Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7](=O)OC(C)(C)C)=[CH:4][C:3]2[CH2:14][CH2:15][CH2:16][C:2]1=2.FC(F)(F)C(O)=O.C(OC=[C:28]1[C:33](=[O:34])[O:32][C:31]([CH3:36])([CH3:35])[O:30][C:29]1=[O:37])C>C(Cl)Cl>[S:1]1[C:5]([NH:6][CH:7]=[C:28]2[C:33](=[O:34])[O:32][C:31]([CH3:36])([CH3:35])[O:30][C:29]2=[O:37])=[CH:4][C:3]2[CH2:14][CH2:15][CH2:16][C:2]1=2
Reactant: CCOC=C1C(=O)OC(C)(C)OC1=O
Reactant: CC(C)(C)OC(=O)Nc1cc2c(s1)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CNc2cc3c(s2)CCC3)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl N-[4H,5H,6H-cyclopenta[b]thiophen-2-yl]carbamate (480 mg, 2.01 mmol, 1.00 equiv) in 15 mL of DCM was added trifluoroacetic acid (460 mg, 4.03 mmol, 2.00 equiv) at 0° C. After stirring at room temperature for 4 h, the resulting solution was concentrated under vacuum. The pH value was adjusted to 8 with saturated aqueous NaHCO3 solution and extracted with dichloromethane (60 mL×3). Then 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione [prepared by heating 2,2-dimethyl-1,3-dioxane-4,6-dione (580 mg, 4.02 mmol, 2.00 equiv) in 6.0 g of (diethoxymethoxy)ethane at 100° C. for 1 h followed by cooling to room temperature] was added to the above extracts. Drying over sodium sulfate followed by concentration in vacuo afforded 5-[([4H,5H,6H-cyclopenta[b]thiophen-2-yl]amino)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (0.54 g, 92%) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH2:21][O:22]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:11][CH2:12][P:13]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.Cl>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][OH:22])[O:11][CH2:12][P:13]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:19])[CH3:20])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)P(=O)(CO[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)P(=O)(CO[C@H](CO)COCc1ccccc1)C(C)C

Procedure:
Compound 5 (31 g) was stirred 4 h with a mixture of dioxane (250 mL) and 1 M HCl (250 mL) till the starting material disappeared (approx. 3 h). Ethyl acetate (500 mL) was added, and the aqueous phase after extraction washed twice more with ethyl acetate (250 mL each). The combined extracts were washed with saturated NaHCO3 solution (2×300 mL) dried with MgSO4 and evaporated in vacuo to give the chromatographically pure material 6 which was directly used for further steps.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:13])=[O:14])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH:17]=1)(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)CC(C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.18 g, 0.34 mmol) in dichloromethane (10 mL) and water (0.1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 2 hours at room temperature. The reaction was then concentrated under reduced pressure to yield a colorless oil. The residue was purified by HPLC using a gradient of 10% to 50% acetonitrile containing 0.1% TFA and water at containing 0.1% TFA over 140 minutes to yield 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid as a lyophilized as a white solid (0.045 g, 28%). MS(APCI) m/z 471.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][NH:11][C:18]([CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[O:19])=[CH:6][CH:7]=1
Reactant: NCCSc1ccc(Cl)cc1
Reactant: O=C(O)C1CCOCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(NCCSc1ccc(Cl)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8203.6 %

