Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([O:28]C)[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[NH4+].O>C(Cl)Cl>[CH:5]1([CH2:10][CH:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:28])[CH:21]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1OC
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A 1.0M solution of boron tribromide in methylene chloride (7.43 mL, 7.43 mmol) at 25° C. was treated with a solution of 3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 113, 0.27 g, 0.74 mmol) in methylene chloride (7.43 mL). This solution was stirred at 25° C. for 1 h. At this time, the reaction was cooled to 0° C. and treated with a dilute aqueous ammonium hydroxide solution. This mixture was stirred at 0° C. for 20 min. At this time, the reaction was poured into water and was extracted with chloroform (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide (38.8 mg, 15.7%) as a white solid: mp 170–173° C.; EI-HRMS m/e calcd for C17H20N2O3S (M+) 332.1194 found 332.1192.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[N:6][N:7]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][NH:10][C:11]4([CH2:14][CH2:13]4)[CH2:12][N:7]3[N:6]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC12CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNC1(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of Intermediate 350G (0.29 g, 0.689 mmol) in DCM (5 mL) was added TFA (3 mL) and the resulting solution was stirred at RT for 2 h. The volatiles were removed under reduced pressure. The residue was basified with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 350H as a yellow solid (0.2 g, 85%). MS(ES): m/z=321 [M+H]+; 1H NMR (300 MHz, chloroform-d) δ ppm 7.71 (dd, J=7.2, 2.3 Hz, 1H), 7.51 (ddd, J=8.3, 4.5, 2.3 Hz, 1H), 7.33-7.11 (m, 1H), 5.33 (br. s., 2H), 4.40 (s, 2H), 4.03 (s, 2H), 1.02-0.88 (m, 2H), 0.80-0.59 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34][CH2:35]C)[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(OC)OC)[CH3:2].[C:38](OCC)(=[O:40])C.CCCCCC>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[NH:5][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:40][CH3:38])[CH:19]=1)[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OCC)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reaction time: 15 h
Yield: 80 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-ethoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (12.0 g, 28 mmol) in ethyl acetate (120 mL) and ethanol (60 mL) solution was added 10% Pd/C (2.4 g). The mixture was hydrogenated at 1 atm for 15 hrs. The solution was filtered through a Celite® plug and evaporated to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester as a colorless oil. (10 g, 80% yield).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:26]=[C:25]([S:37][CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)[N:26]=[C:25]([S:37][CH3:38])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CCN(C)CC2)n1
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
((2R)-2-(Cyclopentylmethyl)-3-{2-[5-fluoro-6-(4-methyl-1-piperazinyl)-2-(methylthio)-4-pyrimidinyl]hydrazino}-3-oxopropyl)(tetrahydro-2H-pyran-2-yloxy)formamide (2.5 g, 22.58 mmol) was dissolved in acetic acid/water (4:1, 1 L) and stirred at RT for 3 days. The reaction mixture was concentrated to dryness and co-evaporated with toluene (20 mL) followed by methanol (50 mL)/triethylamine (20 mL). The residue was dissolved in methanol (120 mL) and triethylamine (20 mL) and purified by Gilson HPLC (10-95% acetonitrile/water, 8 min gradient time) to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[5-fluoro-6-(4-methyl-1-piperazinyl)-2-(methylthio)-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide as a reddish foamy solid (6.90 g, 65.1%). LCMS: (M+H)+: 470.2.
