Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1.O>C1(C)C=CC=CC=1>[Cl:15][C:8]1[N:7]=[C:6]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of cyclopropylamine (1.25 g, 22.0 mmol) in toluene (11 mL) was added over 10 min to an ice-cold solution of 2,6-dichloro-3-nitropyridine (2.00 g, 10.4 mmol) in toluene (10 mL). The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Water (50 mL) was added to the mixture and the phases were separated. The organic layer was washed with brine (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 3:2) to give the title compound (1.97 g, 89% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22° C. sodium hydride (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluormethanesulfonate (728 mg) and stirring was continued at 22° C. for 2 hours. The mixture was partitioned between saturated sodium hydrogen-carbonate solution and ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane and ethyl acetate (3:1) as the eluent to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester as a pale green oil. Mass (calculated) C9H8F3NO3 [235.16]; (found) [M+H]+=236. b) A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) and stirring was continued at 22° C. for 2 hours. The solution was evaporated and the residue triturated with 1N aqueous hydrochloric acid. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. Mass (calculated) C8H6F3NO3 [221.14]; (found) [M−H]−=220.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].N1C=CC=CC=1>ClCCl>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:14]
Reactant: CCOC(=O)CN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Tosyl chloride (14.75 g, 77.37 mmol) was added to a stirring mixture of glycine ethyl ester hydrochloride (9.0 g, 64.48 mmol) and pyridine (11.45 mL, 141.85 mmol) in 100 mL of dichloromethane. After stirring overnight, the mixture was washed with water and dilute NaOH. The combined organics were dried with Na2SO4, filtered, evaporated under reduced pressure to give 16.0 g (96%) of 81, which was used without purification in the next reaction. 1H-NMR (400 MHz, CDCl3): δ 1.18 (t, 3H), 2.42 (s, 3H), 3.76 (d, 2H), 4.08 (q, 2H), 5.22 (m, 1H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ 13.99, 21.55, 44.19, 61.89, 127.28, 129.76, 136.20, 143.81, 168.87 ppm.□ DEPT (100 MHz, CDCl3): CH3 carbons: 13.99, 21.55; CH2 carbons: 44.19, 61.89; CH carbons: 127.28, 129.76 ppm. LC/MS: 95%, m/z=257.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1F
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1F

Procedure:
using isopropyl 2,4-difluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-difluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 112°-115° C.,
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:10][C:11]=2[O:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:24]([O-])([O-:26])=[O:25].[K+]>OS(O)(=O)=O>[CH:1]1([C:6]2[C:11]([O:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([N+:24]([O-:26])=[O:25])=[C:8]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)CCc1ccc(OC(=O)OC)c(C2CCCC2)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)CCc1cc(C2CCCC2)c(OC(=O)OC)cc1[N+](=O)[O-]
Temperature: -2 °C
Yield: 78.9 %

Procedure:
Ethyl 3-(3-cyclopentyl-4-methoxycarbonyloxy-phenyl)propanoate (920 mg, 2.87 mmol) was dissolved in H2SO4 (2.2 mL) and the reaction mixture was cooled to −2° C. internal temperature. KNO3 (348 mg, 3.45 mmol) was added in portions over 1 h maintain the internal temperature at 0° C. After 1 h at 0° C. the reaction mixture was poured over ice (30 mL) and partitioned between dichloromethane/water and separated. The organic layer was washed twice with a saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-40% ethyl acetate/hexanes) afforded ethyl 3-(5-cyclopentyl-4-methoxycarbonyloxy-2-nitro-phenyl)propanoate (827 mg, 76% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.53 (s, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 3.11 (t, J=7.6 Hz, 3H), 2.68 (t, J=7.6 Hz, 2H), 1.99-1.91 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.61 (m, 2H), 1.58-1.53 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35](=[O:36])[C:34]4[CH:38]=[CH:39][N:40]=[C:32]([N:26]5[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]5)[CH:33]=4)[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccnc(N2CCCCC2)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccnc(N5CCCCC5)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-piperidin-1-ylisonicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether=5:6) to yield the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH3:6])=[O:4].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:36])=[N:18][CH:19]=[C:20]([C:22]2[C:23]([CH2:33][O:34][CH3:35])=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:36][C:17]1[N:18]=[CH:19][C:20]([C:22]2[C:23]([CH2:33][O:34][CH3:35])=[N:24][N:25]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][C:3]([NH:5][CH3:6])=[O:4])[CH2:31][CH2:32]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(COC)n2)CC1
Temperature: 75 °C

