Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:8]2[CH:13]=[C:12]([CH2:14]O)[CH:11]=[CH:10][C:9]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:14][C:12]1[CH:11]=[CH:10][C:9]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCC2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a stirred solution of 78.7E (0.185 g, 0.6 mmol) in DCM (6 mL) and DMF (0.04 mL) at 0° C. was added thionyl chloride (0.08 mL, 1 mmol). The reaction was stirred at room temperature for one hour and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.7F as a colorless oil (0.165 g, 84% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([CH3:36])[N:30]=1>>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:32]=[C:31]([CH3:36])[N:30]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: Cc1cc(I)cc(C)n1
Product: Cc1cc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)cc(C)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and 2,6-dimethyl-4-iodo-pyridine [CAS-No. 22282-67-3] (0.23 g, 1.0 mmol) according to the general procedure IVc. Obtained as a light yellow solid (0.057 g, 12%). MS (ISP) 474.2 [(M+H)+]; mp 159° C.
Reaction SMILES: [C:1]([O:4][C@@H](C(N)(C)[C@H](O)C)C)(=[O:3])[CH3:2].[CH3:13][C@:14]([N+:20]([O-])=O)([C@H:17]([OH:19])[CH3:18])[CH2:15][OH:16]>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:20][C@@:14]([CH3:13])([C@H:17]([OH:19])[CH3:18])[CH2:15][OH:16]
Reactant: C[C@@H](O)[C@@](C)(CO)[N+](=O)[O-]
Reactant: CC(=O)O[C@H](C)C(C)(N)[C@@H](C)O
Product: CC(=O)O
Product: C[C@@H](O)[C@](C)(N)CO
Yield: 97 %

Procedure:
Using the procedure described for 5D, (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (6B) gave (+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate (97%) mp 117°-121° (C,H,N).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][Br:1])=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1ccc(CCBr)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 0 °C
Yield: 98 %

Procedure:
4-(2-Bromo-ethyl)-benzoic acid (1.00 g, 4.37 mmol) was dissolved in MeOH (10 mL) and cooled to 0° C. This was followed by dropwise addition of thionyl chloride (0.48 mL, 6.55 mmol). The mixture was refluxed for 2 h, followed by removal of all volatiles by rotary evaporation. The resulting oil was taken up in EtOAc (50 mL) and washed with water (50 mL). The EtOAc portion was separated, dried (Na2SO4) and concentrated to give the product (1.04 g, 98%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H, J=6.54 Hz), 7.29 (d, 2H, J=7.1 Hz), 3.92 (s, 3H), 3.59 (t, 2H, J=7.38 Hz), 3.23 (t, 2H, J=7.34 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:34]=[CH:35][CH:36]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][O:17][C:18]3[CH:31]=[CH:30][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:20][CH:19]=3)[N:13]([CH3:32])[C:12]=2[CH:33]=1.[C:37]([C:39]1[CH:40]=[C:41]([N:45]=[C:46]=[O:47])[CH:42]=[CH:43][CH:44]=1)#[N:38].C(N(CC)CC)C>CN(C)C=O>[C:37]([C:39]1[CH:40]=[C:41]([NH:45][C:46]([NH:3][C:4]2[CH:36]=[CH:35][CH:34]=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH2:16][O:17][C:18]5[CH:31]=[CH:30][C:21]([CH2:22][CH:23]6[S:27][C:26](=[O:28])[NH:25][C:24]6=[O:29])=[CH:20][CH:19]=5)[N:13]([CH3:32])[C:12]=4[CH:33]=3)[CH:5]=2)=[O:47])[CH:42]=[CH:43][CH:44]=1)#[N:38]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(N)c3)cc21
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cccc(NC(=O)Nc4cccc(C#N)c4)c3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
A mixture of 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), 3-cyanophenyl isocyanate (260 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 4 hours and then at 50° C. for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→ethyl acetate as the eluant. The product was recrystallized from methanol to afford the title compound (260 mg, mp 148.4-154.0° C.).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:8]=2[O:7]1)C.Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=1[CH2:33][CH2:34][CH3:35]>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][O:16][C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:3])=[O:17])[O:7][C:8]=3[CH:15]=2)=[C:24]([CH2:33][CH2:34][CH3:35])[C:25]=1[OH:32])(=[O:31])[CH3:30]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CC1CCc2ccc(O)cc2O1
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(CC(=O)O)CC3)ccc(C(C)=O)c1O
Yield: 40.5 %

Procedure:
A 0.9 g sample of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester was alkylated with 3 g of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone using the procedure described in Example 31. The crude product (2.6 g) was chromatographed on 50 g of silica gel giving 1.2 g of the desired ester as a pale-yellow oil (eluted with 19:1 toluene-ethyl acetate). This material was saponified with 2.0 g of lithium hydroxide monohydrate using the procedure described in Example 31. The crude acid (1.1 g) was chromatographed on 50 g of silica gel. Elution with 2:1 and 1:1 toluene-ethyl acetate afforded 682 mg (40.5%) of racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2H-1-benzopyran-2-acetic acid as a pale-yellow solid, mp 107°-109.5° C.
