Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[C:15]([NH2:34])=[N:16][CH:17]=[C:18]([C:20]2[C:21]([CH2:31][O:32][CH3:33])=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:34][C:15]1[N:16]=[CH:17][C:18]([C:20]2[C:21]([CH2:31][O:32][CH3:33])=[N:22][N:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][OH:4])[CH2:29][CH2:30]3)[CH:24]=2)=[CH:19][C:14]=1[C:6]1[O:5][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nn(C2CCN(CCO)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-Bromoethanol (0.051 ml) was added to a stirred suspension of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-piperidin-4-ylpyrazol-4-yl]pyridin-2-amine] (145 mg) and potassium carbonate (124 mg) in DMF (2 ml) at 100° C. The mixture was stirred at 100° C. for 15 hours. The reaction mixture was then purified by preparative HPLC using a Waters OBD reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound as (90 mg) as a solid.
Reaction SMILES: [C:1]([O:5]C(=O)N)(C)(C)C.C(OC(=O)[NH:15][C:16]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([NH2:40])[C:31]([N+:37]([O-])=O)=[CH:32][CH:33]=4)[O:28][C:27]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1)(C)(C)C>CN1C(=O)CCC1.[Pd]>[NH2:15][C:16]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:35](=[O:36])[C:34]4[CH:33]=[CH:32][C:31]5[NH:37][C:1](=[O:5])[NH:40][C:30]=5[C:29]=4[O:28][C:27]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:24][CH:25]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c([N+](=O)[O-])ccc4c3=O)cc2)CCC1
Agent: [Pd]
Solvent: CN1CCCC1=O
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)[nH]c54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
1-[4-(7,8-Diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester: To a solution of {1-[4-(8-amino-7-nitro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (420 mg, 0.8 mmol) in NMP (10 mL) and IMS (3 mL) was added 10% palladium on carbon (350 mg) under a nitrogen atmosphere. The nitrogen was evacuated and replaced with hydrogen (1 atm). The mixture was stirred at RT for 18 hours. The hydrogen atmosphere was evacuated and replaced with nitrogen and the mixture was filtered through a pad of Celite®, eluting with ethyl acetate. The solvent volume was reduced in vacuo and the resultant mixture was poured onto water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 60-70% ethyl acetate in cyclohexane) and the resulting residue triturated with water, filtered and the solid collected to give the title compound as a yellow solid (280 mg, 70%). LCMS (Method H): RT=3.66 min, [M+H]+=498.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5](=[CH2:9])[C:6](=[O:8])[CH3:7].[CH3:10][O:11][C:12](=[O:20])[CH:13]([O:18][CH3:19])[C:14](OC)=[O:15].Cl>CS(C)=O>[CH3:10][O:11][C:12]([C:13]1([O:18][CH3:19])[CH2:9][CH:5]([CH3:4])[C:6](=[O:8])[CH:7]=[C:14]1[OH:15])=[O:20]
Reactant: C=C(C)C(C)=O
Reactant: COC(=O)C(OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(OC)CC(C)C(=O)C=C1O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A 30% solution of 35.8 g of sodium methanolate is made up in 65 ml of dimethyl sulfoxide and, over a period of 20 minutes, is treated at a temperature of from 30 to 35° C. with a mixture of 16.7 g of 3-methyl-3-buten-2-one and 32.4 g of methoxymalonic acid dimethyl ester. The mixture is stirred for 1 hour at a temperature of 35° C., acidified with hydrochloric acid and then extracted several times with dichloromethane. The organic phases are washed with water, dried and concentrated. By crystallising from hot ethyl acetate and hexane, pure 2-hydroxy-1-methoxy-5-methyl-4-oxo-cyclohex-2-enecarboxylic acid methyl ester having a melting point of 117-117.5° C. is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[N:27][CH:28]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:22][C:23]1[CH:28]=[N:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 87.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 18 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (20.0 g) and 5-amino-2-methoxypyridine (8.72 g), as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (23.9 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:13]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([CH3:18])=[CH:15][C:14]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(Cl)c(OCCc2ccc(Br)cc2)c(Cl)c1
Temperature: 80 °C