Procedure:
A solution of 2-chloro-N-methyl-acetamide (0.027 ml) in DMF (1 ml) was added to a stirred mixture of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (100 mg) and potassium carbonate (68 mg) in DMF (5 ml) at 25° C. under argon. The resulting solution was heated at 75° C. overnight. The DMF was evaporated and the residue was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to afford 2-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methoxymethyl)pyrazol-1-yl]-1-piperidyl]-N-methyl-acetamide (53.0 mg) as a solid. NMR Spectrum: (DMSOd6) 1.98-2.06 (m, 2H), 2.09 (dd, 1H), 2.14 (dd, 1H), 2.22-2.31 (m, 2H), 2.64 (d, 3H), 2.86-2.93 (m, 2H), 2.95 (s, 2H), 3.41 (s, 3H), 4.11-4.19 (m, 1H), 4.41 (s, 2H), 7.41-7.48 (m, 2H), 7.66 (bs, 2H), 7.75 (q, 1H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.19 (s, 1H), 8.43 (d, 1H), 8.50 (d, 1H); Mass spectrum: M+H+ 476.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[F:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:38][C@H:39](O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.ClCCl>[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:34][C@H:39]([CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:33])=[CH:30][C:29]=1[F:37])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCC[C@H](C)O
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(OCc2ccccc2)c(F)c1

Procedure:
Triphenylphosphine (7.92 g, 30 mmol) in THF (40 ml) was added dropwise to a stirred solution of compound 11 (7.00 g, 28 mmol), (S)-(+)-octan-2-ol (3.66 g 28 mmol) and diethyl azodicarboxylate (4.87 g, 28 mmol) in THF (100 ml). The reaction solution was left stirring under nitrogen until completion [reaction monitored by TLC (dichloromethane, silica)]. Upon completion, the solvent was removed in vacuo to yield a colourless solid which was purified by column chromatography (dichloromethane) on silica to yield a colourless oil. Yield 10.01 g (99%), [α]D=−22.4° at 25° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.CO.[CH2:12](Cl)Cl>>[CH3:12][C:3]1[N:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: ClCCl
Reactant: O=C(O)c1ccnnc1
Solvent: CO
Product: Cc1nnccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-pyridazinecarboxylic acid (490 mg, 3.9 mmol) in MeOH/DCM (20/10 ml) was added at 0° C. trimethylsilildiazomethane (25.5 mmol). The solution was warm at r.t. and stirred overnight. Volatiles were evaporated in vacuo, the crude dissolved in DCM, washed with NaHCO3 satured and dried over Na2SO4. After filtration and concentration to dryness in vacuo, the crude was purified by column chromatography (DCM:MeOH=98 to 2) to give 400 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.O1CCCC1>CO>[OH:15][CH2:14][C:11]1([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccnc2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2cccnc2)CC1
Temperature: 0 °C

Procedure:
A flask was charged with 1-(tert-butoxycarbonyl)-4-(pyridin-3-yl)piperidine-4-carboxylic acid (4.0 g, 13.1 mmol) and tetrahydrofuran (25 mL). The reaction was placed under nitrogen. To the flask was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 26.1 mL, 26.1 mmol) and heated at reflux for 2 h. The reaction was cooled to 0° C. and quenched with methanol (100 mL). The solution was then concentrated in vacuo. The residue was purified via column chromatography (5% methanol/95% dichloromethane) to yield 3.2 g (84%). Mass Spec.: 293.26 (MH)+. LC: tr=1.65 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 61.7 %

Procedure:
Using general procedure A, N-(4-amino-phenyl)-acetamide (Gowda, D. Channe; Gowda, Shankare, Indian J. Chem. Sect., 39, 9, 2000, 709-711) (675 mg, 4.49 mmol) and 1-Boc-4-piperidone (938 mg, 4.71 mmol) gave 4-(4-acetylamino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (923 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][CH2:30][O:31][C:32]([C@@H:34](O)[CH3:35])=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:24]([C@H:21]1[CH2:20][CH2:19][C@H:18]([CH2:17][CH2:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][C@H:34]([CH3:35])[C:32]([O:31][CH2:30][CH3:29])=[O:33])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:23][CH2:22]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(-c3ccc(O)cc3)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(-c3ccc(O[C@H](C)C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A solution of 4 g of 4-hydroxy-4'-[4-(trans-4-pentylcyclohexyl)-1-butyl]biphenyl, 1.3 g of ethyl L(-)-lactate, 2.9 g of triphenylphosphine and 100 ml of tetrahydrofuran was treated with 1.9 g of diethyl azodicarboxylate. The reaction mixture was stirred at room temperature overnight, then concentrated and suspended with 100 ml of hot hexane. The precipitate which thereby resulted was removed by filtration and the filtrate was concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) and recrystallization from ethanol gave 2.9 g of pure ethyl 2(R)-[4'-[4-(trans-4-pentylcyclohexyl)-1-butyl]-4-biphenylyloxy]propionate with m.p. (C-SB) 71° C. and cl.p. (SB -I) 76° C.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH3:3].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].O>C(O)C>[CH2:25]([O:24][C:20](=[O:23])[CH2:21][CH2:22][N:4]([CH2:1][CH2:2][CH3:3])[C@@H:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][C@H:6]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: CCCN[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Solvent: CCO
Solvent: O
Product: CCCN(CCC(=O)OCC)[C@@H]1CCC2(C[C@H]1C(=O)OCC)OCCO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.3 %

