Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.N#N.CN(C)CCN(C)C.[CH:42]([Li])([CH2:44]C)[CH3:43].C(Br)C=C>CCOCC.O>[CH2:44]([CH:21]1[N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:10]2=[N:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:31])=[CH:6][CH:5]=3)[N:8]=[C:9]2[CH2:23][CH2:22]1)[CH:42]=[CH2:43]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CCC3)cc1
Reactant: [Li]C(C)CC
Agent: CN(C)CCN(C)C
Agent: N#N
Solvent: O
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 16 h

Procedure:
Tert-butyl 2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1) (500 mg, 1.203 mmol) in Et2O (10 ml) degassed with N2 was treated with 1,2-di(dimethylamino) ethane (0.400 ml, 2.65 mmol). The mixture was cooled to −70° C. and treated with sec-butyllithium (1.4M in cyclohexane, 0.945 ml, 1.324 mmol) dropwise, maintaining the temperature at −70° C. After stirring at −70° C. for 2 hours allyl bromide (0.115 ml, 1.324 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 16 hours. The resulting mixture was added dropwise to water (100 ml) and extracted with DCM (×3). The combined organic extracts were concentrated under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-10% EtOAc in iso-hexane afforded the titled compound as a cream coloured solid;
Reaction SMILES: [C:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)=[O:29].CC(O)C>C(#N)C>[Br-:26].[CH3:35][C:32]1[S:33][CH:34]=[C:30]([C:28](=[O:29])[CH2:27][N+:13]23[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]2)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]3)[N:31]=1
Reactant: Cc1nc(C(=O)CBr)cs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CC#N
Product: Cc1nc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cs1
Product: [Br-]
Yield: 35.4 %

Procedure:
(R)-Phenyl-phenylamino-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Diastereoisomer 1 of C2) (75.0 mg, 0.22 mmol) and 2-bromo-1-(2-methylthiazol-4-yl)ethanone (I228) (49.1 mg, 0.22 mmol) in acetonitrile (5 mL) is heated at 100° C. for 75 minutes under microwave irradiation (UPLC-MS monitoring: complete conversion). The solvent is removed and the resulting brown solid is tritured with iPr20/Et2O (1/1) and then with iPrOH to obtain the title compound as a grey powder (43.3 mg, 35% yield, bromide salt, single diastereoisomers).
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[SH:7])([CH3:5])[CH3:4].[H][H].Br[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1>O1CCCC1.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.C1(C)C=CC=CC=1>[CH:11]([Si:6]([CH:3]([CH3:5])[CH3:4])([CH:8]([CH3:10])[CH3:9])[S:7][C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1)([CH3:13])[CH3:12]
Reactant: [H][H]
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(S[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC

Procedure:
1.12 g of sodium hydride are added to a solution of 5 g of triisopropylsilanethiol in 100 ml of tetrahydrofuran. When the evolution of hydrogen has ceased, 2.4 g of Pd(PPh3)4, 100 ml of toluene and 6.9 g of 1-bromo-3,4,5-trimethoxybenzene are added, and the reaction mixture is refluxed for 2 hours, and then evaporated in vacuo. Chromatography over silica gel eluted with a mixture of CH2Cl2/heptane (70/30) enables the expected product to be isolated.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([CH2:12][O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)CCl.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:8]2[C@H:9]([CH2:12][O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:11][C@@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: C[Si](C)(C)OC[C@@H]1CC[C@H](c2ccccc2)N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[Si](C)(C)OC[C@@H]1CC[C@H](c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 47.2 %

