Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[NH:3]1.[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5]1
Reactant: NS(N)(=O)=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(N)(=O)=O)C[C@H](C)N1
Yield: 19.3 %

Procedure:
To a solution of (2R,6S)-2,6-dimethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide as a white solid (0.29 g). A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (0.29 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 5 step i), 0.5 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.940 g
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[CH:5]=[CH:4][N:3]=2)=[CH:25][CH:24]=1
Reactant: CC1(c2ccccc2)CCN(c2ccnc(Cl)n2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1(c2ccccc2)CCN(c2ccnc(-c3ccc(F)cc3)n2)C(=O)O1
Yield: 25 %

Procedure:
To a solution of 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.165 mmol) and 4-fluorophenylboronic acid (32 mg, 0.33 mmol), K2CO3 (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) at 0° C. under N2 was slowly added Pd(Ph3)2Cl2 (10 mg, 20%). The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-(4-fluorophenyl)pyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (15 mg, yield 25%). 1H NMR (CDCl3, 400 MHZ): δ=1.75 (s, 3H), 2.4 (m, 1H), 2.54 (m, 1H), 3.6 (m, 1H), 4.4 (m, 1H), 7.1 (m, 2H), 7.25-7.4 (m, 5H), 8.08 (m, 1H), 8.34 (m, 2H), 8.62 (m, 1H). LC-MS Method 3, tR=1.519 min, m/z=364.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.40 (m, 1H), 2.60-2.70 (d, 1H), 3.60 (m, 1H), 4.40 (t, 1H), 7.10 (t, 2H), 7.20-7.45 (m, 5H), 8.17 (d, 1H), 8.35 (t, 2H), 8.65 (d, 1H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[C:8]([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=1>O1CCOCC1>[Br:1][CH:11]([C:10]([C:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=1[O:18][CH3:19])=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Solvent: C1COCCO1
Product: CCOC(=O)C(Br)C(=O)c1cc(Cl)ccc1OC
Reaction time: 1 h

Procedure:
Bromine (0.70 mL, 13.6 mmol) was added to a solution of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (3.39 g, 13.2 mmol) in dioxane (25 mL) and stirred for 1 hour. The reaction was poured onto ice water, extracted with ethyl acetate, the organics washed with water and brine and evaporated to dryness to give ethyl 2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (method 1) [M+H]+=337.2, RT=3.84 min.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([Cl:9])=[O:8].II>>[F:3][C:4]1[CH:5]=[C:6]([C:10]([Cl:1])=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([Cl:9])=[O:8]
Reactant: Cc1c(F)cc(C(=O)Cl)cc1F
Reactant: ClCl
Agent: II
Product: Cc1c(F)cc(C(=O)Cl)c(Cl)c1F
Yield: 53.2 %

Procedure:
30 g of chlorine are passed into 70 g of 3,5-difluoro-4-methyl-benzoyl chloride and a spatula-tip of FeS and I2 at 40°-45°, with slight cooling. The mixture is then flushed with nitrogen, the residue is coarsely distilled and the distillate is fractionated. 44 g of 3,5-difluoro-4-methyl-6-chlorobenzoyl chloride of boiling point: 109°/16 mbar, nD20 : 1.5342 are obtained. 3,5-Difluoro-2,6-dichloro-4-methyl-benzoyl chloride of boiling point b.p: 109°/13 mbar, nD20 : 1.5274 are obtained from the last runnings.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC(C)C)(C)C.[CH3:21][N:22]=[C:23]=[O:24]>C(N(CC)CC)C>[CH3:21][NH:22][C:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:24]
Reactant: CCCCNc1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)NC)c1ccc(Cl)c(Cl)c1
Yield: 46.8 %