Procedure:
To a solution of 2-[(4-chlorophenyl)sulfanyl]ethanamine (15.32 g, 82 mmol, prepared from 4-chlorothiophenol and 2-chloroethylamine as described before) in DMF (247 ml) was added sequentially tetrahydro-2H-pyran-4-carboxylic acid (9.66 g, 74.2 mmol), EDC (15.65 g, 82 mmol) and HOAt (2.021 g, 14.85 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with 1N HCl, aq NaHCO3, 3M LiCl, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica 1 kg, 50 to 100% EtOAc in hexane), to give N-{2-[(4-chlorophenyl)sulfanyl]ethyl}tetrahydro-2H-pyran-4-carboxamide (1825 g). MS: M+H=300. H1NMR (400 MHz, CDCl3) δ: 7.31 (d, J=9.9 Hz, 2H), 7.26 (d, J=9.9 Hz, 2H), 5.82 (br s, 1 H), 4.40-3.96 (m, 2H), 3.46 (dt, J=7.0, 7.0 Hz, 2H), 3.45-3.36 (m, 2H), 3.05 (t, J=7.0 Hz, 2 H), 2.34-2.26 (m, 1H), 1.82-1.65 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH:2]=1.Cl>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=1
Reactant: OC(Cc1cccnc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: C(=Cc1cccnc1)c1ccccc1
Yield: 71.5 %

Procedure:
A mixture of crude 2-(3-pyridyl)-1-phenylethanol (20 g), glacial acetic acid (200 ml) and concentrated HCl (50 ml) is refluxed for 16 hours, then evaporated to dryness in vacuo. The oily hydrochloride is taken up in water, extracted with ether and methylene chloride, and then liberated with bicarbonate. Extraction (CH2Cl2) and drying (K2CO3) affords 13 g of β-(3-pyridyl)styrene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[F:18])[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[F:18])[C:12]([NH:22][C:21]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:20]=2[F:19])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(Cl)c3)c2)c1

Procedure:
A solution of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid (2.22 g, 8.29 mmol), 2-fluoro-5-methylaniline (1.56 g, 12.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 3.78 g, 9.95 mmol) and N-methylmorpholine (2.00 mL, 18.2 mmol) in dimethylformamide (22 mL) was heated at 90° C. for 2 h. The solvent was evaporated in vacuo at 50° C. To the residue was added water resulting in a thick oil. The water was decanted and the oil dissolved in EtOAc then extracted twice with water, 1M hydrochloric acid and brine. The organic layer was dried (MgSO4), filtered and evaporated to crude 6 (3.37 g). Trituration with dichloromethane (25 mL) gave 3-(2-Chloropyridin-4-yloxy)-4-fluoro-N-(2-fluoro-5-methylphenyl)benzamide as white solid. Yield: 1.788 g, 58%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCc1c[nH]c2ccc(N)cc12

Procedure:
The product from Example 2 (0.05 mmol) is taken into ethanol (3 mL) and hydrogenated 6 h at 3 atmospheres of H2 pressure over a catalytic amount of 10% Pd/C. The catalyst is removed by filtration through Celite and the solvent removed in vacuo, affording the title compound. This product is somewhat air sensitive and is used immediately for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:41][N:42](C=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([NH:42][CH3:41])=[O:25])=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(c2ccc(C(=O)O)cn2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of the compound (0.150 g) obtained in Example 500 in THF (5 mL) were added oxalyl chloride (38 μL) and DMF (3 μL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and to a solution of the residue in THF (2 mL) was added a solution of methylamine (0.0269 g) in THF (5 mL), and the mixture was stirred for 10 min. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (0.039 g, 25%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]4[C:18](=O)[C:17](=[O:20])[C:16]=4[O:21]CC)[CH2:11]3)[CH2:9][N:8]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:5]2=[CH:6][CH:7]=1.[CH3:33][NH2:34].O1CCCC1.N.CO>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]4[C:16](=[O:21])[C:17](=[O:20])[C:18]=4[NH:34][CH3:33])[CH2:11]3)[CH2:9][N:8]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:5]2=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOc1c(N2CCC3(C2)CN(C(=O)Nc2ncc(Cl)s2)c2ccc(Cl)cc23)c(=O)c1=O
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CNc1c(N2CCC3(C2)CN(C(=O)Nc2ncc(Cl)s2)c2ccc(Cl)cc23)c(=O)c1=O