Procedure:
2-(4-Bromophenyl)ethanol (1 eq.) and 2,6-dichloro-4-methylphenol (1.5 eq.) were taken up in freshly deoxygenated toluene (0.1 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:13](Cl)=[CH:12][C:11]([CH3:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.[CH2:19]([OH:24])[C:20]([F:23])([F:22])[F:21]>>[Cl:7][C:8]1[C:13]([O:24][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]([CH3:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cc(OCC(F)(F)F)c(Cl)cc1[N+](=O)[O-]

Procedure:
40.4 g (360 mmol) of potassium tert-butylate were added in portions to 60 ml of trifluoroethanol, while stirring and cooling, and the mixture was heated to 80°-90° C. After cooling, 14.4 g (70 mmol) of 4,5-dichloro-2-nitrotoluene were added and the mixture was stirred at 105° C. for 1 hour. It was concentrated in vacuo and the residue was treated with 300 ml of water to give, after filtration with suction, 12 g of crude product, which were purified over silica gel with n-heptane/ethyl acetate, 10 g of product, melting point 76°-79° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1>>[ClH:2].[Cl:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:7]1[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]2=[C:3]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:25][CH:26]=2)[CH:8]=1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: Clc1ccc(Cl)c(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3cc(Cl)ccc3Cl)nc3c2CCC3)cc1
Yield: 6.1 %

Procedure:
Following General Procedure A1, 4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.060 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.009 g, 10%) as a tan solid. MW=448.77. 1H NMR (DMSO-d6, 500 MHz) δ 14.18 (s, 1H), 10.16 (s, 1H), 7.79 (s, 1H), 7.71-7.64 (m, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.16 (d, j=8.5 Hz, 1H), 6.91 (s, 1H), 3.66 (s, 2H), 3.30 (s, 2H), 3.15-3.06 (m, 2H), 3.0-2.89 (m, 2H), 2.31-2.19 (m, 2H); APCI MS m/z 412 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 97 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 97%). 1H NMR (300 MHz, CDCl3): δ 2.17 (s, 3H), 2.54 (s, 3H), 3.39-3.58 (m, 4H), 3.71-3.90 (m, 4H), 4.14 (s, 3H), 6.89 (d, J=6.4 Hz, 2H), 7.21-7.54 (m, 4H), 7.90 (d, J=6.4 Hz, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C([N:14]1[CH2:22][CH:21]2[CH:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:19][C:20]2=[O:23])[CH2:15]1)C1C=CC=CC=1.C(OC(C)C)(C)C>ClCCCl>[C:30]1([C:17]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]3[CH:21]([CH2:22][N:14]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:15]3)[C:20](=[O:23])[CH2:19][CH2:18]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Solvent: CC(C)OC(C)C
Product: C=COC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h