Reaction SMILES: B.CSC.C(O[C:13]1[CH:30]=[CH:29][C:16]2[CH:17]=[C:18](C3C=CC(OC)=CC=3)[CH2:19][O:20][C:15]=2[CH:14]=1)C1C=CC=CC=1.C1C[O:34]CC1>>[O:20]1[C:15]2[C:16](=[CH:29][CH:30]=[CH:13][CH:14]=2)[CH:17]([OH:34])[CH2:18][CH2:19]1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Reactant: C1CCOC1
Agent: B
Solvent: CSC
Product: OC1CCOc2ccccc21
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Borane-dimethylsulfide complex (BH3—SMe2) (10 M, 1.14 mL, 11.4 mmol) in THF was added dropwise at 0° C. to a solution of compound 1 (1 g, 2.9 mmol) in THF (12 mL), and the resultant mixture was stirred at 0° C. for 4 hrs. After completion of the reaction, the mixture was quenched with H2O (7 mL), and then continually stirred for 5 min, followed by addition of 10% NaOH (2 mL) and 37% H2O2 (0.36 mL). After stirring for 30 min, the mixture was extracted with CH2Cl2 (30 mL×5). The organic layers were combined and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:4), thus giving the title compound 4 as a colorless crystal (0.63 g, 60% yield).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:24]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:9]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(Br)c1ccc(OC)cc1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(O)c1cccc(OC(C(=O)OCC)c2ccc(OC)cc2)c1
Reaction time: 40 h

Procedure:
To a stirred mixture of 10 g of 3-(α-hydroxyhexyl)phenol, 7.8 g of potassium carbonate, and 4 g of potassium iodide in 400 ml of DMF was added 13.2 g of Ethyl 2-bromo-2(4-methoxyphenyl)acetate and stirring was continuted at room temperature for 40 hours. The reaction mixture was then diluted with water, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The oily residue (8 g) was chromatographed by HPLC using EtOAc-hexane (1:4) as eluent to give pure product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:13]([OH:14])=[C:12]([Cl:15])[CH:11]=[C:10]([CH3:16])[CH:9]=1.[Br:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=1>O.C(O)CC>[Br:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][O:14][C:13]2[C:8]([Cl:7])=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[Cl:15])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCOc1ccc(Br)cc1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: Cc1cc(Cl)c(OCCOc2ccc(Br)cc2)c(Cl)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
K2CO3 (29.3 g, 212 mmol) was dissolved in water (162 mL). 1-Propanol (150 mL) was added. A sol. of 2,6-dichloro-para-cresol (25 g, 141 mmol) in 1-propanol (150 mL) was added. Methanesulfonic acid 2-(4-bromo-phenoxy)-ethyl ester (41.6 g, 141 mmol) was added. The mixture was stirred at 85° C. for 6 h. The heating oil bath was removed, and water (330 mL) was added dropwise when the internal temperature had reached 78° C. The beige suspension was allowed to cool to rt. The mixture was filtered, and the precipitate was washed with water. Drying the precipitate under high vacuum at 30° C. for 48 h yielded the title compound (43 g, 81%). LC-MS: tR=1.15 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH3:13].[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][N:5]3[CH3:13])[CH:20]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CN1CC(=O)Nc2ccc(Br)cc21
Product: CN1CC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared according to the procedure for Example 5 from 6-bromo-4-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.8 g, 20 mmol), and 3-nitrophenylboronic acid (4.8 g, 30 mmol). A red powder (0.95 g, 16%): mp 237-243° C. 1H-NMR (DMSO-d6) δ2.88 (s, 3H), 6.9 (d, J=7.9 Hz, 1H), 7.01 (d, J=2 Hz, 1H), 7.11 (dd, J=7.9, 2.0 Hz, 1H), 7.7 (t, J=7.9 Hz, 1H), 8.1 (m, 2H), 8.37 (t, J=0.7 Hz), MS (ESI) m/z 283 (M)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:50][CH2:49][C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NCc1cccnc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCc3cccnc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3-pyridylmethylamine (12.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-3-pyridylmethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (36.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+]([O-])=O)=[C:9]([C:11](=[N:13][OH:14])[CH3:12])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][N:13]=[C:11]([CH3:12])[C:9]=2[CH:10]=1
