Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([OH:21])[CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C(O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CNCC=C1c1ccc(F)cc1

Procedure:
To a dichloromethane solution (14 mL) of tert-butyl 4-(4-fluorophenyl)-3,4-dihydroxypiperidine-1-carboxylate (1.45 g, 4.66 mmol) synthesized in Reference Synthesis Example 39, trifluoroacetic acid (14 mL) was added and the resultant solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure by 4 mL and saturated sodium bicarbonate aqueous solution was added to the concentrated solution, followed by extraction from the resultant mixture with ethyl acetate three times. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography to obtain the title compound of Reference Synthesis Example 40a (189 mg, yield 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.[ClH:12]>CO>[ClH:12].[ClH:12].[NH2:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: COC(=O)c1cncc(N)c1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CNC[C@H](N)C1

Procedure:
To the solution of methyl 5-aminopyridine-3-carboxylate (700.0 mg) in MeOH (20 ml) was added 2 M aqueous solution of HCl (7 ml). And the mixture was hydrogenated (ca. 4 atm) for 1 day in a Parr low-pressure hydrogenation apparatus with a 5 wt. % Rh on Al2O3 catalyst (451.9 mg) at 80° C. Rh on Al2O3 catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was solidified from the mixed solvent of CHCl3 and MeOH to give methyl cis-5-aminopiperidine-3-carboxylate dihydrochloride as a cream-colored solid.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18].Cl>C(O)C>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[N:12]=[C:17]([OH:18])[CH:16]=[C:15]([OH:22])[N:11]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccc(Cl)cc2)n1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
To sodium ethoxide (48 ml of a 21% wt solution in ethanol diluted with a further 130 ml ethanol) was added 4-chlorobenzamidine (8 g) and diethyl malonate (6.67 ml) and the solution left to stir at 40° C. for 96 hrs. The reaction mixture was subsequently cooled to 5° C. and acidified cautiously to pH 2 using concentrated hydrochloric acid. The solid thus precipitated was filtered, washed with excess cold water, then 50 ml diethyl ether and dried in vacuo yielding the title compound (7.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][NH2:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:21]/[NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:19])[CH:3]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N/N=C/c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromopicolinaldehyde (2.0 g, 10.8 mmol) and 4-methylbenzenesulfonohydrazide (2.0 g, 10.8 mmol) were mixed in MeOH (20 mL) and dichloromethane (20 mL). The mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure to give 3.80 g (theoretical) of the title compound as a yellow solid m/z ES+ 354, 356 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]C(O)=O)=[CH:24][CH:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:20])[NH:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:3]2[C:4](=[O:5])[CH:6]3[CH:11]([C:12](=[O:13])[C:2]=2[CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7]3)=[CH:26][CH:27]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: CC1=C(Cc2ccc(NC(=O)OC(C)(C)C)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 12 %

Procedure:
As starting materials for the coupling reaction menadione and (4-tert-Butoxycarbonylamino-phenyl)-acetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (cyclohexane:ethyl acetate=3:1, UV), 527 mg (1.4 mmol, 12% yield) of P_TM45 were isolated as yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCNCC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)c(C)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of 0.80 g (2.70 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.41 g (3.20 mmol) of N-ethyl-3-pyrrolidinemethanamine, 0.82 g (8.10 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The precipitate was filtered, washed with acetonitrile and ether, and dried to give 0.90 g of the title compound, mp 198°-199° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].CC(C)([O-:19])C.[K+].[OH-].[K+].Cl>O.CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([OH:19])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(Cl)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c(Cl)c1O
Temperature: 85 °C
Yield: 20.9 %

Procedure:
A solution of 2,3-dichloro-4,6-dinitrophenol (2.2 g, 0,008 mol, from previous example), 4.5 g of potassium t-butoxide, 0.4 g of potassium hydroxide, 30 mL of N-methyl pyrrolidinone, and 15 mL of water in a 100 mL round-bottomed flask with stir bar is heated to 85° C. for 6 hours. Upon completion, the reaction mixture is poured into 50 mL of aqueous hydrochloric acid. The resulting product is isolated by filtration, washed with cold water, and air dried. The product is recrystallized from a minimal amount of methanol to yield 1.97 g of 2-chloro-4,6-dinitroresorcinol (95% yield) (85% overall from 1,2-dichloro-3,5-dinitrobenzene).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(CCCCO)cc1OC
Yield: 98.4 %

