Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]=2[CH3:20])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH3:20])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2nc(C(C)(C)C)cs2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)cs1

Procedure:
Methyl 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoate (Step A, 7.3 g, 25.2 mmole) was stirred with lithium hydroxide (1.5 g, 63.5 mmol) in 20 mL of 1,4-dioxane and 10 mL of water for 3 hours. It was concentrated to dryness to collect 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoic acid as a white solid. This was used in the next step without any further purification. LCMS (M+H)+: 276.0
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([OH:33])=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(O)CBr
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11]C(OC)OC)[C:5]=1[N+:17]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[Pd].O>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([N:17]2[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:3][OH:20])[CH:10]=[CH:11]2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1cccc(CCC(OC)OC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3cccc(CO)c32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Hydrogenate 3-(3,3-dimethoxypropyl)-2-nitrobenzoic acid methyl ester (7.8 g, 0.029 mol) in 100 mL of tetrahydrofuran with 0.743 g 5% Pd/C at 60 psi for 24 hours. Filter and concentrate. Dissolve the resulting product in 30 mL of tetrahydrofuran, and add it dropwise to a suspension of lithium aluminum hydride (2.2 g, 0.058 mol) in 100 mL of tetrahydrofuran at 0° C. Allow the reaction to warm to room temperature, and stir for 2 hours. Quench the mixture with saturated Rochelle salt and extract with ethyl acetate. Dry and concentrate. Dissolve the product in in 30 mL of acetic acid and add 4-oxopiperidine-1-carboxylic acid tert-butyl ester (6.3 g, 0.032 mol). After 10 minutes, add sodium cyanoborohydride (9.2 g, 0.032 mol) and stir the mixture for 1 hour. Heat the mixture at 100° C. for 3 hours, cool, and pour into water. Neutralize the solution with potassium carbonate and extract with ethyl acetate. Dry and concentrate. Dissolve the crude mixture in 100 mL of methanol and treat with 20 mL of 1N sodium hydroxide for 3 hours. Remove the methanol in vacuo, and extract the mixture with ethyl acetate. Dry and concentrate. Purify by flash chromatography using 4:1 hexanes/ethyl acetate to give 4.1 g of 4-(7-hydroxymethylindol-1-yl)piperidine-1-carboxylic acid tert-butyl ester. FAB MS 330.
Reaction SMILES: [CH2:1]1[C:3]2([CH:9]([C:10]([OH:12])=[O:11])[C:4]32[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:2]1.S(Cl)(Cl)=O.O[CH2:18][N:19]1[C:23](=[O:24])[C:22]2[CH2:25][CH2:26][CH2:27][CH2:28][C:21]=2[C:20]1=[O:29].C(N(CC)CC)C>C1C=CC=CC=1.CCOCC>[CH2:2]1[C:3]2([CH:9]([C:10]([O:12][CH2:18][N:19]3[C:20](=[O:29])[C:21]4[CH2:28][CH2:27][CH2:26][CH2:25][C:22]=4[C:23]3=[O:24])=[O:11])[C:4]32[CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:1]1
Reactant: O=C(O)C1C2(CCCC2)C12CC2
Reactant: O=C1C2=C(CCCC2)C(=O)N1CO
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(OCN1C(=O)C2=C(CCCC2)C1=O)C1C2(CCCC2)C12CC2

Procedure:
Dispiro(2.0.4.1)nonan-9-carboxylic acid (0.66g) was converted to the corresponding acid chloride by refluxing with thionyl chloride (1ml) in benzene (20 ml) for 1 hour. The acid chloride, N-hydroxymethyl-3,4,5,6-tetrahydrophthalimide (0.7g) and triethylamine (0.5g) were then stirred together in ether (50 ml) for 6 hours. After removal of solvent under reduced pressure the residue was purified by chromatography on silica gel using dichloromethane as eluent. The required product was obtained as an oil R.I. nD18 1.5318.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2O[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.FC(F)(F)C(O)=O>C(O)CCC>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:26]([CH:23]3[CH2:25][CH2:24]3)[CH:19]=[N:20][N:21]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)OCc1ccccc1
Temperature: 110 °C
Yield: 30.8 %