Procedure:
A mixture of 100 g of N-n-butyl-3,4-dichloroaniline (described in West German Pat. No. 1,902,419), 250 ml of isopropyl ether, 10 ml of triethylamine and 60 g of methyl isocyanate was stirred for 18 hours at room temperature and the solvent was distilled off under reduced pressure. The residue was added to petroleum ether (b.p.=65°-75° C.) and after cooling, the precipitate formed was recovered by vacuum filtration to obtain 59 g of N-methyl-N'-n-butyl-N'-(3,4-dichlorophenyl)-urea melting at 58° C.
Reaction SMILES: [OH:1][CH:2]([C:29]1[CH:38]=[C:37]([CH3:39])[C:32]2[NH:33][C:34](=[O:36])[O:35][C:31]=2[CH:30]=1)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][C:19]4[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=4[NH:17][C:16]3=[O:28])[CH2:11][CH2:10]2)[N:6]=[N:7][CH:8]=1.CO>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:18]2[NH:17][C:16](=[O:28])[N:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:5]4[N:6]=[N:7][CH:8]=[C:3]([C:2]([C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)=[O:1])[CH:4]=4)[CH2:14][CH2:13]3)[CH2:21][CH2:20][C:19]=2[CH:22]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(O)c4cc(C)c5[nH]c(=O)oc5c4)cnn3)CC1)C(=O)N2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)cnn3)CC1)C(=O)N2
Reaction time: 20 h

Procedure:
0.13 g (0.049 mmol) 3-(1-{5-[hydroxy-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-methyl]-pyridazin-3-yl}-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 1.0 g (12 mmol) manganese(IV)-oxide in 100 mL DCM were stirred overnight at RT. Then 500 mg manganese(IV)-oxide were added and the mixture was stirred for a further 20 h. Then the reaction mixture was combined with 10 mL MeOH, filtered off and evaporated down. The residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccccc1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccccc3)nc21
Temperature: 184 °C

Procedure:
A solution of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 in 1.00 g (10.70 mmol) of aniline was maintained at reflux (184° C.) for 3 minutes. Most of the excess aniline was evaporated at reduced pressure. The remaining gum was dissolved in 1.0 mL of ethyl acetate. Crystals developed on inducement; wt 0.088 g. Further purification to remove dark colors was effected by silica gel chromatography, eluting with chloroform and then 50% hexane-ethyl acetate to obtain pure crystalline product; wt 0.046 g; mp 247°-249° C.
Reaction SMILES: [F:1][CH:2]1[C:7]([Si](C)(C)C)=[C:6]([F:12])[CH:5]=[C:4]([S:13][CH3:14])[C:3]1([CH2:16][O:17][CH3:18])[OH:15].C(O)C(F)(F)F.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][CH:2]1[CH:7]=[C:6]([F:12])[CH:5]=[C:4]([S:13][CH3:14])[C:3]1([CH2:16][O:17][CH3:18])[OH:15]
Reactant: COCC1(O)C(SC)=CC(F)=C([Si](C)(C)C)C1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: COCC1(O)C(SC)=CC(F)=CC1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A reaction mixture containing the trimethylsilyl derivative (28, 0.51 g, 1.74 mmol) in 10 mL of freshly distilled THF was treated with trifluoroethanol (0.18 g, 1.82 mmol) and tetrabutylammonium fluoride (1 M solution in THF, 1.74 mL, 1.74 mmol) at -78° C. under argon (FIG. 2E). The reaction mixture was allowed to stir at -78° C. for 20 min and at room temperature for 30 minutes. The reaction was quenched by the addition of water, followed by extraction with ethyl ether (2×15 mL). The combined organic extracts were washed with water, dried (MgSO4), filtered, and the solvent removed under vacuo. Silica gel chromatography (5% EtOAc:hexanes) gave the pure product as a colorless oil (270 mg, 71%). 1H NMR (CDCl3) δ 6.6-6.64 (m, 2H, ArH), 5.11 (s, 2H, CH2), 3.63 (s, 3H, CH3), 2.42 (s, 3H, CH3).
Reaction SMILES: [CH3:1][CH:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1)[CH:3]([CH3:6])[CH2:4][CH3:5].[ClH:26].C(OCC)(=O)C>>[ClH:26].[CH3:1][CH:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]=2[N:18]=1)[CH:3]([CH3:6])[CH2:4][CH3:5]
Reactant: CCC(C)C(C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(C)C(C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of the compound obtained in step 1 (0.10 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.055 g, 67%) as a white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[CH:15]=1.[C:18]([NH:25][CH2:26][C:27]#[CH:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:21]([O:20][C:18](=[O:19])[NH:25][CH2:26][C:27]#[C:28][C:14]1[CH:13]=[N:12][C:11]([NH2:17])=[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:15]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2s1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 80 °C