Procedure:
To a solution of (2R,5S)-2-phenyl-5-trimethylsilanyloxymethyl-pyrrolidine (0.98 g, 3.9 mmol) in ClCH2CH2Cl (5 mL) was added 1.9 mL (13.7 mmol, 3.5 eq) of Et3N and 1.45 g (6.86 mmol, 1.8 eq) of 4-chlorobenzenesulfonyl chloride. The mixture was heated at 70° C. for 16 hr. After cooling to room temperature, the mixture was diluted with CH2Cl2 (20 mL), washed with water (10 mL), saturated brine (10 mL), dried (Na2SO4) and concentrated under vacuum. The crude product was chromatographed on silica gel (2% EtOAc/hexane) to give 0.78 g (46%) of (2R,5S)-1-(4-chloro-benzenesulfonyl)-2-phenyl-5-trimethylsilanyloxymethyl-pyrrolidine as a yellow gum.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:17][C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH:13]=2)[CH:8]=1)(=O)=O.[CH:27]1[C:36]2[C:31](=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH:27]1[C:36]2[C:31](=[C:32]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([NH:17][C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH:11]=[CH:10]4)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: O=C(Nc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cccs1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc2cc(-c3cccc4cnccc34)ccc2c1)c1cccs1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a microwave vial containing 6-(thiophene-2-carboxamido)naphthalen-2-yl trifluoromethanesulfonate (0.100 g, 0.2 mmol), in 1,4-Dioxane (3 mL), was added isoquinolin-5-ylboronic acid (0.129 g, 0.8 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), and Potassium Carbonate (2 M, 0.50 mL, 1 mmol). The vial was capped and placed into CEM Microwave for 10 minutes at 80° C., while supplying 50 Watts of power through power-max. The mixture was diluted with DCM (2 mL) and water (2 mL). The aqueous layer was extracted with DCM (3×10 mL). The combined organics was dried over sodium sulfate, filtered, and concentrated in-vacuo. The crude was purified from reverse-phase HPLC. This gave a yellow colored amorphous solid, which was titled product (0.078 g, 0.2 mmol). MS (ESI pos. ion) m/z: 381 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.CCOCC>O1CCCC1.C(N(CC)CC)C>[Br:22][CH2:20][C:19]([C:7]1[CH:8]=[C:9]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:21]
Reactant: COc1c(N2CCOCC2)cc(C(C)=O)cc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(N2CCOCC2)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
After dissolving the 1-[3-(tert-butyl)-4-methoxy-5-morpholinophenyl]-1-ethanone (76 g) in tetrahydrofuran (600 ml), triethylamine (110 ml) and tert-butyl dimethylsilyltrifluoromethanesulfonate (75 ml) was added dropwise while cooling on ice. The reaction mixture was stirred for 30 minutes while cooling on ice and then N-bromosuccinimide (70 g) was gradually added. After stirring the reaction mixture for 30 minutes, 2 l of ether was added and the mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (33.7 g) as light yellow crystals.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[C:2]#[CH:3].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(OCC)C.O>[CH3:15][S:16]([O:7][CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])(=[O:18])=[O:17]
Reactant: C#CCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: C#CCOCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A solution of 1.7 g of 11b and 3 ml of triethyl amine in 20 ml of diethyl ether was treated at 0° C. with 1.5 ml of methanesulfonyl chloride. The mixture was stirred for an additional 30 min and then diluted with 35 ml of water and extracted with ethyl acetate. The combined organic layers were washed with 1M aq. K2CO3 solution and water, dried and concentrated, to provide 2.45 of 11c as a colorless oil; Rf 0.45 (heptane/ethyl acetate 1/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]=[S:12]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:11]([NH:10][C:13](=[O:14])[O:15][CH2:16][CH3:17])=[S:12])=[N:7][CH:8]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1ccc(N)nc1
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(OC)cn1
Yield: 62.3 %

Procedure:
In the same manner as in Reference Example 30 and using 5-methoxypyridin-2-amine (1.05 g, 8.43 mmol), DMSO (5 mL) and ethyl isothiocyanatoformate (1.44 g, 11.0 mmol) as starting materials, the title compound (1.34 g, 62%) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].Cl.O>N1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Yield: 78.1 %