Procedure:
A mixture of (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester (200 mg, 0.68 mmol), cyclopropylamine (0.5 mL, 7.2 mmol), trifluoroacetic acid (0.05 mL, 0.65 mmol) in anhydrous 1-butanol (3 mL) was heated at 110° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature and the solvent was removed. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. Solvent was removed after drying with sodium sulfate and purified by silica gel chromatography (rf=0.26 in 20:1 ethyl acetate/methanol) to obtain [3-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-phenyl]-carbamic acid benzyl ester as a white powder (70 mg, 31%). M+1=335.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][C:21](OCC)=[O:22])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH2:21][OH:22])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCO)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propanoate (3.39 mmol. 1 eq) in THF (10 ml) was slowly to a suspension of LAH (7.47 mmol, 2.2 eq) in THF (7.5 ml) at 0° C. and the mixture was stirred for 30 min. The mixture was subsequently warmed to room temperature and stirred for 1 h. A water/THF mixture was then added, the mixture was filtered over Celite and the filtrate was concentrated in vacuo. The crude product (0.88 g) was employed in the following stage without further purification.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([N:25]1[CH2:9][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(Br)CCBr
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN1Cc1ccccc1
Yield: 52.4 %

Procedure:
(Wasserman, H. H. et al. J Org. Chem. 1981, 46(15), 2991-2999). A mixture of (±)ethyl 2,4-dibromobutanoate (39) (15 g, 54.8 mmol), triethylamine (16.6 g, 164 mmol) and benzylamine (5.87 g, 54.8 mmol) was heated to reflux for 3 hours then concentrated under reduced pressure to give a solid suspension. Water (150 ml) was then added and the mixture extracted with ether (2×100 ml). The organic phase was dried and then concentrated under reduced pressure and the residue purified by dry flash chromatography on silica (hexanes then 1:3 ethyl acetate/hexanes) to give 40 as a pale yellow oil (6.3 g, 53%); 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 4.16-4.03 (m, 2H), 3.82 (d, J=12.6 Hz, 1H), 3.73 (dd, J=8.4, 8.4 Hz, 1H), 3.61 (d, J=12.8 Hz, 1H), 3.34 (ddd, J=7.4, 7.4, 2.0 Hz, 1H), 2.95 (ddd, J=7.4, 7.4, 7.4 Hz, 1H), 2.44-2.31 (m, 1H), 2.27-2.16 (m, 1H), 1.20 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.5, 137.1, 129.0, 128.7, 128.2, 127.1, 64.5, 62.4, 60.5, 50.8, 21.5, 14.0.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1>>[CH2:1]([C:8]1[S:9][C:10]([C:15]2[C:14]([Br:13])=[CH:19][N:18]=[C:17]([Cl:20])[N:16]=2)=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccs2)cc1
Reactant: Clc1ncc(Br)cn1
Product: Clc1ncc(Br)c(-c2ccc(Cc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-benzylthiophene and 5-bromo-2-chloropyrimidine in a manner analogous to Example 255, Step 1. MS (M+H)+ 365.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH:21][C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-])=O)=[N:17][NH:16][C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].C(O)C>>[CH3:3][C:2]([NH:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH:21][C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH2:29])=[N:17][NH:16][C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)(NC(=O)c1cc2[nH]nc(NC(=O)c3ccccc3[N+](=O)[O-])c2o1)c1ccccc1
Solvent: CCO
Product: CC(C)(NC(=O)c1cc2[nH]nc(NC(=O)c3ccccc3N)c2o1)c1ccccc1
Yield: 59.3 %

Procedure:
To a solution of 3-(2-Nitro-benzoylamino)-1H-furo[3,2-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide (1 g, 0.0023 mol) in ethanol (30 mL) tin chloride dihydrate (2.08 g, 0.00923 mol) was added. The mixture was heated to reflux for 4 hours. After cooling, the solvent was evaporated to dryness and the crude purified by flash column chromatography on silica gel (eluting with dichloromethane-methanol 4713. The isolated product was triturated with ethyl ether and dry under vacuum, furnishing 550 mg of the title compound (59% yield).
Reaction SMILES: [CH:1]1([C:5]([CH2:10][SH:11])([CH2:8][SH:9])[CH2:6][SH:7])[CH2:4][CH2:3][CH2:2]1.[CH3:12]OC(OC)OC>C1C=CC=CC=1>[CH:1]1([C:5]23[CH2:6][S:7][CH:12]([S:9][CH2:8]2)[S:11][CH2:10]3)[CH2:2][CH2:3][CH2:4]1
Reactant: SCC(CS)(CS)C1CCC1
Reactant: COC(OC)OC
Solvent: c1ccccc1
Product: C1CC(C23CSC(SC2)SC3)C1
Yield: 41.2 %

