCl
Product: CSc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 34 %

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid and 4-fluoroaniline by following the General Procedure for EDC couplings as disclosed in the general experimental section above. Crude reaction mixture was purified via flash chromatography (EtOAc:Hexanes, 2:1) to afford the title compound (0.125 g, 34%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@H:34]([CH3:35])[CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>>[CH2:21]([O:20][C:18]([C:13]1[N:14]([CH2:35][C@H:34]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH3:33])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: C[C@@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C[C@@H](C)NC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from ethyl 5-benzyloxyindole-2-carboxylate (commercially available), (R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/010169) and potassium tert-butoxide, to give the desired compound as a light yellow solid (>100%). The so-obtained product was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([CH:30]=O)[CH:24]=[CH:23]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClC(Cl)C>[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([CH2:30][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:24]=[CH:23]3)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc2cc(OCCCCc3ccccc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: c1ccc(CCCCOc2ccc3cc(CN4CCCCC4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution in 6-(4-phenylbutoxy)-2-formylnaphthalene (50 mg) in dichloroethane (0.5 mL), piperidine (20 μL) and triacetoxy sodium borohydride (72 mg) were added, followed by stirring at room temperature for 18 hours. The reaction mixture was added with a 1N aqueous sodium hydroxide solution, and then the mixture was extracted with chloroform. After concentrating the organic layer, the obtained residue was purified by silica gel column chromatography (dichloroform:methanol:acetic acid=120:10:1) to give the title compound (60 mg) having the following physical properties.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:28][CH:29]([CH3:32])[CH2:30][OH:31]>>[OH:31][CH2:30][CH:29]([NH:28][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])[CH3:32]
Reactant: CC(N)CO
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CC(CO)NC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-aminopropan-1-ol via General Procedure B. The product was purified via reverse phase HPLC to give 22.3 mg of 260. MS (Q1) 438.8 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>FC1C=C(C=CC=1)CN.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:4]4[CH:5]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: NCc1cccc(F)c1
Solvent: CCO
Product: O[C@H](CNCc1cccc(F)c1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 3-fluorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.O[N:16]=[C:17]([C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[NH2:18]>>[CH3:9][O:8][CH2:6][C:5]1[CH:4]=[C:3]([C:12]2[O:13][N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:21][CH:20]=3)[N:16]=2)[CH:2]=[CH:11][C:10]=1[C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: NC(=NO)c1ccc(N2CCCC2)nc1
Product: COCc1cc(-c2nc(-c3ccc(N4CCCC4)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and N′-hydroxy-6-pyrrolidin-1-ylpyridine-3-carboximidamide (UkrOrgSynthesis, BBV-073346). After purification by flash chromatography (silica, EtOAc/cHex) followed by a crystallization from a mixture of MTBE and heptane, the title compound was obtained as an off-white powder. HPLC (Method A), Rt: 4.1 min (purity: 99%). UPLC/MS, M+(ESI): 417.1, M−(ESI): 415.2. Elemental analysis: [C26H26N4O2-0.2H20] calculated: C, 72.60%; H, 6.19%; N, 13.03%. found: C, 72.68%; H, 6.45%; N, 13.05%.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:13][CH3:14])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[N+]([O-])(O)=O.[Br:19]Br>O.[N+]([O-])([O-])=O.[Ag+]>[Br:19][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:3][CH:2]([CH3:1])[CH2:13][CH3:14])[C:8]([OH:10])=[O:9]
Reactant: CC[C@H](C)Cc1ccc(C(=O)O)cc1
Reactant: BrBr
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCC(C)Cc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.1 %

Procedure:
A solution of silver nitrate (177 g, 1.1 mol) in water (500 ml) was dropwise added to a solution in water (500 ml), of a mixture of (S)-4-(2'-methylbutyl)benzoic acid (200 g, 1.0 mol), nitric acid (680 ml) and bromine (183 g, 1.1 mol), under ice-cooling, followed by agitating the mixture at room temperature for 5 hours, feeding it into ice water, filtering deposited crystals, adding a 10% sodium carbonate aqueous solution (2 l), sufficiently agitating the mixture, filtering off a remaining insoluble substance, acidifying the filtrate with sulfuric acid, filtering deposited crystals and recrystallizing from acetic acid (1 l) to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid (106.0 g, m.p. 78.8°-79.7° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[O:13])[N:6]=[CH:5]2.Cl[C:21]1[C:22]2[N:23]([CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:25][N:26]=1>C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:21]3[C:22]4[N:23]([CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:25][N:26]=3)[CH2:16]1)=[O:13])[N:6]=[CH:5]2
Reactant: O=C(N[C@H]1CCNC1)c1ncc2cc(Cl)ccc2n1
Reactant: Clc1nccn2cccc12
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc2cc(Cl)ccc2n1
Temperature: 90 °C
Yield: 6 %