Procedure:
4-(3,4-Dimethoxyphenyl)butyric acid (13 g, 58 mmol) was dissolved in dry THF (150 mL) then BH3.THF (110 mL, 1M solution, 110 mmol) was added drop wise with vigorous stirring under an argon atmosphere. The reaction mixture was then stirred overnight at room temperature. After this time, the reaction was quenched with water and 10% HCl solution at 0° C. and extracted with ethyl acetate. The organic fraction was dried with sodium sulfate and passed through a pad of silica gel. The solvent was removed at reduced pressure to give 23 (12.0 g, 99%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.62 (m, 4H), 2.0 (s, 1H), 2.62 (m, 2H), 3.65 (m, 2H), 3.82 (s, 3H), 3.84 (s, 3H) 6.67-6.82 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20](Br)[CH:21]=[CH2:22]>C1COCC1>[CH2:22]([NH:9][C:3]1[C:2]([Br:1])=[N:7][C:6]([Br:8])=[CH:5][N:4]=1)[CH:21]=[CH2:20]
Reactant: Nc1ncc(Br)nc1Br
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCNc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 3,5-dibromo-pyrazin-2-ylamine (5.06 g, 20.00 mmol) in 100 mL of THF was added a solution of LiHMDS in THF (1M, 24 mL) at RT. The reaction mixture was stirred at RT for 2 hr, then allyl bromide (3.5 mL, 40 mmol) was added. The reaction mixture was stirred at RT overnight and quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried (MgSO4) concentrated, and purified by SiO2 chromatography (200 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 3.51 g of allyl-(3,5-dibromo-pyrazin-2-yl)-amine as a yellow oil (60% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:19])(=[N:12][C:13](=[O:18])[NH:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.Cl.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([CH3:19])(=[N:12][C:13](=[O:18])[NH:14][CH:15]([CH3:16])[CH3:17])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)NC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)NC(=O)N=S(C)(=O)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
18.61 g iron powder in 198 ml ethanol and 1.93 ml conc. hydrochloric acid were stirred for 30 minutes at room temperature. 7.8 g (27.34 mmol) (RS)—S-(3-nitrophenyl)-N-(isopropylcarbamoyl)-S-methylsulfoximide in 20 ml methanol were added. The mixture was stirred at 60° C. for 2 hours and filtered over a bed of silica gel. The residue was washed with hot ethanol. The combined filtrates were evaporated. The crude residue was purified by column chromatography (silica gel, dichloromethane:dichloromethane/ethanol 1:1) to give 4.53 g (65% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27]>C1(OC2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A mixture of 2 (500 mg, 2.95 mmol), potassium carbonate (1.62 g, 11.8 mmol) and 2-fluoro-4-nitrophenol (603 mg, 3.85 mmol) were heated to 170° C. in diphenyl ether (10 ml) for 5 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography, eluent gradient EtOAc-hexane (9:1) to EtOAc, to afford the title compound 3 (660 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.60 (d, J=5.54 Hz, 1H), 8.14 (m, 3H), 7.80 (d, J=5.47 Hz, 1H), 7.61 (d, J=5.48 Hz, 1H), 7.36 (t, J=7.63 Hz), 6.65 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)=[CH:20][C:19]=1[F:18]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: COC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1F