Procedure:
To a solution of 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (3.37 g, 11.0 mmol) in dioxane (50 mL) were added N-(Boc)-propargylamine (1.705 g, 11.0 mmol), Pd(PPh3)4 (0.250 g, 2 mol %), CuI (0.04 g), and NEt3 (1.85 mL, 13.2 mmol). The mixture was heated under nitrogen at 80° C. for 48 h. The reaction mixture was concentrated, taken up with CH2Cl2 (120 mL), washed with water (3×30 mL), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude material was purified by column chromatography on silica gel using EtOAc/Hexanes (1:4) to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=1.56 (s, 9H), 4.22 (d, J=2.4 Hz, 2H), 4.99 (bs, 1H), 7.40-7.61 (m, 4H), 7.88 (d, J=6.8 Hz, 1H), 8.05-8.08 (m, 2H), 8.32 (d, J=1.8 Hz, 1H), MS (ES+): m/z=381.14 (100) [MH+]. HPLC: tR=3.87 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:27]1[C:26]2[CH:31]=[CH:32][C:23]([CH2:22][CH2:21][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:24][C:25]=2[O:30][CH2:29][CH2:28]1
Reactant: BrCCc1ccc2c(c1)OCCO2
Reactant: CC(C)(N)COC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(COC(c1ccccc1)c1ccccc1)NCCc1ccc2c(c1)OCCO2

Procedure:
A mixture of 2-amino-1-diphenylmethoxy-2-methylpropane (369 mg -- see Preparation 1), 6-(2-bromoethyl)benzodioxan (243 mg -- see Preparation 10), potassium carbonate (415 mg) and potassium iodide (166 mg) in acetonitrile (40 ml) was heated under reflux for 48 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica (7 g) using ethyl acetate plus 0-5% methanol as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil which was characterised as a hemihydrate (130 mg, 31%).
Reaction SMILES: [Br:1]Br.Cl[C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1>C(O)(=O)C>[Br:1][C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1
Reactant: BrBr
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Solvent: CC(=O)O
Product: CC(C)NC1=NS(=O)(=O)c2sc(Br)cc2N1
Temperature: 100 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
Bromine (0.12 ml, 2.3 mmol) was added dropwise to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (280 mg, 1.0 mmol) in 10 ml of acetic acid and the mixture was stirred for 24 h at 100° C. in a sealed flask. The cooled mixture was evaporated to dryness and the residue was triturated with water to give a solid, which was recrystallised from ethanol/water (1:1) affording 118 mg (39%) of the title compound contaminated with 10% of the starting material; mp ca. 279° C. (aqueous ethanol); 1H-NMR (DMSO-d6): δ1.16 (d, 6H, 2×CH3), 3.86 (m, 1H, CH), 7.14 (s, 1H, H-5), 7.18 (br, 1H, NH), 10.74 (s, 1H, NH); MS: m/e 323/325 (M+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:65]1[CH2:70][CH2:69][CH:68]([SH:71])[CH2:67][CH2:66]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:11]=[C:2]([S:71][CH:68]2[CH2:69][CH2:70][CH2:65][CH2:66][CH2:67]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: SC1CCCCC1
Reactant: COC(=O)c1cc(Cl)cc(Br)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Cl)cc(SC2CCCCC2)c1C
Yield: 88.3 %