Procedure:
Methanesulphonyl chloride (58.3 g, 0.509 mole) was added in one portion to a stirred solution of 97% 4-chloro-3-nitroaniline (86 g, 0.485 mole) in pyridine (80 ml) and xylene (500 ml). The temperature rose to 50° and the mixture was allowed to stand for a further 2 hr before addition of a mixture of 10M-hydrochloric acid (100 ml) and water (100 ml). The brown solid which was collected and washed successively with xylene (50 ml) and water (3×50 ml). The damp material was crystallized from methanol (800 ml) to give a solid which was collected, washed with methanol (2×50 ml) and dried to give the product 95 g (78%) m.p. 163°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH:29][C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (1.76 g, 11.1 mmol) and DIEA (1.93 ml, 11.1 mmol) in THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.39 mmol) in THF (5 ml) at 25° C. After addition, the reaction mixture was stirred at 80° C. for 48 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:DCM:EtOAc=2:1:1) to give the title compound as a yellow solid (0.62 g, 32%). NMR (400 MHz) 12.37 (s, 1H), 9.83 (s, 1H), 8.25 (m, 1H), 7.98 (d, J=11.2 Hz, 1H), 6.75 (m, 1H), 5.95 (s, 1H), 1.90 (m, 1H), 0.96 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14](O)=[CH:13][C:12]=2[CH2:11][C@H:10]4CCCCCO)[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH3:5][C@:4]12[CH2:20][CH2:19][C@H:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=43)[C@@H:6]1[CH:7]=[CH:8][C:3]2=[O:2]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1C=CC2=O

Procedure:
A solution of 36.12 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 hours at room temperature with 2.76 g of para-toluenesulfonic acid. Then, it is concentrated by evaporation in a vacuum to ⅓ of the volume, taken up with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 31.7 g of 3-hydroxy-7α-5-hydroxypentyl)-estra- 1,3,5(10),15-tetraen- 17-one is obtained as crystals with a melting point of 194-196° C.
Reaction SMILES: O=O.FC(F)(F)C(O)=O.[Cl:10][C:11]1[CH:12]=[C:13]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[CH:20][C:19]([C:33]([N:35]3[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]3)=[O:34])=[N:18]2)[CH:14]=[CH:15][CH:16]=1.ClC1C=C(N2C(C3C=CC=C(OC(F)(F)F)C=3)=CC(C(O)=O)=N2)C=CC=1.N1(C(OC(C)(C)C)=O)CCNCC1>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:31])([F:30])[F:32])[CH:23]=3)=[CH:20][C:19]([C:33]([N:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]3)=[O:34])=[N:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3cccc(OC(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: O=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
Under exclusion of oxygen, 5 ml of dichloromethane and 1 ml of trifluoroacetic acid were added to 140 mg (0.25 mmol) of tert-butyl 4-{[1-(3-chlorophenyl)-5-(3-trifluoromethoxy-phenyl)-1H-pyrazol-3-yl]carbonyl}piperazine-1-carboxylate, prepared from the compound of example 9A and tert-butyl piperazine-1-carboxylate in analogy to example 1, and the mixture is stirred for 12 hours at room temperature. The reaction mixture is diluted with dichloromethane and washed with a sodium bicarbonate solution and a sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. 101 mg (88% yield of theory) of product are obtained. By thorough drying in high vacuum at 60° C. an analytical sample is freed of solvent residues.
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH2:16][OH:17])[C@H:11]([Br:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH2:16][O:17][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C@H:11]([Br:18])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1ccccc1)N1C[C@@H](Br)[C@H](OCCO)C1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CN(C(=O)c3ccccc3)C[C@H]2Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
92 g (0,239 mol) of trans-1-benzoyl-3-bromo-4-(2-hydroxyethoxy)-pyrrolidine, 32 g (0.316 mol) of triethylamine, and 1 g of 4-dimethylaminopyridine are dissolved in 750 ml of toluene. 60 g (0.31 mol) of tosyl chloride in 450 ml of toluene are added dropwise. The batch is stirred two days at room temperature, water is added, and the aqueous phase separated and extracted with toluene. The toluene solutions are washed with 10% hydrochloric acid, dried over magnesium sulfate, concentrated, dissolved in ethyl acetate, and filtered through silica gel. The filtrate is concentrated.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>O1CCCC1>[CH3:4][C:2]([C:5]1[C:10]([O:11][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:1])[CH3:3]
Reactant: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-hydroxy-2-methyl pyrimidine (9.8 g, 44.1 mmoles) is dissolved in 100 mL of tetrahydrofuran and added dropwise to a suspension of sodium hydride (1.2 g, 48.5 mmoles) in THF (50 mL) at 0° C. The reaction mixture is warmed to room temperature over 15 minutes. 2-Methoxy-ethoxymethyl chloride (7.1 g, 57.3 mmoles) is added to the reaction mixture at room temperature. After being stirred at room temperature for 4 hours, the reaction is quenched by the addition of saturated ammonium chloride and the tetrahydrofuran is evaporated. The organics are extracted into 300 mL of ether. The ether is washed with 100 mL of brine and dried over magnesium sulfate. Evaporation of the solvent gives the crude product which is purified by flash chromatography (silica, 10% ether/hexane). Yield of 4,6-bis (1,1-dimethylethyl)-5-[(2-methoxyethoxy) methoxy]-2-methylpyrimidine=11.3 g (82%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:9]2([CH:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:33][C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])[CH2:13][C:12](=[O:14])[NH:11][CH:10]2[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[CH3:22])[C:23]1=[O:32])(=[O:48])[CH3:47]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 2 h
Yield: 78.3 %

