Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:2]=1.[C:16]([O:20][C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[C:16]([O:20][C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]1[CH:29]=[C:28]([NH:30][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)=[O:14])[CH:27]=[N:26]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCn1cc(N)cn1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (1.60 g, 7.87 mmol) in DCM (15 mL), tert-butyl(2-(4-amino-1H-pyrazol-1-yl)ethyl)carbamate (1.80 g, 7.96 mmol), DIPEA (6.8 mL, 39.86 mmol) and HATU (7.485 g, 19.69 mmol) was added. After stirring the reaction mixture at rt for 18 h, the reaction mixture was diluted with DCM and H2O. The org. layer was separated and the aq. layer was extracted with DCM (3×). The combined org. layers wered dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (EtOA/hex 3:7 to 1:1) yielded tert-butyl(2-(4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)ethyl)carbamate as a white solid. LC-MS conditions B: tR=0.8 min, [M+H]+=412.46.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[CH:19][C:9]([O:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10][CH:11]=1)=[O:14])[CH3:17]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)c1ccc(Oc2ccccn2)cc1
Reaction time: 6 h
Yield: 25.9 %

Procedure:
2-Bromopyridine (1.98 mL, 20.0 mmol), ethyl 4-hydroxybenzoate (6.71 g, 40.0 mmol) and potassium carbonate (2.78 g, 20.0 mmol) were mixed and the mixture was stirred for 6 hours at 150° C. to 160° C. After allowed to stand for cooling, 20 mL of 8% aqueous solution of sodium hydroxide were added to the reaction mixture, which was extracted with diethyl ether. The extracted solution was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=10:1 v/v) to obtain 1.26 g (26%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[CH2:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][Cl:20]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:2]([CH3:1])=[CH2:3])[C:5]1=[O:13]
Reactant: ClCCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a stirred solution of 8.5 parts of 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one in 45 parts of N,N-dimethylformamide are added portionwise 1.7 parts of a sodium hydride dispersion 78%. After stirring for 1 hour at room temperature, the whole is cooled to 0°-5° C and 8.65 parts of 1 -bromo-3-chloropropane are added dropwise (slowly). Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto crushed ice and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 5.5 parts (44%) of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one; mp. 115° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:45]=[CH:44][C:35]2[C@H:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:37][O:38][C:34]=2[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][O:30][C:32]1[CH:45]=[CH:44][C:35]2[C@H:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:37][O:38][C:34]=2[CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1ccc(OCc2ccccc2)c(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)ccc3OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
(R)-(4-(Benzyloxy)-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 36a (637 mg, 1.69 mmol) was dissolved in 20 mL of dichloromethane, followed by addition of methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (423 mg, 2.03 mmol) and triphenylphosphine (532 mg, 2.03 mmol). The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (411 mg, 2.03 mmol), then warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure to obtain the crude title compound methyl 2-((S)-6-((4-(benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 36b (1 g) as a brown oil, which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:40]([O:42][CH3:43])=[O:41].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:40](=[O:41])[O:42][CH3:43])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(C)CNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N(CC(C)C)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(isobutylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (25.6 mg, 0.0502 mmol) in CH2Cl2 (0.5 mL) was added methyl chloroformate (7.7 μL, 0.100 mmol), followed by EtN(i—Pr)2 (70 μL, 0.402 mmol) The reaction was stirred at room temperature for 24 hours, and then methyl chloroformate (7.7 μL, 0.100) and EtN(i—Pr)2 (70 μL, 0.402 mmol) were added. The reaction was stirred for 96 hours and then diluted with EtOAc (20 mL), and washed with saturated NaHCO3 solution, brine, and 1 N HCl (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded methyl [2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]isobutylcarbamate. Rf=0.29 (25% EtOAc/hexanes). LCMS=617.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.87 (m, 1H), 7.78-7.76 (m, 2H), 7.24-7.17 (m, 3H), 5.73-5.71 (m, 1H), 5.01-4.75 (m, 2H), 4.07-3.06 (m, 3H), 1.83-1.75 (m, 1H), 1.27-1.21 (m, 3H), 0.99-0.91 (m, 6H), 0.70-0.68 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH3:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.COC(OC)(OC)C1C=CC=CC=1>O.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:12])[C:4]=1[C:5]([C:18]1[C:19]([O:23][CH3:24])=[C:20]([O:21][CH3:22])[C:15]([O:14][CH3:13])=[CH:16][C:17]=1[CH3:25])=[O:7]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: Cc1c(F)ccc(F)c1C(=O)O
Agent: COC(OC)(OC)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(F)ccc(F)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
9.3 g (54.3 mmol) of 3,6-difluoro-2-methylbenzoic acid and 9.88 g (54.3 mmol) of 3,4,5-trimethoxytoluene were introduced into 250 ml of absolute dichloromethane, and 54 g (380 mmol) of pulverulent phosphorus pentoxide were then added. The mixture was stirred for 16 hours at room temperature. According to HPLC check, the trimethoxytoluene had not been reacted completely. A further 13.5 g of phosphorus pentoxide were added. After a further four hours, the reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were then dried and concentrated. The crude product was purified by reversed-phase MPLC (eluent acetonitrile/water 7:3). This gave 12.2 g of the compound I.5-02 (36 mmol, 67% yield).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:34])[C@H:9]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C@@H:8]1[C:15]([O:17][CH:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].N(CCO)(CCO)CCO.[SH2:45]>O>[CH3:6][C:7]1([CH3:34])[C@H:9]([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C@@H:8]1[C:15]([O:17][CH:18]([C:32](=[S:45])[NH2:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: S
Solvent: CN(C)C=O
Solvent: OCCN(CCO)CCO
Solvent: O
Product: CC1(C)[C@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C(N)=S)c1cccc(Oc2ccccc2)c1
Yield: 98 %

