Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH:18]1[CH2:28][CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]1([C:5]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[CH:4][CH2:3][CH2:2][N:18]2[CH2:28][CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCC=C(c1ccccc1)c1ccncc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CCCN(CCC=C(c2ccccc2)c2ccncc2)C1

Procedure:
1-Bromo-4-phenyl-4-(4-pyridyl)but-3-ene (1.0 g, 3.5 mmol), ethyl nipecotate (0.72 g, 4.6 mmol) and potassium carbonate (1.93 g, 14.0 mmol) in acetone (30 ml) were stirred at room temperature for 5 days. The reaction mixture was filtered, and evaporated to a residue which was purified by flash chromatography on silica gel (Merck Art 9385). Elution with dichloromethane/ethanol/25% ammonium solution (190:9:1) provided the title compound as an oil. T.l.c. rf=0.23 (SiO2, CH2Cl2 /EtOH/NH3 (190:9:1)).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[C:9]=23)[CH2:3]1.[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)#[N:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]3[N:15]([CH3:28])[C:16](=[O:27])[N:17]([CH2:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[C:9]=23)[CH2:3]1)#[N:30]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cc(N2CCC[C@@H](N)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC[C@@H](NCc3ccccc3C#N)C2)c2c(n1)n(C)c(=O)n2Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
15.1 g (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile (40.1 mmol) was added in a reaction bottle, to which 30 mL DMF was added. 8.6 g 2-cyano-benzyl bromide (44 mmol) and 11 g potassium carbonate (80 mmol) were added at 0° C. The reaction was continued for 3 h by stirring at room temperature. The reaction solution was extracted with dichloromethane, and washed with saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and evaporated to dryness to afford 19.68 g crude product with a yield of 99.8%.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:16][CH:17]=2)=[N:9][CH:10]=1.[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][NH:32][CH:33]=1)[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27](=[O:40])[CH2:28][C:29]1[C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:31][N:32]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:16][CH:17]=3)=[CH:7][CH:6]=2)[CH:33]=1)[CH3:25]
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (554 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl(3-phenyl-1-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]acetate (594 mg, yield: 66%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 75–76° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13](CS([O-])(=O)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[Cl:21][C:22]1[C:23]([OH:29])=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:29][CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=3)[CH2:15][CH2:14]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH2:10])=[O:4].C(=O)([O-])O.[Na+].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][C:22](Cl)=[O:23].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:22](=[O:23])[CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)[C@H]1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cc1cccs1
Yield: 80 %

Procedure:
To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 10 ml of tetrahydrofuran and 5 ml of 1N-sodium hydrogen carbonate, which is previously stirred under ice-cooling, is added dropwise a solution of 0.32 ml of 2-thienyl acetyl chloride in 10 ml of tetrahydrofuran. To the mixture, after being stirred for 10 minutes, are added 100 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium chloride, followed by stirring, and the organic layer is separated. The aqueous layer is subjected to extraction with 30 ml of ethyl acetate, and the extract is combined with the organic layer. The whole organic layer is washed with a saturated aqueous solution of sodium chloride (20 ml×2), dried and concentrated under reduced pressure. To the residue is added 4 ml of a mixed solution (ethyl acetate:hexane=1:2), and the resulting crystals are collected by filtration and dried to afford 430 mg (80%) of cis-3 -(2-thienylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 133°-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:46]([N:48]([CH2:51]C)[CH2:49]C)[CH3:47].ClCC[S:56](Cl)(=[O:58])=[O:57].CNC>O1CCCC1.O>[CH3:49][N:48]([CH3:51])[CH2:46][CH2:47][S:56]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1)(=[O:58])=[O:57]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCN(CC)CC
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(=O)(=O)CCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.12 mmol) was dissolved in 3.75 ml tetrahydrofuran. Triethylamine (50 μl, 0.36 mmol) and 2-chloroethanesulfonyl chloride (15 μL, 0.14 mmol) were added and the mixture was stirred at room temperature during 2 h. Dimethylamine 2M in tetrahydrofuran (301 μl, 0.60 mmol) was added and the mixture was stirred again at room temperature during 4 h. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30% dichloromethane-2-propanol) to obtain 15 mg (13% yield, 77% purity) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26][CH2:27][CH3:28])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@H:9]1[O:17][C@H:14]([CH2:15]O)[C@@H:12]([OH:13])[C@H:10]1[OH:11].S(Cl)([Cl:31])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26][CH2:27][CH3:28])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@H:9]1[O:17][C@H:14]([CH2:15][Cl:31])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: O=S(Cl)Cl
Reactant: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
The title compound was prepared according to general method C. (S)-2-Chloro-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine [Knutsen, L. J. S., Lau, J., Sheardown, M. J., Thomsen, C.; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666](0.35 g, 0.8 mmol) was dissolved in acetonitrile (5 ml) and cooled on an ice-water bath. Under a nitrogen atmosphere, thionyl chloride (0.34 g, 0.2 ml, 2.4 mmol) (see Borchardt, R. T., Huber, J. A. and Wu, Y. S., Journal of Organic Chemistry, 1976, 41, 565-567) was added and a precipitate appeared which dissolved over the following 15 min. Pyridine (0.13 ml, 0.13 g, 1.6 mmol) was introduced gradually, the reaction mixture became yellow in colour and was allowed to reach room temperature gradually. After stirring the mixture overnight, ice was added and the reaction mixture was neutralised to pH 7 with aqueous sodium bicarbonate prior to extraction with ethyl acetate (2×10 ml). The combined extracts were dried (MgSO4) and evaporated to provide the intermediate 2,3-O-sulphinyl derivative (0.35 g), to which was added methanol (5 ml), water (1 ml) and 25% aqueous ammonia solution (0.25 ml) and this mixture was stirred for 16 h. The solution was evaporated in vacuo, and the resultant residue was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and 10% ammonia in ethanol (17:3), to provide the title (S)-2,5'-dichloro-5'-deoxy-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine (0.12 g, 34%) as a foam, 1H-NMR (400 MHz, DMSO-d6) δ1.50-1.60 (1H, br, pyrrolidine C--H), 1.78 (2H, br q, pyrrolidine C--H), 1.92-2.03 (1H, br, pyrrolidine C--H), 3.85, 3.95 (2H, ABX, H-5'a and H-5'b), 4.09 (1H, br dd, H-4'), 4.17 (1H, dd, H-3'), 4.67 (1H, dd, H-2'), 5.49, 5.62 (2H, 2d, 2'- and 3'-OH), 5.87 (1H, d, H-1'), 8.38 (1H, s, H-8), 9.34 (1H, br s, --NH). HPLC retention time 9.65 min. (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 99% purity at 250 nm). C16H22Cl2N6O4.0.25 H2O requires C, 43.9; H, 5.2; N, 19.2. Found: C, 43.7; H, 5.4; N, 19.4%.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]([CH3:35])([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][OH:25].C(OCC)C>C(Cl)Cl>[CH3:22][C:23]([CH3:35])([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:24]=[O:25]
Reactant: CC(C)(CO)COCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C=O)COCc1ccccc1