Reactant: CC(=NO)c1cc(Oc2ccc(Br)cc2F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc2ccc(Oc3ccc(Br)cc3F)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2.0 g sample of the oxime prepared as above was combined with 1.2 g of potassium carbonate in 25 ml of dimethyl sulfoxide and the mixture was allowed to stir at room temperature for two days. The resulting mixture was diluted with water and extracted with ether. The ether extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting oil was distilled in a Kugelrohr apparatus to obtain 0.6 g of a thick, amber oil, the nmr spectrum of which was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OC3CCCC3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OC3CCCC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol), (phenyl acetylene (110 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 186 mg (70%). HPLC-MS: m/z: 487.1 (M+H)+; Rt: 3.17 min.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:13][P:14](Cl)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>O1CCCC1.O>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][P:14]([CH3:13])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CP(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
The methylphenylphosphinic acid 4-nitrophenyl ester is prepared in the following way: A suspension of 173 mg of NaH at 50% in oil, in 2 ml of anhydrous tetrahydrofuran, is stirred at ambient temperature under argon. A solution of 500 mg of 4-nitrophenol in 2 ml of anhydrous tetrahydrofuran is added dropwise at ambient temperature. After stirring for approximately 1 hour at ambient temperature, a solution of 630 mg of methylphenylphosphinic chloride in 2 ml of anhydrous tetrahydrofuran is added dropwise over about ten minutes. After stirring for approximately 2 hours, the reaction medium is diluted with 20 ml of distilled water and the aqueous phase is extracted with 2×20 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated under reduced pressure in a rotary evaporator. 995 mg of methylphenylphosphinic acid 4-nitrophenyl ester are obtained with a purity of 50%.
Reaction SMILES: [OH-:1].[Na+].[NH2:3]O.C[O:6][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)=O>C1COCC1.CO.O>[OH:1][NH:3][C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)=[O:6]
Reactant: COC(=O)c1ccc2ccn(Cc3ccc(OC)cc3)c2c1
Reactant: NO
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc3ccc(C(=O)NO)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of sodium hydroxide (0.2 g, 5 mmol) and 50% aqueous hydroxylamine (2 mL) was added 1-(4-methoxy-phenylmethyl)-1H-indole-6-carboxylic acid methyl ester (0.32 g, 1.0 mmol) dissolved in THF/MeOH (4 mL, 1:1). After stirring 1 hr at room temperature, the solution was diluted with water (4 mL) and the volatile solvents were removed in vacuo. The solution was then neutralized to pH=7-8 with 1N HCl. The resulting precipitate was isolated by filtration to provide 1-(4-methoxy-phenylmethyl)-1H-indole-6-carboxylic acid hydroxyamide as a white powder (0.25 g, 84% yield). 