Procedure:
Vinyl chloroformate (56 cc) is added dropwise in the course of 10 minutes to a solution, cooled to +5° C., of (3aRS,7aRS)-2-benzyl-7,7-diphenylperhydro-4-isoindolone (193 g) in 1,2-dichloroethane (1225 cc). After stirring for 30 minutes at between 10° and 20° C., the reaction mixture is heated to reflux for 90 minutes, cooled and concentrated to dryness under reduced pressure (2.7 kPa then 1 kPa). The crystalline mass obtained is stirred vigorously with cold isopropyl ether (200 cc). The crystals obtained are drained, washed with isopropyl ether (2×100 cc) and dried. (3aRS,7aRS)-7,7-Diphenyl-2-vinyloxycarbonylperhydro-4-isoindolone (177 g), m.p. 178° C. is obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=O)=O.[Br-:48].[Li+].O1CCCC1>O>[Br:48][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:25]2[CH:30]=[CH:29][C:28]([N:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCOS(C)(=O)=O)cc3)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCBr)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a dry schlenk flask was added 3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propyl methanesulfonate (4.06 g, 6.20 mmol). The flask was evacuated under vacuum and filled with nitrogen. Lithium bromide (5.39 g; 62.0 mmol) and tetrahydrofuran (6.2 mL) were added under nitrogen. The mixture was allowed to stir at 60° C. overnight. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 100 mL of cold water. The product was extracted using 3×50 mL ether. The organic layers were combined and washed with 3×50 mL of water. The resulting ether layers were dried over Na2SO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The residual solvent was removed in vacuo (3.12 g, 78.2%). 1H NMR (400 MHz, C3D6O) δ 6.97 (m, 8H), 6.86 (m, 8H), 6.80 (s, 4H), 4.09 (t, J=5.9 Hz, 2H), 3.75 (s, 9H), 3.66 (t, J=6.6 Hz, 2H), 2.28 (q, J=6.2 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.39, 155.34, 143.71, 143.51, 142.22, 127.05, 126.27, 126.03, 123.90, 123.70, 116.10, 115.40, 114.61, 66.34, 55.62, 33.25, 31.05. HRMS-EI (m/z): [M]+ calcd for C36H35BrN2O4, 640.18; found, 640.1). Anal. Calcd for C36H35BrN2O4: C, 67.60; H, 5.52; N, 4.38. Found: C, 67.43; H, 5.61; N, 4.24.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[CH3:11][Si:12]([CH3:24])([CH3:23])[O:13][C:14]([C:16]([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH2:17])=[CH2:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:17][C:16]([O:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([O:13][Si:12]([CH3:23])([CH3:11])[CH3:24])[CH2:15][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: C=C(O[Si](C)(C)C)C(=C)O[Si](C)(C)C
Reactant: COC(=O)C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1

Procedure:
Under argon, a solution of 7.1 g (50 mmol) of acetylenedicarboxylic acid dimethyl ester in 30 ml of toluene is added dropwise to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (95%) and then boiled under reflux for 19 hours. The reaction mixture is cooled, the solvent is evaporated off and the residue is distilled under a high vacuum (0.1 mbar,124°-127°), yielding the title compound in the form of a yellow, highly viscous oil, 1H-NMR (CDCl3): δ=0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](OS(C)(=O)=O)[CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[C:14]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]2=3)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1)[CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]1=2)=[N+:33]=[N-:34]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(C(N)=O)nc2)CCN(C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
Methanesulfonic acid-1-(6-carbamoyl-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl ester (300 mg, 0.678 mmol) was dissolved in 5 mL DMF, and sodium azide (88 mg, 1.357 mmol) was added, and the mixture heated at 100° C. for 1 h. The reaction mixture was monitored by LCMS. After completion of reaction, the reaction mixture was cooled to RT and diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (4×40 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to yield 5-[1-azido-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylic acid amide (135 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (dd, 1H), 8.1 (t, 1H), 7.9 (t, 1H), 7.33 (dd, 1H), 7.26 (s, 1H), 7.06 (t, 1H), 5.3 (t, 1H), 4.7 (dd, 1H), 4.42 (dd, 1H), 4.4 (dd, 2H), 4.3 (m, 1H), 3.8 (m, 1H),3.6 (m, 1H), 3.34 (dd, 1H), 3.1 (d, 3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers V-22a-b.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:25][CH2:26][N:27]([S:46]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)(=[O:48])=[O:47])[CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)c4ccccc4)CC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethylamine (50 μL, 0.287 mmol) and benzenesulfonyl chloride (29 μL, 0.230 mmol) were added sequentially. The solution was stirred overnight at room temperature, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (48-82% CH3CN:H2O) to provide 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin-4-ol. MS ESI: [M+H]+ m/z 576.1. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 7.93 (d, J=9.2 Hz, 2H), 7.75 (dd, J=8.7, 10.3 Hz, 2H), 7.73 (s, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (s, 1H), 6.10 (s, 1H), 3.54 (d, J=12.3 Hz, 1H), 2.58 (t, J=12.3 Hz, 2H), 2.54-2.37 (m, 1H), 2.28 (s, 3H), 2.08 (t, J=16.1 Hz, 2H), 1.80 (d, J=14.6 Hz, 2H). rhSYK activity=++
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][CH:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:2]1.C([O:25]P(OCC)OCC)C.O=O>O1CCCC1.CCOCC>[CH2:22]1[CH2:1][O:2][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][CH:5]([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:21]1.[CH2:22]1[CH2:1][O:2][C:3]2([C:12]3[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=3[O:13][CH3:14])[CH2:6][C:5]([OH:25])([C:17]([O:19][CH3:20])=[O:18])[CH2:4]2)[O:21]1
Reactant: CCOP(OCC)OCC
Agent: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Agent: O=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Reaction time: 0.33 h
Yield: 66 %