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-fluoro-4-methoxycarbonyl-phenylboronic acid gives “A80”; method 1: HPLC/MS: 1.48 min, [M+H]=367;
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:22][Si](C)(C)C)=[C:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:16][O:17][C:18](=[O:22])[C:19]([CH3:21])([CH3:20])[CH:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: OC(c1cccc(F)c1)c1ccc(Br)s1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1cccc(F)c1)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of (5-bromo-thiophen-2-yl)-(3-fluoro-phenyl)-methanol (3.40 mmol) and (1-methoxy-2-methyl-propenyloxy)-trimethyl-silane (3.45 ml, 17 mmol) in dichloromethane (10 ml) at 0° C. was added a solution of titanium tetrachloride in dichloromethane (1M solution, 7.4 ml, 7.4 mmol) slowly. After being stirred at 0° C. for 10 minutes and room temperature for 3 hours, the reaction mixture was poured onto an iced aqueous K2CO3. The solution was extracted with dichloromethane. The organic layer was washed, dried (MgSO4) and concentrated to give 3-(5-bromo-thiophen-2-yl)-3-(3-fluoro-phenyl)-2,2-dimethyl-propionic acid methyl ester as a viscous yellow oil (1.104 g, 87.5% yield). LC/MS (m/z) 393.13 [(M+23)+]; HPLC Rt: 3.883 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][N:12]3[C:16](=[O:17])[CH2:15][CH2:14][C:13]3=[O:18])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][N:12]3[C:16](=[O:17])[CH2:15][CH2:14][C:13]3=[O:18])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=C1CCC(=O)N1Cc1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (459 mg, 1.72 mmol) (obtained as described in Reference Example 69(2)) in methylene chloride (50 ml) were added methanesulfonyl chloride (0.16 ml, 2.06 mmol) and triethylamine (0.29 ml, 2.06 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (515 mg, yield 87%) as a pale yellow solid.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:26]2[N:27]=[C:28]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[S:29][C:30]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:16]=1[F:15]
Reactant: Fc1cc(CBr)ccc1Cl
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(F)c1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxy late (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(O[CH:6]([CH3:8])[CH3:7])=O.[CH2:15]([O:17][C:18]([C:20]1[N:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([OH:29])=[CH:24][CH:23]=2)=[O:19])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C>O1CCCC1>[CH2:15]([O:17][C:18]([C:20]1[N:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH:6]([CH3:8])[CH3:7])=[CH:24][CH:23]=2)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1cc2cc(OC(C)C)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropyl azodicarboxylate (0.15 ml, 0.75 mmol) was added to an anhydrous tetrahydrofuran (THF) solution (2.5 ml) of 5-hydroxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (175 mg, 0.48 mmol), triphenylphosphine (197 mg, 0.75 mmol), and 2-propanol (0.2 ml, 4.0 mmol), and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-isopropoxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colorless gum-like material (166.7 mg, 87%).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:32])[CH2:27][CH2:26]1
Reactant: CN1CCC(C(=O)O)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 42.7 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1methyl-4-piperidinecarboxylic acid hydrochloride (5.4 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.7g), and after the residue obtained has been recrystallized twice successively in ethanol and then in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-1-oxo-3-isoindolinyl 1-methyl-4-piperidinecarboxylate (5.6 g), m.p. 136° C. and then 157° C., is obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([NH:29]C(=O)OC(C)(C)C)[CH2:21][O:22]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](OC[C@H](N)CO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 2 L three neck flask fitted with a thermometer, mechanical stirrer, under argon was added 4 (46 g, 0.089 mol) and CH2Cl2 (1 L). The clear colorless solution was cooled to 0° C. with an ice/methanol bath. The TFA (132 g, 1.16 mol) was added in one portion. After stirring for 3 hr 30 min and allowing to warm to 20° C., the reaction was complete by HPLC. The reddish brown solution was concentrated under reduced pressure. Toluene (1×100 mL and 1×50 mL) was added to the residue and twice concentrated to remove excess TFA. To the resulting red oil was added methanol (600 mL) and water (200 mL). Potassium carbonate (110 g) was added to the resulting solution and stirred vigorously for 2 hr and 15 min. Dichloromethane (1.2 L) was added to the stirring solution. The aqueous layer was separated and extracted with CH2Cl2 (1 L). The organic layers were combined and dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to 44 g of a cloudy orange oil. The oil was dissolved in CH2Cl2 (200 mL) and dried again over MgSO4 (6 g), filtered and concentrated under reduced pressure to 39 g of product 5 as an orange oil. HPLC analysis showed a purity of 54% at a retention time of 2.8 min at 215 nm (Hewlett Packard series 1100 HPLC instrument, using an Alltech Alltima column (C18, 5μ, 250×4.6 mm), with a flow rate of 1.0 mL/min at 40° C., conditions 0:5:95; Water:Al:MeOH, Al consists of 700 mL of water, 300 mL of methanol, and 3 mL of triethylamine adjusted to pH 3.4 with phosphoric acid). There were three major impurities by HPLC at retention times of 3.1 min (21%), 3.4 min (15%) and 3.8 min (9%). The product 5 was carried on without further purification 1H NMR (60 MHz, CDCl3) δ 7.0-7.7 (m, 10H), 3.4-3.9 (m, 5H), 1.8-2.2 (br s, 1H), 1.1 (s, 9H).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][N:13]([C+:15]([N:17]([CH3:19])[CH3:18])Cl)[CH3:14].[CH3:20][N-:21][CH3:22].[Li+]>C(#N)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][N:13]([CH3:14])[C:15](=[N+:21]([CH3:22])[CH3:20])[N:17]([CH3:19])[CH3:18]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: C[N-]C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.50 g (4.89 mmol) of bis(dimethylamino)chlorocarbenium tosylate and 0.25 g (4.90 mmol) of lithium dimethylamide are dissolved in 15 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 5 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 1.49 g of hexamethylguanidinium tosylate, corresponding to a yield of 96.6%.