Procedure:
Into 20 ml of N,N-dimethylformamide were dissolved 2.50 g of 3-phenoxy-α-cyanobenzyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate and 1 ml of triethanolamine, and hydrogen sulfide gas was bubbled into the solution at room temperature over a period of 15 hours. The resultant reaction mixture was poured into 500 ml of water and extracted with diethyl ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate and distilled to remove diethyl ether. By the above procedure there were obtained 2.63 g of 3-phenoxy-α-thiocarbamoylbenzyl cis-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate [Compound (27)] having the NMR spectrum shown hereinbelow (yield: 98%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[C:30]([F:36])[C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20]([O:37][CH3:38])[N:19]=1>CN1C(=O)CCC1>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[C:34]2[C:29]=1[CH2:28][CH2:27][N:26]2[C:24]([C:22]1[CH:21]=[C:20]([O:37][CH3:38])[N:19]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:23]=1)=[O:25]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 25 °C

Procedure:
0.982 g (4.50 mmol) 1-Piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 500 mg (1.54 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone in 3.0 mL NMP were stirred for 12 h at 130° C. After the reaction mixture had cooled to RT the precipitate formed was filtered off and purified by preparative HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:40])=[C:33]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[OH:28]>>[CH2:1]([O:8][NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:25][CH2:26][C@H:27]([OH:28])[C:29]3[CH:30]=[CH:31][C:32]([OH:40])=[C:33]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C(=O)NOCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)NOCc4ccccc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-benzyloxy-4-(4-oxo-piperidine-1-yl)-benzamide (which was obtained in Example 155) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >70° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.40 (m, 2H), 1.70-1.90 (m, 2H), 2.50-2.95 (m, 5H), 2.92 (s, 3H), 3.70-3.85 (m, 2H), 4.47 (dd, J=8.0, 4.2 Hz, 1H), 4.89 (s, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.30-7.50 (m, 5H), 7.60 (d, J=9.0 Hz, 2H); MS (ES) m/z: 555.3 (MH+); HRMS Calcd. for C28H35N4O6S(MH+): 555.2272. Found: 555.2260.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.C(O)C>[Pt]=S.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[NH2:13]
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: S=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(CCC(=O)O)ccc1Cl
Temperature: 50 °C
Yield: 99.8 %