Procedure:
To a stirred solution of methyl 3-bromo-5-chloro-2-methylbenzoate (1.0 g, 3.79 mmol) in 1,4-dioxane was added N,N-diisopropyl ethylamine (0.98 g, 7.59 mmol). The reaction mixture was purged with argon for 20 min. then Pd(OAc)2 (0.042 g, 0.189 mmol), Xanthphos (0.22 g, 0.38 mmol) and cyclohexylthiol (0.44 g, 3.79 mmol) was added to it sequentially and again purged with argon for 10 min. The reaction mixture was then refluxed for 16 h. On completion, water was added, and the product extracted with ethyl acetate. The organic layer was dried over sodium sulphate and the product was purified by silica gel column to afford the title compound (1.0 g, 83%)
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].[Br:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1F>C1COCC1>[Br:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A 0.2 M solution of cyclopropyl methanol (441 uL, 5.5 mmol) in THF stirred at 0° C. under an atmosphere of nitrogen was treated with 2 equal portions of KOtBu (579 mg, 5.2 mmol). After 5 min the ice bath was removed; the mixture was stirred for 30 min at rt before resubmerging in the ice bath and cooling to 0° C. A solution of 2-bromo-1-fluoro-4-nitrobenzene (1 g, 4.5 mmol) in THF (3 mL) was added dropwise. After 20 min, the ice bath was removed and the mixture was stirred overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 ml). The combined organic layers were washed brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 50%) in hexanes to afford the title compound (1.07 g, 88%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH2:5][OH:6])[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].C(O)(=O)C>C(#N)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:2]2([CH2:5][OH:6])[CH2:3][O:4][C:23]([CH3:24])=[N:1]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1=NC(CO)(CCc2ccc(OCc3ccccc3)cc2)CO1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol (31.1 g, 0.10 mol) in acetonitrile (2.38 l) is added triethylortho acetate (17.1 ml, 0.12 mol, 1.2 eq) and acetic acid (5.48 ml, 0.11 mol, 1.1 eq), the reaction mixture is then stirred at 80° C. for 5 hours. The reaction mixture is then concentrated under vacuum, {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol is isolated after crystallization with ethyl acetate.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]1([CH:28]([OH:44])[CH2:29][O:30][CH2:31][CH2:32][O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[O:45]1[CH:50]=[CH:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[C:18]1([CH:28]([O:44][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50][O:45]2)[CH2:29][O:30][CH2:31][CH2:32][O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Reaction time: 0.17 h

Procedure:
0.82 g of pyridinium p-toluenesulfonate was added to a solution of 6.3 g of 1-(1-naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 2.97 ml of 3,4-dihydro-2H-pyran dissolved in 63 ml of methylene chloride at room temperature. The resulting mixture was stirred at the same temperature for 20 minutes and further at 35°-40° C. for 10 minutes. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.53 g of colorless, oily 1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.ClCCCl>CC(O)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(Br)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.6 %

Procedure:
Sodium triacetoxyl-borohydride (470 mg, 2.21 mmol) was added to a solution of 4-bromo-phenylamine (252 mg, 1.47 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (324 mg, 1.47 mmol) in 10 ml of 1,2-dicloroethtane (DCE), 0.5 ml of HOAc was added. The mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed by rotovap to give 656 mg of crude (4-bromo-phenyl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. It was used for next step without further purification.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:8]([NH:11][C:12]([N:2]([O:1][C:12]([NH:11][CH2:8][CH2:9][CH3:10])=[O:13])[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4])=[O:13])[CH2:9][CH3:10]
Reactant: O=C(NO)C1CC1
Reactant: CCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)ON(C(=O)NCCC)C(=O)C1CC1

Procedure:
N-hydroxycyclopropanecarboxamide (5.0 grams), n-propyl isocyanate (9.3 grams) and 5 drops of triethylamine were stirred at room temperature in about 100 ml of methylene chloride for about 12 hours. The reaction mixture was then concentrated leaving an oily residue which crystallized upon scratching. This solid was then recrystallized from a mixture of cyclohexane and isopropanol and dried. Upon drying, the desired N-((propylamino)carbonyl)-N-(((propylamino)carbonyl)-oxy)cyclopropanecarboxamide was obtained as a white solid, m.p. 76°-78° C.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][N:8]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc(C2CCNC(C3CCCCC3)C2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(c2ccccc2)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-cyclohexyl-4-phenylpiperidine (2.85 g, 11.71 mmol) in CH2Cl2 (58.5 ml) was added benzyl chloroformate (2.507 ml, 17.56 mmol) and triethylamine (2.45 ml, 17.56 mmol). The reaction was stirred at room temperature for 2 hours. Added water and extracted 3 times with CH2Cl2. The combined organics were dried, concentrated, and purified on silica gel 20% EtOAc/Hexanes. Separated cis and trans on the AD column, 20% IPA/Hexanes w/DEA. Peak 1 corresponds to the cis racemic mixture with one trans diastereomer and peak2 is a single trans diastereomer. Obtained 2.5 g racemic cis/trans peak1. Resolved on the OJ column 20% EtOH/Hexanes w/DEA: Peak 1: 0.68 g pure cis undesired, peak 2 1.75 g cis/trans mixture.