Procedure:
In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 78.8 g (0.21 moles) of pyridinium dichromate, Aldrich Chemical, see Tetrahedron Lett., 399 (1979), ibid., 731, (1980) and 200 ml of dry CH2Cl2. The mixture was vigorously stirred and a solution of 26.8 g (0.138 mole) of 2,2-dimethyl-3-(phenylmethoxy)propanol, the product of Example 1a, in 50 ml of CH2Cl2 was added in one portion. The reaction was followed by gas liquid chromatography (GC) and required four days stirring at room temperature. The black brown reaction mixture was poured into 200 ml ethyl ether and the mixture was filtered through a dry silica gel column to obtain a colorless solution. Removal of solvent gave a residue which was distilled through a vigreux column to obtain the title compound, a colorless liquid, bp 72°-75°/0.02 mmHg.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=O)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[CH2:20]([OH:23])[CH2:21][OH:22].[C:24]1(C)C=CC(S(O)(=O)=O)=C[CH:25]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH:6]([CH:21]2[CH2:20][O:23][CH2:25][CH2:24][O:22]2)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(=O)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: c1ccccc1
Product: CCC1(COCc2ccccc2)CC(C2COCCO2)C(C)(C)O1
Yield: 86 %

Procedure:
1 g of the ketone of Example 6, 250 mg of ethylene glycol and a few milligrams of para-toluenesulphonic acid in 20 ml benzene were heated at reflux temperature in a Dean/Stark apparatus for 16 hours. The resulting mixture was washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated to give 1.16 g crude material which was purified on a silica gel column using 3% acetone in petrol as eluant to give 1.0 g (86%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10]CC)=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].[OH-].[Na+].Cl>CO.C1COCC1>[Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1[nH]nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (Intermediate 1A, 2.01 g, 10.7 mmol) in MeOH (8.2 mL) and THF (8.2 mL) was added 2N aq. NaOH solution (27 mL, 53.3 mmol). The reaction mixture was stirred at room temperature overnight, then cooled to 0° C. and neutralized with 1N aq. HCl solution (pH=3-4). The resulting solid was collected by filtration and washed with water to give the title compound (1.50 g, 87%) as a white solid. 1H NMR (DMSO-d6) δ 2.19 (br s, 3H); MS (ESI+) m/z 160.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)CC1SC(N)=NC=1.ClC(CC1C=C(F)C=CC=1OC)C=O.[NH2:31]C(N)=S>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH2:31])[CH:14]=1
Reactant: COc1ccc(F)cc1Cc1cnc(N)s1
Reactant: NC(N)=S
Agent: COc1ccc(F)cc1CC(Cl)C=O
Solvent: CCO
Product: COc1ccc(F)cc1N