Procedure:
A slurry of 4-chloro-3-nitrocinnamic acid (12.2 g, 53.2 mmol), ethyl alcohol (50 mL) and ethyl acetate (20 mL) was treated with 5% Platinum sulfide on carbon (0.6 g) and was placed in a Parr autoclave. The autoclave was placed under a hydrogen atmosphere and heated overnight at 50° C. After cooling to room temperature, the reaction mixture was filtered through celite, and was concentrated in vacuo to yield 10.6 g of 3-(4-chloro-3-aminophenyl)propionic acid.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2)C1
Yield: 99.1 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.21 mmol), a solution of phenylboronic acid (222 mg, 1.82 mmol) in ethanol (1.4 ml), 2N aqueous sodium carbonate solution (5 ml) and tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.146 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (390 mg, 99.0%) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[N:26]=[C:25]([C@@:27](O)([CH3:42])[CH2:28][NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:24]([F:44])=[C:23]([Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH:22]=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[Br:20][C:21]1[N:26]=[C:25]([C:27]2([CH3:42])[CH2:28][N@@:29]2[S:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:24]([F:44])=[C:23]([Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH:22]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@](C)(O)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CC[Si](CC)(CC)c1cc(Br)nc(C2(C)C[N@]2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C2(C)C[N@@]2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of triphenylphosphine (21.55 g, 82 mmol) and (R)—N-(2-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-hydroxypropyl)-4-nitrobenzenesulfonamide (37.56 g, 69 mmol) in 510 ml THF was cooled to 4° C. A solution of diethyl azodicarboxylate in toluene (40% by weight, 38.8 g, 89 mmol) was added in a dropwise while maintaining the temperature below 10° C. The cooling bath was removed and the rm was stirred at rt for 1 h. The reaction mixture was diluted with approx. 1000 ml toluene and THF was removed by evaporation at the rotavap. The resulting toluene solution of crude product was pre-purified on a silca gel column by eluting with hexanes/5-17% EtOAc. Purest fractions were combined, evaporated and crystallized from TBME/hexane to yield 29.2 g of the title compound as white crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>O.O1CCOCC1.C(OCC)(=O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][OH:11]
Reactant: NNc1ccc(Cl)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCCc1c[nH]c2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
A mixture of (4-chlorophenyl)hydrazine hydrochloride (5.26 g; 28.50 mmol) and 3,4-dihydro-2H-pyran (2.63 mL; 28.50 mmol) in a mixture of water (9 mL) and dioxane (36 mL) was stirred at 100° C. for 48 hours. After cooling to room temperature the mixture was diluted with ethyl acetate. The aqueous layer was separated and further extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 6% methanol in dichloromethane) to afford 3.85 g (64%) of 3-(5-chloro-1H-indol-3-yl)propan-1-ol as an oily residue.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:16][C@@H:17]2[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C@H:19]([C:35]([N:37]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH:46]=[CH:45][N:44]=[CH:43]4)[CH2:38]3)=[O:36])[CH2:18]2)=CC=1.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>[SH:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)=[O:23])[C@H:19]([C:35]([N:37]2[CH2:41][CH2:40][C@H:39]([N:42]3[CH:46]=[CH:45][N:44]=[CH:43]3)[CH2:38]2)=[O:36])[CH2:18]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4ccnc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2ccnc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
585 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-(imidazol-1-yl)pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in a mixture of 5 ml of anisole and 15 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 1 hour and then at 35° C. for a further 30 minutes. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and the resulting residue was washed four times with diethyl ether, to give a colorless powder. This powder was suspended in ethyl acetate, and the suspension was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated and washed with an aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.9 g of the title compound, as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:17])([CH3:16])[O:6][C@@H:7]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]#[CH:14])[C:8]1=[O:15])([CH3:4])[CH3:3].C(NCC)C.C=O.N#[C:26][Br:27]>C(OCC)C.O1CCOCC1.C(O)(=O)C>[Br:27][CH2:26][C:14]#[C:13][CH2:12][N:9]1[CH2:10][CH2:11][C@@H:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:17])[CH3:16])[C:8]1=[O:15]
Reactant: N#CBr
Reactant: C#CCN1CC[C@@H](O[Si](C)(C)C(C)(C)C)C1=O
Agent: C=O
Solvent: CC(=O)O
Solvent: CCNCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(CC#CCBr)C1=O
Yield: 17.9 %

Procedure:
The title compound is prepared by the procedure of Example 23 using 10.7 g of (R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propargyl-2-pyrrolidinone, 8.7 ml of diethylamine, 3.2 g of paraformaldehyde, 0.10 g of cuprous chloride, 15 ml of acetic acid and 100 ml of dioxane. Ten grams of the diamine intermediate is treated with 3.5 g of cyanogen bromide in 150 ml of diethyl ether to give 2.05 g of the desired compound as a yellow oil. [α]D26° =+26° (methylene chloride).
Reaction SMILES: [OH-].[Na+].[N:3]([O:5][CH2:6]CCC)=O.[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]#[N:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(OC)(OC)(=O)=O>O.CCOCC.CC(C)=O>[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([C:20]#[N:21])=[N:3][O:5][CH3:6])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCON=O
Reactant: N#CCc1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: O
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
95% sodium hydroxide (0.40 g, 6 mmol), acetone (10 ml) and butyl nitrite (0.62 g, 6 mmol) were added to 2-phenoxybenzyl cyanide (1.05 g, 5 mmol). The mixture was stirred at room temperature for 1.5 hours. Dimethyl sulfate (0.76 g, 6 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, ether (10 ml) and 1N aqueous sodium hydroxide solution (10 ml) were added, and the mixture was stirred at room temperature for 0.5 hour. After stirring, water (100 ml) was added. The mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-phenoxy-α-methoxyiminobenzyl cyanide (1.18 g, Yield: 93.5%, E/Z=23/77).