1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.93 (s, 1H), 7.97 (s, 1H), 7.64 (d, 1H, J=3.2 Hz), 7.58 (d, 1H, J=8.9 Hz), 7.45 (d, 1H, J=8.3 Hz), 7.19 (d, 2H, J=8.3 Hz), 6.87 (d, 2H, J=8.3 Hz), 6.52 (d, 1H, J=3.2 Hz), 5.38 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](Br)=[CH:16][C:15]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:44]([O:46][CH3:47])=[O:45]>O1CCCC1>[CH3:47][O:46][C:44](=[O:45])[C:17]1[CH:16]=[C:15]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][C:18]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (100 μl) was added to a solution of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (154 mg, 0.28 mmol) in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere at −78° C. Solution stirred at −70° C. for 30 minutes to give an orange solution. The ion was quenched with methyl chloroformate (100 μl, 3 eq) and allowed to warm to room temperature for 30 minutes. The solution was quenched with saturated aqueous ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (3×5 ml). The combined extracts were washed with water (2×5 ml) and saturated aqueous sodium chloride solution (5 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate in hexane (gradient 20% to 60% ethyl acetate) to give 2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (72 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH:19]=O.C(O)(=O)C.[NH2:32][C@H:33]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:35]2[CH:47]=[C:48]([C:52]([F:55])([F:54])[F:53])[C:49]([CH3:51])=[CH:50][C:34]1=2.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[C:43]([O:42][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:33]([NH:32][CH2:19][C:18]2[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=[C:16]([F:15])[CH:17]=2)[C:34]2[CH:50]=[C:49]([CH3:51])[C:48]([C:52]([F:55])([F:53])[F:54])=[CH:47][C:35]1=2)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
Add sodium triacetoxyborohydride (0.40 g, 1.89 mmol) to a mixture of 3-fluoro-5-trifluoromethyl benzaldehyde (0.096 mL, 0.69 mmol), acetic acid (0.030 mL, 0.625 mmol)) and (S)-tert-Butyl 5-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 13) (0.215 g, 0.63 mmol) in dichloroethane (3.0 mL). Stir the mixture at room temperature under an atmosphere of nitrogen for 20 h. Add a saturated solution of sodium bicarbonate, separate the layers and extract the aqueous layer with dichloromethane. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-30% ethyl acetate in hexane), to afford the title compound (0.32 g, 98%). MS (ES+): 521 (M+H).
Reaction SMILES: O=[CH:2][CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[H][H]>CO.[Pt]=O>[CH2:10]([NH:17][CH2:2][CH2:3][C@H:4]([OH:5])[C@@H:6]([OH:7])[CH2:8][OH:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC[C@H](O)[C@H](O)CO
Reactant: [H][H]
Reactant: NCc1ccccc1
Agent: O=[Pt]
Solvent: CO
Solvent: O
Product: OC[C@H](O)[C@@H](O)CCNCc1ccccc1
Yield: 59.5 %

Procedure:
2-Deoxy-D-ribose (100 g; 0.746 mole) and benzylamine (96 g; 0.897 mole) were dissolved in methanol (400 ml) and water (40 ml) and hydrogenated at 50° C and 50 p.s.i. in the presence of platinum oxide catalyst (4.0 g) until hydrogen uptake was complete. The catalyst was filtered off and the filtrate was cooled in an ice bath. The resulting crystalline precipitate was collected, washed with cold methanol, and dried to give 5-(benzylamino)-1,2(S),3(S)-trihydroxypentane (100 g; 59.5% yield). A sample was recrystallized from ethyl acetate, m.p. 117°-118.5° C, δ (DMSO-D6) 7.3 (5H, s); 3.9 (3H, m, exchangeable with D2O); 3.7 (2H, s); 3.4 (4H, m); 2.6 (2H, m); 1.6 (2H, m). νmax. 3370, 3310, 3290 cm-1. (Found: C, 64.3; H, 8.5; N, 6.1. C12H19NO3 requires: C, 64.0; H, 8.5; N, 6.2%). (A).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.N1C=CC=CC=1>ClCCl>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)N1CCC2(CC1)OCCO2
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Butyryl chloride (0.53 g, 5 mmol) in dry dichloromethane (5 ml) was added dropwise with stirring to 4-piperidone ethylene ketal (0.72g, 5 mmol) and pyridine (0.5 ml) in dry dichloromethane (10 ml). The solution was stirred at 20° C. overnight then washed successively with dilute HCl, saturated sodium bicarbonate solution and water and dried (sodium sulphate). Evaporation of the solvent gave the product as a clear syrup (0.66 g). MS (+EI) 213 (M+), 1H NMR (CDCl3) 3.98 (4H, s), 3.70 (2H, t), 3.53 (2H, t), 2.33 (2H, t), 1.61-1.83 (6H, m), 0.97 (3H, t).