Reaction SMILES: [N:1]([C@H:4]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[CH:5]=[O:6])=[N+]=[N-].[OH:15][CH:16]1O[C@H](CO)[C@H](O)[C@H](O)[C@H:17]1N>>[C:16]([NH:1][C@@H:4]1[C@@H:7]([OH:8])[C@@H:9]([OH:10])[C@@H:11]([CH2:13][OH:14])[O:12][CH:5]1[OH:6])(=[O:15])[CH3:17]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reactant: [N-]=[N+]=N[C@@H](C=O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
The process which comprises reacting an anomeric mixture of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl nitrate with sodium acetate in acetic acid to form the 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-D-galactopyranosyl acetates, isolating said product, hydrolyzing said isolated product in an aqueous acid to provide 2-azido-2-deoxy-D-galactose, and reducing the 2-azido-2-deoxy-D-galactose and then N-acetylating the D-galactosamine product to form N-acetyl-D-galactosamine.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20]CCCCCCCCCCO)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54]>>[Si:1]([O:18][CH2:19][CH2:20][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCC#CC#CCCCCCCCCCO
Reactant: CC(C)(C)[Si](OCCCCCCCCCCCCO)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OCCCCCCCCCC#CC#CCCCCCCCCCO)(c1ccccc1)c1ccccc1
Yield: 26 %

Procedure:
This substance was synthesized following the same procedure as for (1) and obtained in comparable yields using 9.40 g of (3) (28.1 mmol) as diol component. 4.25 g of 1-(tert-Butyldiphenylsilyl)oxy-10,12-Docosadiyne-22-ol (7.24 mmol) was obtained in a yield of 26%. 1H NMR (250.13 MHz): δ (ppm)=1.05 (s, 9H, tert-butyl), 1.26 (br, 20H, —CH2—CH2—CH2—CH2—CH2—), 1.53 (m, 8H, —O—CH2—CH2— and —C≡C—CH2—CH2—), 2.24 (t, 4H, 3J=6.8 Hz, —C≡C—CH2—), 3.64 (t, 2H, 3J=6.5 Hz, —Si—O—CH2), 3.65 (t, 2H, 3J=6.5 Hz, HO—CH2—), 7.40 (m, 6H, phenyl), 7.69 (m, 4H, phenyl). 13C NMR (75.48 MHz): δ (ppm)=25.69, 25.72, 26.9, 28.30, 28.34, 28.8, 29.00, 29.04, 29.30, 29.34, 29.4, 32.5, 32.8, 63.1, 64.0, 127.5, 129.5, 134.1, 135.6.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>C(O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[C:3]([O:5][CH2:6][CH3:7])[C:2](=[O:1])[CH2:8][CH2:9][CH3:10])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCCC(=O)C(=NNc1ccc([N+](=O)[O-])cc1)OCC
Reaction time: 0.5 h

Procedure:
To a solution of the ester (D28) (0.53 g, 3.6 mM) in ethanol (20 ml) was added 4-nitrophenylhydrazine (0.56 g, 3.6 mM) and the suspension stirred for 0.5 h. Concentrated hydrochloric acid (2 ml) was added to give a brown solution. After stirring for 0.5 h the solution was cooled in ice and the precipitated title compound filtered off (0.72 g; 69%).