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 45, with the exceptions that the 5-chloro-N-(5-chlorothiazol-2-yl)-1′-(2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained in Example 450 was used instead of ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate, and that a solution of methylamine-tetrahydrofuran was used instead of a saturated solution of ammonia-methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:11][CH:10]([O:12][C:13]2[C:18]([C:19]3[CH2:20][CH2:21][O:22][CH2:23][CH:24]=3)=[CH:17][N:16]=[C:15](Cl)[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:9][CH:10]([O:12][C:13]2[C:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][N:16]=[CH:15][N:14]=2)[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)ncc2C2=CCOCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CC(Oc2ncncc2C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of {3-[2-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-pyrimidin-4-yloxy]-cyclobutyl}-carbamic acid tert-butyl ester (2.2 g, 5.76 mmol) in MeOH (40 mL) was added Pd/C (1.0 g). The reaction solution was stirred at room temperature overnight under H2 atmosphere. LCMS showed that the staring material was consumed completely. The mixture was filtered and concentrated to give the product (1.2 g, 3.44 mmol, yield: 60%). ESI-MS (M+1): 350 calc. for C18H27N3O4 349.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41]C(OCC[Si](C)(C)C)=O)[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]>[N+](C)([O-])=O.[Cl-].[Zn+2].[Cl-]>[NH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]/[CH:35]=[CH:34]/[C@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCNC(=O)OCC[Si](C)(C)C)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCN)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-propyl-10-(2-trimethylsilanyl-ethoxycarbonylamino)-dec-4-enoate (298 mg, 0.415 mmol) was dissolved in nitromethane (1.5 mL), and zinc chloride (235 mg, 1.72 mmol) was then added at room temperature. The mixture was stirred for 4 hours, and then purified by preparative HPLC to obtain 192 mg (0.335 mmol, 81% yield) of tert-butyl (E)-(2S,3S)-10-amino-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-propyl-dec-4-enoate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@@H:4]1[C:7]([O:9][CH3:10])=[O:8].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.CC1(C)N([O])C(C)(C)CCC1.O>C(Cl)Cl>[CH:2]([C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9][CH3:10])=[O:8])=[O:1]
Reactant: COC(=O)[C@H]1CC[C@H]1CO
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H]1CC[C@H]1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
To a stirred solution of (1S,2R)-methyl 2-(hydroxymethyl)cyclobutanecarboxylate (100 mg, 0.694 mmol) in DCM (5 mL) was added bis(acetoxy)iodobenzene (335 mg, 1.040 mmol) and TEMPO (10.84 mg, 0.069 mmol) at 0° C. The temperature of the reaction was allowed to slowly warm to RT and stirred for 6 h. Water was added to reaction mass and the compound was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 40% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford Intermediate 238A as yellow oil (50 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1H) 3.71 (s, 3H), 3.69-3.36 (m, 2H), 2.31-2.16 (m, 4H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])[CH3:11].Cl[CH2:18][O:19][CH3:20]>ClCCl>[CH3:18][O:19][CH2:20][O:16][CH2:15][CH2:14][CH2:13][C:10](=[O:12])[CH3:11]
Reactant: COCCl
Reactant: CC(=O)CCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCCC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Compound 27 intermediates: To diisopropylethyl amine (18.48 g, 143 mmol) in 200 mL of dichloromethane was added 3-acetyl-1-propanol (13.28 g, 130 mmol) at 0° C. After the solution was stirred for 0.5 hour, chloromethylmethyl ether (13.08 g, 162.5 mmol) was added while the temperature was maintained at 0° C. The resulting solution was stirred for another 1 hour, brought to room temperature and stirred overnight. Organic solvent was removed via rotary evaporation. The residue was treated with 100 mL of brine and extracted with 3×150 mL of diethyl ether. The organic layers were combined, dried over Na2SO4 and concentrated via rotary evaporation. The crude product was purified via a flash chromatography with dichloromethane as eluent to afford 5-methoxymethoxy-2-pentanone (14.3 g, yield: 75) as a pale oil.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C>[CH3:46][C:42]1[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=1)[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Cc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(Cc2cc(O)c(=O)[nH]n2)c1