Procedure:
Ethyl 8-(propylamino)-trans-1,4-dioxaspiro[4.5]-decane-7-carboxylate (129.6 g, 0.48 mole) was dissolved in ethanol (1500 ml), then ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed overnight, then additional ethyl acrylate (479 g, 4.8 mole) was added. The mixture was refluxed for 24 hours, at which time a third addition of ethyl acrylate (479 g, 0.48 mole) was made, followed by 60 hours of reflux. The mixture was then cooled to room temperature, poured into water, and the hydrogen ion concentration was adjusted to pH 10. The product was extracted with methylene chloride, dried with sodium sulfate and evaporated to give 177.4 g of crude product. This was purified by HPLC to give 102.1 g of the title product (59.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)NCc1cccc(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)NCc1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
219 mg N-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide (prepared in Example 1) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 228 mg 2-benzyloxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (127 mg, 40% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:20][CH:21]=[O:22])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][CH:20]([C:17]1([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH2:19][CH2:18]1)[CH:21]=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C2(CC=O)CC2)cc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(C(Cl)C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-Proline (10 mg, 0.1 mmol) was added to a solution of [1-(4-methoxyphenyl)cyclopropyl]acetaldehyde (100 mg, 0.53 mmol) in chloroform (1 mL) at 0° C. followed by addition of N-chlorosuccinimide (84 mg, 0.63 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was diluted with hexanes and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexanes (0-10%) to afford the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:17][N:18]([CH3:22])[C:19]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH:4]=3)[CH:16]=2)[CH:12]=[CH:13]1)=[O:20]
Reactant: CN1CC=C(c2ccc3cc[nH]c3c2)CC1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2ccc3ccn(C(=O)N(C)C)c3c2)CC1

Procedure:
From 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (16.6 mg, 0.0735 mmol), dimethylcarbamyl chloride (15.8 mg. 0.147 mmol) and 1M NaN(TMS)2(0.147ml) in 0.5 ml of THF at 0° C. Yield 12.5 mg (60%), the reaction being carried out according to Example 6.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCNCC4)s3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCN(CCCCO)CC4)s3)ccc21

Procedure:
The preparation was carried out as already described starting from 70 mg (0.20 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-5-yl]piperidine and 43 μl (0.30 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[Na].[CH3:17][OH:18]>>[Cl:12][C:11]1[C:2]([O:18][CH3:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: CO
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Agent: [Na]
Product: COc1nc2ccc([N+](=O)[O-])cc2nc1Cl
Temperature: 50 °C
Yield: 58 %

Procedure:
A slurry of 6.1 g (25 mmol) of 2,3-dichloro-6-nitroquinoxaline in 70 ml of dry methanol was heated to 50° C and treated dropwise over 5 h with 0.7 g (30 mmol) of sodium dissolved in 70 ml of dry methanol. The mixture was stirred over night at 50° C., cooled and filtered. The resulting precipitate was washed with cold ethanol and water and finally chromatographed on silica gel with toluene to give 3.5 g (58%) of the title compound; m.p. 155-158° C.; 1H-NMR (DMSO-d6): δ4.17 (s, 3H, CH3), 8.05 (d,J=9 Hz, 1H, H-8), 8.48 (dd, J7-8 =9 Hz, J7-5 =2 Hz, 1H, H-7), 8.73 (d, J=2 Hz, 1H, H-5).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[S:1])[NH:3][C:4]=4[CH:10]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Agent: N
Product: S=c1[nH]c2ccc(-c3nc(-c4cccnc4)no3)cc2[nH]1

Procedure:
The title compound was prepared according to Method C using 2-mercapto-5-benzimidazolecarboxylic acid (Princeton) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, CD3OD) δ 7.38 (d, J=8.5 Hz, 1 H), 7.65 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 7.86 (d, J=1.0 Hz, 1 H), 8.00 (dd, J=8.1, 1.7 Hz, 1 H), 8.45 (dt, J=8.0, 1.9 Hz, 1 H), 8.81 (dd, J=4.9, 1.5 Hz, 1 H), 9.26 (dd, J=2.2, 0.9 Hz, 1 H) ppm; MS (DCI/NH3) m/z 296 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][CH2:14][CH2:13][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Product: COC(=O)c1ccc(OCCCc2ccccc2)cc1
Yield: 90.1 %

Procedure:
Using the general method of Compound 80 Part A, methyl 4-hydroxybenzoate (3.0 g, 19.7 mmole)was reacted with 1-bromo-3-phenylpropane (3.1 mL, 20.4 mmole) to provide 4.8 g of methyl 4-(3-phenylpropyloxy)benzoate as a white crystalline solid, m.p. 61.0°-61.5° C.