Procedure:
(ii)(b) A solution of the lithium enolate of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate was prepared in tetrahydrofuran as described in part (ii)(a) of this Example from 9.84 g of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate. The enolate was added over a period of 5 minutes at -78° C. to a stirred solution of 11.2 ml of dry triethylphosphite in 60 ml of tetrahydrofuran through which a rapid stream of oxygen was passing. The passage of oxygen was maintained for 50 minutes and the temperature was held at -78° C. The reaction was then quenched by the addition of 8.8 ml of acetic acid. The cooling bath was removed and, after 5 minutes, 200 ml of water were added. After a further 20 minutes, most of the tetrahydrofuran was evaporated and the product was extracted into four 100 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with 200 ml of 10% aqueous potassium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated to give a yellow oil which was dissolved in 130 ml of ether and left to crystallise. There were obtained 6.86 g (66%) of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 74°-75° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[I:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[I:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:15]=[CH:14]2
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Ic1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (9.88 g, 58.1 mmol) was added to a suspension of 5-iodo-1H-indazole (8.86 g, 36.3 mmol) and Cs2CO3 (50.8 g, 456 mmol) in anhydrous DMSO (100 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (100 mL) was added and the aqueous solution was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (2×200 mL), dried over MgSO4 and concentrated under reduced pressure. Flash chromatography on silica gel (9:1 Et2O/Et3N) afforded 6.473 g (52%) of the title compound as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.08 (br d, J=13 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.60 (dd, J=87, 1.3 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 4.50 (t, J=7.4 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 2.59-2.50 (m, 4H), 1.82-1.70 (m, 4H).
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH3:8])[CH:5]=[N:6][OH:7])([O-:3])=[O:2].[CH3:10][N:11]([S:15][C:16]([CH3:23])([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:17])[C:12](F)=[O:13].C(N(CC)CC)C>O1CCOCC1>[CH3:10][N:11]([S:15][C:16]([CH3:17])([C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH3:23])[C:12]([O:7][N:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:9])[CH3:8])=[O:13]
Reactant: CC(C)(C=NO)[N+](=O)[O-]
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=CC(C)(C)[N+](=O)[O-]
Yield: 7.8 %

Procedure:
Prepared as in Example 1 by reacting 2.78 g (0.021 m) of 2-nitro-2-methylpropionaldoxime, 5.0 g (0.21 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl fluoride and 2.13 g (0.021 m) of triethylamine in 50 ml of dioxane. The product was purified by column chromatography to yield 0.55 g of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(C=O)c2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(CO)c2)c1=O
Temperature: 25 °C
Yield: 54.4 %

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-formylphenyl)-1,2-dihydropyridin-2-one (585 mg) was dissolved in 20 ml of methanol, 260 mg of sodium borohydride were added with ice cooling and the mixture was stirred at room temperature for one night. The reaction solution was diluted with ethyl acetate, washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo and purified by an NH silica gel column chromatography (ethyl acetate). The resulting crude crystals were recrystallized from ethyl acetate-diethyl ether to give 320 mg of the title compound.