Reaction SMILES: C(N1CCC(OC2C=CC3N4CCCNC(=O)C4=CC=3C=2)CC1)(C)C.[CH2:26]([O:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]1)=[C:35]([Br:50])[CH:34]=2)=[O:30])[CH3:27].[C:51]([O:55][C:56]([N:58]1[CH2:62][C@H:61]([CH3:63])OS1(=O)=O)=[O:57])([CH3:54])([CH3:53])[CH3:52].CC(C)([O-])C.[K+]>>[CH2:26]([O:28][C:29]([C:31]1[N:32]([C@H:61]([CH3:63])[CH2:62][NH:58][C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:57])[C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH:41]1[CH2:46][CH2:45][N:44]([CH:47]([CH3:49])[CH3:48])[CH2:43][CH2:42]1)=[C:35]([Br:50])[CH:34]=2)=[O:30])[CH3:27]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2n1[C@H](C)CNC(=O)OC(C)(C)C
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid ethyl ester, (S)-5-methyl-2,2-dioxo[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO 02/010169) and potassium tert-butoxide, to give the desired compound as a light yellow oil (53%). The thus obtained crude product was used without further purification for the next step.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].CO[C:10](=O)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][Si](C(C)(C)C)(C)C)=[C:15]([O:27][Si](C(C)(C)C)(C)C)[CH:14]=1>O1CCCC1>[CH3:4][C:3]1[N:5]=[C:10]([CH:11]=[CH:12][C:13]2[CH:14]=[C:15]([OH:27])[C:16]([OH:19])=[CH:17][CH:18]=2)[O:1][N:2]=1
Reactant: CC(=N)NO
Reactant: COC(=O)C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-hydroxy-acetamidine (0.17 g, 2.29 mmol) in dry tetrahydrofuran (5 mL) was added slowly into the suspension of 60% sodium hydride (0.14 g, 3.5 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at 0° C. to 10° C. The reaction mixture was stirred for 30 min at room temperature. 3-[3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acrylic acid methyl ester (compound of Example 1, Step 1; 0.5 g, 1.18 mmol) in dry tetrahydrofuran (5 mL) was added into the reaction mixture and heated at 60° C. for 8 h. The reaction mixture was cooled at 0° C. and quenched with MeOH (2 mL) to destroy excess sodium hydride. The reaction mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (2×10 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to dryness. The crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]([NH2:29])=[O:28])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]3([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17]C3)[C:6]=2[N:26]=1.[CH2:30]([O:37]C[C@H](NC(=O)OC(C)(C)C)CI)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(=O)N[C@@H](C)CI)(C)(C)C.N(C(OC(C)(C)C)=O)[C@H](CO)COCC1C=CC=CC=1.C(OC(=O)NC1(CI)CC1)(C)(C)C>>[NH2:1][C:2]1[C:3]([C:27](=[O:28])[NH2:29])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:17][O:37][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:6]=2[N:26]=1
Reactant: CC(C)(C)OC(=O)NC1(Cn2c3ccccc3c3cc(C(N)=O)c(N)nc32)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](CI)COCc1ccccc1
Agent: CC(C)(C)OC(=O)NC1(CI)CC1
Agent: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Agent: C[C@@H](CI)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21

Procedure:
(R)-tert-butyl 1-(2-amino-3-carbamoyl-9H-pyrido[2,3-b]indol-9-yl)-3-(benzyloxy)propan-2-ylcarbamate (xvi-d) was prepared following the procedure detailed in the preparation of 63, substituting (S)-tert-butyl 1-(benzyloxy)-3-iodopropan-2-ylcarbamate (prepared as detailed in the synthesis of xxvii from commercial N-Boc-L-Ser(Bzl)-ol) for tert-butyl[1-(iodomethyl)cyclopropyl]carbamate. NH4OAc QC conditions. M+H=490.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11](OC)(OC)(OC)[CH3:12]>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:11]([CH3:12])=[N:1][C:2]=2[CH:7]=1
Reactant: COC(C)(OC)OC
Reactant: COc1ccc(O)c(N)c1
Product: COc1ccc2oc(C)nc2c1
Reaction time: 24 h

Procedure:
A solution of 2-amino-4-methoxyphenol 17 (8 g, 57.4 mmol) in trimethyl orthoacetate 18 (50 mL) was heated to reflux and allowed to stir for 24 h. The reaction was allowed to cool and the excess 18 was evaporated (in vacuo). The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and treated with activated carbon Norit A. The resulting solution was filtered through Celite 521 and evaporated to yield an oil. The oil was chromatographed on silica gel (20% ethyl acetateihexanes) to yield compound 19 as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCN
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCNCC(OC)OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 2-methoxyethanamine (100 mg, 1.33 mmol) in DMF (2 mL) was added K2CO3 (276 mg, 1.99 mmol) and 2-bromo-1,1-dimethoxyethane (236 mg, 1.39 mmol). The mixture was stirred at 80° C. for 3 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated to give 2,2-dimethoxy-N-(2-methoxyethyl)ethanamine as a yellow oil in 91% yield and used in the next step without purification.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17]>C(O)C.O>[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:2][OH:3])[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17]
Reactant: CSc1c(F)cc(CC(=O)c2ccccc2)cc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1c(F)cc(CC(=NO)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
Hydroxylamine hydrochloride (5.5 g, 0.079 mol) and sodium acetate (6.5 g, 0.079 mol) were added to a slurry of 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone in ethanol (120 mL) and water (30 mL). The mixture was heated and held at reflux for 1 hour, then cooled and allowed to stir for 18 hours at room temperature. Additional water (50 mL) was added, and the mixture concentrated to half its volume. Dilute HCl was added, and the mixture extracted with dichloromethane (1×100 mL), 3×50 mL). The combined extracts were washed with dilute sodium bicarbonate, dried with magnesium sulfate, and concentrated to give a light yellow oil, that was crystallized from ethyl acetate/hexanes to afford 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone oxime as white solid (6.2 g, 53%). A second crop (2.3 g, 73% net yield) was also collected. 1H NMR (CDCl3/400 MHz) 7.57-7.60 (m, 2H), 7.35-7.37 (m, 3H), 6.80-6.84 (m, 1.7H), 6.75-6.77 (m, 0.3H), 4.14 (s, 1.7H), 3.83 (s, 0.3H), 2.39 (s, 3H). HRMS m/z 244.0773 (M+H+, calcd 244.0764). Anal. Calcd for C15H13F2NOS: C, 61.42; H, 4.47; N, 4.78. Found: C, 61.44; H, 4.50; N, 4.84.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].CCN(CC)CC>C(#N)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:2]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 30 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzoic acid (1.85 g, 0.01 mol), 4-[4-(3,4-dichlorophenyl)butyl]-phenylamine (2.94 g, 0.01 mol) and Et3N (2.80 mL) in acetonitrile (110 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and concentrated in vacuo to remove the solvent. The residue was dissolved in CH2C2 and washed with diluted HCl. The organic layer was dried Na2SO4), concentrated in vacuo to give a crude solid. Purification by flash chromatography (silica gel, CH2Cl2) yielded 1.40 g (0.003 mol, 30%) of the desired product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1COCC1.CCCCCC>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:22])[OH:18])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(B(O)O)cc1)N1CCOCC1
Temperature: -60 °C
Reaction time: 0.75 h

Procedure:
To a solution of 25 g of the compound obtained in Step A (70.8 mmol) and 26 ml of triisopropyl borate in 400 ml of THF cooled to −60° C. there are added, dropwise, over 45 minutes and under a gentle current of nitrogen, 53 ml of a 1.6M solution of BuLi (84.9 mmol) in hexane. The reaction solution is then stirred for 1 hour 30 minutes at −60° C. and is subsequently returned to ambient temperature over 2 hours. The reaction mixture is treated with about 100 ml of 1N HCl and is extracted 3 times with ethyl acetate. The organic phases are collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained is chromatographed on an SiO2 column, eluting with CH2Cl2 and then with a mixture of CH2Cl2/MeOH 98/2 and then 95/5. After evaporation of the fractions, the residue is triturated in ethyl ether to yield the title product after filtration.
Reaction SMILES: C1COCC1.Br[C:7]1[C:15]2[O:14][C:13]([F:17])([F:16])[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[N:18]1[O:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]=12.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1>[F:16][C:13]1([F:17])[O:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C@:22]34[CH2:23][O:24][CH2:25][CH2:26][C@H:21]3[CH2:20][O:19][NH:18]4)[C:15]=2[O:14]1
Reactant: FC1(F)Oc2cccc(Br)c2O1
Reactant: C1CC2CON=C2CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC1(F)Oc2cccc([C@]34COCC[C@H]3CON4)c2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
THF (2.0 ml) was added to a solution of 4-bromo-2,2-difluoro-1,3-benzodioxol (1.96 g) in toluene (20 ml). The mixture was cooled to −78° C., and a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (873 mg).