Procedure:
To a solution of the crude amine in 0.16 mL of diisopropylethylamine was added 1-chloropyrrolo[1,2-a]pyrazine (0.047 g, 0.31 mmol) followed by 1 drop of 1-butyl-3-methylimidazolium tetrafluorborate. The reaction was heated at 90° C. for 20 h. Purification of the residue by HPLC afforded (S)-6-chloro-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)quinazoline-2-carboxamide (0.05 g, 0.013 mmol, 6%). 1H NMR (400 MHz, CD3OD) δ 9.60 (s, 1 H), 8.26(s, 1 H), 8.17 (d, J=9.1 Hz, 1 H), 8.07 (dd, J=1.8, 9.1 Hz, 1 H), 7.76 (d, J=1.5 Hz, 1 H), 7.72 (d, J=5.8 Hz, 1 H), 7.57 (s, 1 H), 6.93 (m, 1 H), 6.85 (d, J=5.8 Hz, 1 H), 5.06-4.84 (m, 1 H), 4.82-3.60 (br, 4 H), 2.65-2.40 (br, 2 H); MS: (ES) m/z calculated for C20H17ClN6O [M+H]+ 393.2, found 393.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:3]=1.[C:17]([C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21])([OH:19])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:25]2[CH:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:17]([OH:19])=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:3]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:5]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCc2ccsc2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCc2ccsc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 4.7 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-thiophen-3-ylmethyl-amine (216 mg, 0.84 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [312 mg, 1.5 mmol, see Example 49(b) step 2], Cs2CO3 (821 mg, 2.52 mmol), and tetrakis(triphenylphosphine) palladium (0) (92 mg, 0.08 mmol) in ethylene glycol dimethyl ether (2.5 mL) and water (0.5 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{2-methoxy-6-[(thiophen-3-ylmethyl)-amino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [15 mg, 4.6%, Example 71] as a solid. LCMS RT=1.94 minutes, MS: 384 (M+H). IC50=393 nM
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9]Br.C(Cl)(Cl)Cl.CO>C(OC)(C)(C)C>[Br:9][C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6]
Reactant: Oc1ccc(O)cc1
Reactant: BrBr
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of hydroquinone Q-1 (10 g, 90.90 mmol) in MTBE (methyl tert-butyl ether) (100 mL) at −5° C. was added bromine (17.4 g, 90.90 mmol). The reaction mixture was stirred at 0° C. for 30 min. Solvent was removed in vacuo and the crude product was purified by column chromatography (SiO2, 2% MeOH—CHCl3) to afford compound Q-2 (13 g, 75%) as a solid. TLC Rf=0.6 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 6.94 (app d, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.72 (dd, J=8.7, 2.8 Hz, 1H), 5.19 (s, 2H) (Synlett 2000, 11, 1561-1564).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][CH2:17]Br)=[O:14])=[O:8])(=[O:3])[CH3:2].N1C=CC=C(C(N)=[O:36])C=1>CO>[C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][CH2:17][OH:36])=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCCBr)c1
Reactant: NC(=O)c1cccnc1
Solvent: CO
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCCO)c1
Yield: 55.1 %

Procedure:
2-Bromoethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)amino]benzoate (compound of Example 123) (0.63 g) and 3-pyridinecarboxamide (0.17 g) are dissolved in methanol (10 ml), and the mixture is refluxed overnight. Methanol is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. Ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with silica gel (eluant, chloroform). The fractions containing the desired compound are collected, and chloroform is distilled off under reduced pressure to give the title compound (0.3 g) as an oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C(O)(=O)C>C(OCC)(=O)C>[CH3:42][C:2]1([CH3:1])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]12C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 38.6 %

Procedure:
In 10 ml of ethyl acetate was dissolved 400 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregn-6-en-5α-ol, followed by addition of 0.2 ml of acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 150 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene showing the following physical properties.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([Cl:9])[C:7]=1[CH3:8].C([Li])CCC.[Cl-].[NH4+]>C1COCC1>[Cl:9][C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[CH:2][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(Br)c(C)c1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(C)cc(C)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
3-bromo-5-chloro-6-methoxy-2,4-dimethylpyridine (930 mg) was added to THF (10 mL). The solution was cooled to −78° C., and n-butyllithium (2.6 M solution in n-hexane, 1.428 mL) was added, followed by stirring at the same temperature for one hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with DCM. The organic layer was washed with brine and dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (300 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[CH3:18][O:19][CH:20]([O:31][CH3:32])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](F)[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:23]2[CH:22]=[C:21]([CH:20]([O:31][CH3:32])[O:19][CH3:18])[CH:26]=[CH:25][C:24]=2[N+:27]([O-:29])=[O:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1ccccc1
Yield: 54.1 %