Procedure:
A mixture of 2-cyclobutyl-2-mercaptomethylpropane-1,3-dithiol (4 g, 20 mmol), trimethylorthoformate (2.5 g, 24 mmol) and Amberlyst 15 ion-exchange resin (1 g) was heated to reflux with stirring under a nitrogen atmosphere for 1 hour in dry benzene (100 ml). The mixture was filtered and evaporated to leave a residue which was washed with diethyl ether to give 4-cyclobutyl-2,6,7-trithiabicyclo[2.2.2]octane as a white solid (1.8 g, 43%) mp 112°-114° C., [M+1]+ 219.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:30])[C@@H:20]([NH2:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].O.[C:37]([O:40][C:41]1[C:42]([CH3:50])=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45])(=[O:39])[CH3:38]>C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:30])[C@@H:20]([NH:29][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[C:41]([O:40][C:37](=[O:39])[CH3:38])[C:42]=1[CH3:50])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)CSc1ccccc1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccc(C(=O)N[C@@H](CSc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)c1C
Yield: 101.1 %

Procedure:
(3S, 4aS, 8aS)-2-((2R, 3R)-3-Amino-2-hydroxy-4-phenylthiobutyl)-decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [14], 9.39 g) and sodium hydrogencarbonate (4.55 g, 54.2 mmol) were added to a suspension of water (40 ml) and ethyl acetate (40 ml). A solution of 3-acetoxy-2-methylbenzoyl chloride (4.37 g, 20.6 mmol) in ethyl acetate (40 ml) was dropwise added to the suspension with stirring under ice-cooling. The mixture was further stirred for one hour under ice-cooling and water (20 ml) was added. The organic layer was separated and washed with a saturated aqueous solution (20 ml) of sodium hydrogencarbonate. After drying over magnesium sulfate, the solvent was distilled away under reduced pressure to give (3S, 4aS, 8aS)-2-[(2R, 3R)-3-(3-acetoxy-2-methylbenzoylamino)-2-hydroxy-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide (12.7 g, yield 96%) as colorless amorphous. 1H-NMR (CDCl3, 300 MHz) δ: 7.5-7.1 (m,8H), 7.1-7.0 (m,1H), 5.51 (brd.s,1H), 4.48 (m,1H), 4.07 (m,1H), 3.81 (dd,J=13.7,9.2Hz,1H), 3.41 (dd,J=13.7,4.7Hz,1H), 2.91 (dd,J=11.7,2.0Hz,1H), 2.56 (dd, J=12.9,9.1Hz,1H), 2.44 (m,1H), 2.32 (s,3H), 2.27 (s,3H), 2.3-2.1 (m,2H), 1.99 (m,1H), 1.9-1.1 (m,11H), 1.07 (s,9H)
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17]2)[CH:11]=1)[C:6](=[O:8])[O-:7])(C)C>[Pd].CO>[NH:18]1[CH2:19][CH2:20][CH:16]([C:12]2[CH:11]=[C:10]([CH2:9][NH:5][C:6](=[O:8])[O:7][C:10]([CH3:15])([CH3:11])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17]1
Reactant: CC(C)(C)N(Cc1cccc(C2CCN(Cc3ccccc3)C2)c1)C(=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C2CCNC2)c1
Yield: 175.9 %

Procedure:
A suspension of 1,1-dimethylethyl[[3-[1-(phenylmethyl) -3-pyrrolidinyl]phenyl]methyl]carbamate (4.50 g, 12.3 mmol) and 20% palladium on charcoal catalyst (0.30 g) in methanol (100 mL) was hydrogenated in a Parr apparatus at 3 atm. The suspension was filtered through a pad of Celite and the filtrate concentrated to give an orange oil. This oil was chromatographed (silica gel, dichloromethane-methanol 1:1 containing 1% ammonia) to give the title compound (2.99 g, 88%) as a pale yellow oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CO.[CH3:11][Si](C=[N+]=[N-])(C)C>C(OCC)C>[CH3:11][O:7][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CCCCC(=O)O
Solvent: CCOCC
Solvent: CO
Product: C=CCCCC(=O)OC