Procedure:
At room temperature, to a mixture of racemic (2′S, 3S, 4′R)-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (540 mg, 0.8 mmol) and acetic anhydride (98 mg, 0.96 mmol) in DCM (20 mL) was added DMAP (10 mg, 0.08 mmol) slowly. After the mixture was stirred for 2 h, the solution was washed by 0.5N HCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give the title compound as a white solid (450 mg).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC=C(Cl)C=1)=[O:6])[CH3:3].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]O)=O)[CH:20]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>C(Cl)CCl>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[O:27]1)=[O:6])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)NC(=O)C(=O)C=Cc1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: CC(C)NC(=O)C1OC1c1cccc(Cl)c1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-chlorocinnamoylcarboxamide (22.4 g.), m-chloroperbenzoic acid (23.6 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.3 g.), and ethylene dichloride as described in Example 7, and purified by recrystallization from ether. The compound melted at 131°-133°, and weighed 14.5 g.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.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:8]1([CH3:7])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1cccs1
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
Product: Cc1ccccc1-c1cccs1
Temperature: 25 °C
Yield: 344.3 %

Procedure:
Sodium carbonate (5 ml., 2M aqueous solution) followed by 2-methylphenylboronic acid (0.294 g, 2.4 mmol) were added to a solution of 2-bromothiophene (0.542 g, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg) in toluene (5 ml) and ethanol (5 ml) under nitrogen. The mixture was refluxed for 2 hours, cooled to room temperature and extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and evaporated. The residue was flash chromatographed on silica gel using hexane as eluent to afford 1.2 g of 2-(2-tolyl)thiophene as a colorless gum.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:21]>CO>[CH2:1]([O:8][CH2:9][C:10]([NH2:21])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)C=C(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 14.48 g (0.6129 mol) of ethyl 4-benzyloxy-3-oxo-butanoate in 145 ml of methanol, 20.54 g (0.3258 mol) of ammonium formate was added, and the resulting mixture was heated under reflux for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was evaporated off under reduced pressure. To the reside, 100 ml of ethyl acetate and 100 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, washed twice with each 50 ml of a brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective ethyl 4-benzyloxy-3-amino-2-butenoate (7.61 g, colorless liquid). The yield was 52.8%.