Procedure:
5-(5-Fluoro-2-methoxy-benzyl)-thiazol-2-ylamine A mixture of 2-chloro-3-(5-fluoro-2-methoxy-phenyl)-propionaldehyde (crude from above) and thiourea (29.2 g, 0.384 mol) in ethanol (400 mL) was heated to reflux for 15 hours. The solvent was removed and the residue was diluted with dichloromethane (300 mL), sodium hydroxide (10% aqueous solution, 150 mL) and water (200 mL). The aqueous phase was extracted twice with dichloromethane (150 mL). The combined organic layer was washed with water, a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and evaporated to dryness. The crude product was recrystallized from a mixture of ethyl acetate and hexanes to give the pure product (6.5 g, 0.027 mol, 6.2% from 5-fluoro-2-methoxy-phenylamine). ESI-MS m/z calc. 238.1, found 239.2 (M+1)+ 1H NMR (CDCl3): δ 6.90-6.81 (m, 2 H), 6.79-6.76 (m, 2 H), 4.75 (br, 2 H), 3.91 (s, 2 H), 3.82 (s, 3 H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4](O)[CH2:3][CH2:2]1.[BrH:9].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:10]([O:8][CH:1]1[CH2:2][CH2:3][CH2:4][CH:5]([Br:9])[CH2:6]1)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[C:10]([O:8][C@H:1]1[CH2:2][CH2:3][C@H:4]([Br:9])[CH2:5][CH2:6]1)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: OC1CCC(O)CC1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Br
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC1CCCC(Br)C1
Product: CC(C)(C)C(=O)O[C@H]1CC[C@H](Br)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
A mixture of 3- and 4-bromocyclohexanols (3.6 g, 20 mmol)(the mixture of 3- and 4-bromocyclohexanols was obtained by treating 1,4-cyclohexanediol with hydrobromic acid (48 wt % in water) under reflux followed by conventional treatments) was treated with pivaloyl chloride (3.7 mL, 30 mmol) in pyridine (50 mL), which was then stirred at room temperature for 4 hours. After evaporation in vacuum, the crude mixture was purified by silica gel chromatography (hexane/ethyl acetate=20/1) to give 3-bromocyclohexyl pivaloate (trans/cis=33/67, 0.63 g, 12%) and trans-4-bromocyclohexyl pivaloate (0.79 g, 15%) as colorless oily substances.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:23](=O)[CH:22]([CH2:33][Sn](C)(C)C)[CH2:21]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.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[Si:1]([O:18][CH2:19][CH:20]1[CH2:21][CH:22]2[CH:23]([CH2:33]2)[N:24]1[C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C[Sn](C)(C)C)C[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC2CC21
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of (5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxo-3-((trimethylstannyl)methyl)pyrrolidine-1-carboxylate (D30) (3.1 g, 6.86 mmol) in THF (200 ml) cooled at −78° C., LiEt3BH 1M sol in THF (17.2 ml) was added dropwise. The reaction was left at −78° C. for 2 hrs then water (50 ml) and the reaction extracted with Et2O (3×100 ml). The organic phases were combined, dried over Na2SO4 and evaporated in vacuo to afford a residue which was dissolved in DCM (120 ml) and cooled at 0° C. TFA (1.31 ml, 17.2 mmol) was added and the reaction was stirred 10 min at this temperature. K2CO3 sat sol (100 ml) was added and the mixture extracted with DCM (3×100 ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo to afford a residue which was purified by BiotageSNAP-Si column (50 g) eluting with a mixture cHex/EtOAc 95/5. Collected fractions after solvent evaporation afforded the title compound (D31) (2.1 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH2:30][NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]#[C:44][CH3:45])=[CH:37][CH:36]=2)(=[O:34])=[O:33])([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([NH:31][CH2:30][C:21]([N:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)([C:22]([O:24][CH3:25])=[O:23])[C:26]([O:28][CH3:29])=[O:27])(=[O:34])=[O:33])=[CH:36][CH:37]=1)[C:43]#[C:44][CH3:45]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
2.8 ml of trifluoroacetic acid are added to a solution of 2.1 g (4 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]malonate diluted in 30 ml of dichloromethane. After stirring at ambient temperature for 24 h, a saturated aqueous solution of sodium hydrogen carbonate is added to pH=8 and the reaction medium is extracted with dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, and then filtered and evaporated. 1.7 g (98%) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate are obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(Oc4ccccc4)c3)c2cc1OC
Temperature: 139 °C
Yield: 77.8 %

Procedure:
A mixture of 0.248 g (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.204 g (1.1 mmol) of 3-phenoxyaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 3 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.309 g (78%) of the desired product as cream crystals. MP 253-254° C.; mass spectrum (electrospray, m/e,): 397.0(M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.OB(O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1>C1(C)C=CC=CC=1.CO.C(=O)([O-])[O-].[Na+].[Na+].O.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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccc2ccccc2c1
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: O
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2ccc3ccccc3c2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 2-bromonaphthalene (5.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.56 g) in toluene (50 ml) was added a solution of dihydroxy(3-nitrophenyl)borane (4.44 g) in methanol and 2M sodium carbonate solution in water (12 ml). The resulting mixture was stirred at 80° C. for 4 hours and extracted with ethyl acetate. After evaporation of the solvent, the crude residue was crystallized from hexane to give 3-(2-naphthyl)-1-nitrobenzene (5.4 g).