Procedure:
Hex-5-enoic acid methyl ester was prepared as follows. Hex-5-enoic acid (2.00 g, 17.5 mmol) was dissolved in diethyl ether (8 mL) and methanol (4 mL) and cooled to 0° C. To this solution was added 2.0 M Trimethylsilyl diazomethane (9 mL) dropwise. It was noted that a yellow TMS-diazomethane solution dissipates upon stirring with the reaction mixture, and the reaction is deemed complete when the yellow color persists. Caution should be observed, as the reaction is associated with vigorous gas evolution. When the yellow color persists in the reaction mixture, TLC analysis was conducted and confirmed consumption of the acid. The solvent was evaporated under reduced pressure carefully (product is somewhat volatile) and replaced with ethyl acetate. The solution was washed with saturated NaHCO3, dried, and the filtrate was used directly in the next step. 1H NMR (400 MHz) CDCl3 δ 5.45 (m, 1H), δ 4.9 (m, 2H), δ 3.65 (s, 3H), δ 2.20 (t, 2H), δ 2.05 (m, 2H), δ 1.70 (m, 2H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:30][C@H:31]2[O:33][CH2:32]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C>[O:33]1[CH2:32][C@H:31]1[CH2:30][O:14][C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9H-Carbazol-4-ol (0.367 g, 2.0 mmol) was placed in a flask with DMF (10 mL) and NaH (60% dispersion in oil, 77 mg, 2.0 mmol) and stirred for 30 min at room temperature. (S)-glycidyl 3-nitrobenzene sulfonate (0.52 g, 2.0 mmol) was added to the reaction mixture, which was then stirred at room temperature for 14 hours. The reaction was quenched with NaHCO3 (saturated) and then extracted with ethyl acetate (3×). The organic layer was dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield crude product which was purified by silica gel chromatography (60% Ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Si]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[SiH3]O[SiH3].ClCCl.CO.N>C1COCC1>[OH:26][CH:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][N:12]=3)=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(Cc2ccc(N)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CN2CCC(O)CC2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [5-(4-chlorophenyl)pyridin-2-yl]propynoic acid and 4-[4-(tert-butyldimethylsilanyloxy)piperidin-1-ylmethyl]phenylamine. The cleaving of the silyl group is carried out by adding tetrabutylammonium fluoride to a solution of the silylether in THF. Yield: 0.25 g (43% of theory); melting point: 186° C.-190° C.; C26H24ClN3O2 (M=445.94); calc.: molecular ion peak (M+H)+: 446/448; found: molecular ion peak (M+H)+: 446/448; Rf value: 0.6 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=NOCCO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc(F)cc2)cc1
Yield: 89.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 547 mg of 2-[1-(4'-fluorobiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 27), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.29 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][O:7][C:8]1[C:9](=O)[C:10](=[O:14])[C:11]=1[O:12]C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[Cl-]>CCCCCC.C1COCC1.CCOC(C)=O>[CH2:2]([C:9]1[C:10](=[O:14])[C:11](=[O:12])[C:8]=1[O:7][CH3:6])[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: COc1c(OC)c(=O)c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCc1c(OC)c(=O)c1=O
Reaction time: 2 h
Yield: 48 %

Procedure:
n-BuLi (8.13 ml of a 1.6M solution in hexane, 13 mmol) was added slowly to a solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione (1.42 g, 10 mmol) in THF (100 ml) at −78°. After 2 h, trifluoroacetic anhydride (2.12 ml, 15 mmol) was added. After a further 30 min the cold solution was poured into NH4Cl(aq) (100 ml) and EtOAc (100 ml) and stirred well. The aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 30:70) gave the title compound as a yellow oil (803 mg, 48%). δH (CDCl3) 4.42 (3H, s), 2.60 (2H, t, J 7.6 Hz), 1.71-1.61 (2H, m), 1.44-1.32 (2H, m), 0.94 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 169 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[NH2:24]>>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:28][CH:27]=1)(=[O:25])[NH2:24]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(N)=O)cc3)c(F)cn2c1=O
Yield: 85.9 %

Procedure:
Ethyl 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and (4-carbamoyl-phenyl)-boronic acid (305.7 mg, 1.85 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (540 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.6 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.85 mmol of 1-(3-amino-propyl)-pyrrolidin-2-one LC/MS [8.70 min; 483 (M+1)].