Procedure:
A mixture of 0.250 g (1 mmole) of 2-amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (V.1), 0.215 g (1 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene, 0.488 g (1.5 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 100 degrees overnight. The cooled mixture was diluted with 30 mL of water and then extracted three times with 20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 0.240 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VIA a) as an orange solid.
Reaction SMILES: [C:1]([CH:6]([C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36]2[O:41][CH2:42][O:43][C:35]=2[CH:34]=1)[O:7][C:8]1[C:13]([CH2:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH2:27][CH3:28])[C:19]2=[O:29])=[CH:10][C:9]=1[CH2:30][CH2:31][CH3:32])([O:3]CC)=[O:2].[OH-].[Na+]>CO>[C:1]([CH:6]([C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36]2[O:41][CH2:42][O:43][C:35]=2[CH:34]=1)[O:7][C:8]1[C:9]([CH2:30][CH2:31][CH3:32])=[CH:10][C:11]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH2:27][CH3:28])[C:19]2=[O:29])=[CH:12][C:13]=1[CH2:14][CH2:15][CH3:16])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(=O)n(CC)c3ccccc32)cc(CCC)c1OC(C(=O)OCC)c1cc(OC)c2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cn2c(=O)n(CC)c3ccccc32)cc(CCC)c1OC(C(=O)O)c1cc(OC)c2c(c1)OCO2
Temperature: 25 °C

Procedure:
The product from Step D was taken up in 10 mL of methanol and 4 mL 5N NaOH(aq) was added with stirring at room temperature. The reaction was stirred for 3 hours and the volatiles removed in vacuo. The resultant slurry was diluted with 50 mL H2O and acidified with 1N HCl (aq) and extracted with 3×20 mL ethyl acetate. The combined organics were concentrated in vacuo. Trituration of the resultant oil with ethyl ether gave 64 mg (82%-2 steps) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH3:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH3:17])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([C:24]([F:37])([F:23])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CCC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 11 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(1-trifluoromethyl-propoxy)-benzoic acid (Example A19) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 11%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: C([NH:4][C:5]1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[S:7][CH2:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[S:7][CH2:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C1=C(NC(C)=O)C(CCCCC(=O)N2CCCCC2)SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(N)C(CCCCC(=O)N2CCCCC2)SC1
Temperature: 22 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
To a solution of 8.2 g (.022 mole) of 3-acetamido-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid piperidide in 80 ml of methanol was added 40 ml of 1 N sodium hydroxide. The reaction was stirred at room temperature (22°C.) for 3 hrs. and was immediately worked up by first removing methanol under vacuum. The aqueous, basic residue was partitioned between 50 ml of water and 100 ml of methylene chloride. The basic, aqueous phase was extracted three times with 30 ml portions of methylene chloride. The methylene chloride was dried over sodium sulfate, filtered, and evaporated to afford 2.45 g (0.0075 mole, 34%) of 3-amino-4-carbomethoxy-2,5-dihydro-2-thiophenevaleric acid piperidide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:15]=[CH:14]3)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CN(C=O)C>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/c2ccc3c(=O)n(-c4ccccn4)ncc3c2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1c2ccc(/C=C/c3ccc(O)cc3)cc2cnn1-c1ccccn1
Temperature: 180 °C
Yield: 55 %

Procedure:
Trans-6-[2-(4-methoxyphenyl)ethenyl]-2-(2-pyridyl)-1(2H)-phthalazinone (7 g) and pyridine hydrochloride were thoroughtly mixed and heated to 180° C. for 21/2 hours. The solution was cooled to about 120° C.; then DMF (30 ml) was added followed by water (80 ml). The mixture was cooled to 20° C., filtered and the precipitate was washed with isopropanol. The solid mass was recrystallized from DMF to give 3.7 g of the phenol, mp=272° C.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=3[CH:21]=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:12][C:13]1[N:18]2[C:19]3[N:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=3[C:21]([I:8])=[C:17]2[CH:16]=[CH:15][N:14]=1)(=[O:11])[CH3:10]
Reactant: COc1ccnc2c1cc1ccnc(NC(C)=O)n12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: COc1ccnc2c1c(I)c1ccnc(NC(C)=O)n12
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
NIS (18 mg, 0.078 mmol) was portionwise added to a cooled (0° C.) solution of 9-Acetylamino-4-methoxypyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine (20 mg, 0.078 mmol) in CH2Cl2 (15 ml). The mixture was stirred for 15 min. The solution was diluted with CH2Cl2 (50 ml) and washed twice with water. The organic layer was dried and evaporated to obtain 20b (27 mg, 93%).