Reaction SMILES: O[C@H](CCCCCCCCCC(C)C)CC(OC)=O.[CH3:20][CH:21]([CH3:40])[CH2:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](=[O:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36]>>[OH:39][C@H:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([CH3:40])[CH3:20])[CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)CC(=O)CCCCCCCCC=CCC(C)C
Agent: COC(=O)C[C@H](O)CCCCCCCCCC(C)C
Product: COC(=O)C[C@H](O)CCCCCCCCCCCC(C)C
Yield: 91.6 %

Procedure:
In a manner similar to the synthesis of compound 114, compound 113 (100 mg, 0.338 mmol) was reduced by a two step procedure to afford 115 as a colorless oil (93 mg, 92%, two steps). Rf=0.50 (hexane/ethyl acetate, 4/1, v/v); [α]25D=−6.0° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 3.95 (m, 1H, H-3), 3.66 (s, 3H, OCH3), 2.47 (dd, 1H, J2a,2b=16.2 Hz, J2a,3=3.3 Hz, H-2a), 2.36 (dd, 1H, J2a,2b=16.2 Hz, J2b,3=9.0 Hz, H-2b), 1.53-1.32 (m, 3H, H-4, H-15), 1.21-1.03 [m, 20H, H-(5-14)], 0.81 (d, 6H, J15,16=6.3 Hz, H-16); 13C NMR (75 MHz, CDCl3): δ 173.47 (C═O), 67.97 (C-3), 51.67 (CH3O), 41.08 (C-2), 39.02 (C-12), 36.51 (C-4), 22.62 (C-14). HR MS (m/z) calculated for C18H36O3 [M+Na], 323.2557; found, 323.1925.
Reaction SMILES: C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:12][CH:13]([F:15])[F:14])(=O)=O.Cl.Cl.[C:20]([C:24]1[O:28][N:27]=[C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]3[C:49]4[C:44](=[CH:45][C:46]([O:56][CH3:57])=[C:47]([O:50][C@H:51]5[CH2:55][CH2:54][NH:53][CH2:52]5)[CH:48]=4)[N:43]=[CH:42][N:41]=3)[CH:34]=2)=[O:31])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C>[C:20]([C:24]1[O:28][N:27]=[C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]3[C:49]4[C:44](=[CH:45][C:46]([O:56][CH3:57])=[C:47]([O:50][C@H:51]5[CH2:55][CH2:54][N:53]([CH2:12][CH:13]([F:15])[F:14])[CH2:52]5)[CH:48]=4)[N:43]=[CH:42][N:41]=3)[CH:34]=2)=[O:31])[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O[C@H]1CCN(CC(F)F)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of a solution of NaHCO3 (47 mg in 1.5 mL, 0.561 mmol) and ethyl acetate (3 mL), 2,2-difluoroethyl trifluoromethanesulfonate (48 μL, 0.22 mmol) was added. After heating at 40 C, (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride (110 mg, 0.187 mmol) was added. The reaction mixture was stirred at 40° C. for 1 h. The mixture was diluted with ethyl acetate and organic layer was washed with brine. After drying over MgSO4, the solvent was evaporated and the crude product purified on silica gel, using dichloromethane/methanol as mobile phase. Yield: 40 mg (37%). 1HNMR (dmso-d6): δ 9.58 (1H, s), 9.00 (1H, s), 8.56 (1H, s), 7.59 (1H, s), 7.47 (1H, s), 7.40 (2H, m), 7.25 (1H, d), 6.97 (1H, d), 6.48 (1H, s), 5.15 (1H, m), 5.15 (1H, m), 3.99 (3H, s), 2.91 (6H, m), 2.40 (1H, m), 1.90 (1H, m), 1.27 (9H, s). LC-MS (ESI) m/z 583 (M+H)+.