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-methylphenyl)methyl]pyridazine (Intermediate 57) except that the solvent mixture used for the hydrogenation was made up from tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2(O)[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[CH3:39][C@:16]12[CH2:15][CH2:14][C@H:13]([O:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH3:40])[CH2:29][C@H:28]1[CH2:27][CH2:26][C@@H:25]1[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:38])[C:24]1=[CH:23][CH2:22][C@@H:21]2[C:31]1[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](c5ccc(=O)oc5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl) hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-(tert-butoxy carbonylamino)propanoate (35 mg, 0.063 mmol, 1 eq) in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to room temperature after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC(CH2Cl2:MeOH=10:1) to afford the (S)-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-aminopropanoate. LCMS (M+H+) m/z 440.8.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][C:13]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:16]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:15][C:14]=1[C:35]1[O:39][N:38]=[C:37]([CH3:40])[C:36]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)C1C=CC=CC=1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:36]2[C:37]([CH3:40])=[N:38][O:39][C:35]=2[C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:17]([OH:19])=[CH:18][C:13]=2[OH:12])=[CH:46][CH:45]=1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(C=Cc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: ClB(Cl)Cl
Product: COc1ccc(-c2c(C)noc2-c2cc(C=Cc3ccccc3)c(O)cc2O)cc1

Procedure:
Similarly, 4-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-6-styryl-benzene-1,3-diol (Example 24) was prepared by boron trichloride deprotection of 5-(2,4-Bis-benzyloxy-5-styryl-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (prepared from styryl boronic acid coupling of bromo isoxazole intermediate, Example 3))
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([O:39]C)=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:10]([C:37]([OH:39])=[O:38])=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:23][CH2:24]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(N2CCN(CCCCNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCN1CCN(c2nc(C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(4-(4-(tert-butoxycarbonylamino)butyl)-piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 4.1; 1.2 mmol) in a mixtire of methanol (2.5 ml) and water (2.5 ml) was added sodium hydroxide (2.5 mmol). The reaction mixture was stied at r.t. for 4 hr. The mixture was quenched with water and 2N HCl until pH=6 was reached. The mixture was extracted with AcOEt (2×). The organic layer was dried (MgSO4), and filtered to afford a solid (400 mg), that was used as such in the next step.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cc(F)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(F)ccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Yield: 79.1 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-fluoraniline, 3.5 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2), whereby 3.0 g of 2-fluoromethyl-3-(2-methyl-4-fluorophenyl)-6-nitro-4(3H)-quinazolinone are obtained as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[BH4-].[Na+].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:17])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Br)ccc1CBr
Yield: 73.4 %

Procedure:
Treat a mixture of 4-bromo-2-(trifluoromethyl)benzaldehyde (6.52 g, 25.8 mmol) and methanol (250 mL) in a 500 mL flask with sodium borohydride (778 mg, 20.6 mmol). Stir the reaction at room temperature for 1 hour then dilute with ethyl acetate (300 mL). Wash with water (2×200 mL) and saturated sodium chloride solution (1×200 mL), then dry over anhydrous magnesium sulfate. After filtering, concentrate the solution under vacuum to dryness. Add dimethylformamide (250 mL) to the residue and cool in an ice bath before treating with carbon tetrabromide (12.78 g, 38.5 mmol) and triphenylphosphine (10.11 g, 38.5 mmol) for 3 hours. Add ethyl acetate (300 mL) and wash with water (2×200 mL) then saturated sodium chloride solution (1×200 mL). Dry over anhydrous magnesium sulfate and concentrate under vacuum. Purify the crude product via silica gel chromatography eluting with hexanes to afford 6.02 g (74%) of the product as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, 1H, J=1.9 Hz), 7.68 (dd, 1H, J=1.9 Hz, J=8.3 Hz), 7.47 (d, 1H, J=8.3 Hz), 4.57 (s, 2H).