Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.Cl>C(#N)C.O1CCOCC1>[Cl:22][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(CCc2cccnc2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Clc1nnc(CCc2cccnc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Under exclusion of air, 2.4 g (9.55 mmol) 4-[2-(pyridin-3-yl)ethyl]phthalazin-1(2H)-one in 36 ml acetonitrile is mixed with 2.18 ml (23.8 mmol) phosphoryl chloride and 4.75 ml 4 N HCl in dioxane and stirred for 3.5 h at 60° C. After cooling to RT, the product is filtered off as hydrochloride and washed with CH3CN. The crystals are dissolved in about 10 ml H2O, mixed with 15 ml H2O and 1.5 ml sat. NH3 solution and extracted immediately 3 times with EtOAc. Drying (Na2SO4) of the organic phases and evaporation yield the title compound; FAB-MS (M+H)+=270.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2](=[O:3])[O:4][CH2:5][CH3:6])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: CCOC(=O)Cl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC
Yield: 81.3 %

Procedure:
Using the general method of Example 55, ethyl chloroformate (46 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.15 g of ethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis Calculated for C20H28N6O2: %C, 62.48; %H, 7.34; %N, 21.86; Found: %C, 61.73; %H, 7.28; %N, 21.62.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1.[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
In an atmosphere of argon, a mixture of 34 mg (4.3 mmol) of lithium hydride and 5 ml of DMF was put in a 100 ml flask. To the flask was then connected a dropping funnel which contained 804 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 10 ml of DMF. The solution of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was then added dropwise to the aforementioned mixture with stirring in 5 minutes. The mixture was further stirred for 50 minutes. To the mixture was then added a mixture of 704 mg of 2-bromoethyl acetate and 1 ml of DMF. The mixture was then stirred for 22 hours. After the termination of reaction, the mixture was concentrated under reduced pressure. The resulting residue was then extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/1 mixture of ethyl acetate and normal hexane). As a result, 708 mg of ethyl 2-[2-(4-chlorophenyl)imino-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]acetate was obtained as a low polarity substance, and 96 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate was obtained as a high polarity substance. To a mixture of 89 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate and 5 ml of ethanol was then added 14 mg of fumaric acid. The mixture was then stirred at room temperature for 1 hour. After the termination of reaction, the reaction was concentrated under reduced pressure, and then recrystallized from ethanol to obtain 104 mg of ethyl 2-[N-(4-chlorophenyl)-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]acetate 0.5 fumarate.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:22]=[O:23])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CN(C)C=O
Reactant: CON=C1CCc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CON=C1CCc2cc(C=O)ccc21
Temperature: -60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of the product of Step 1 (112 g, 0.46 mol) in THF (1500 ml) at −60° C. under argon, was added n-BuLi (325 ml, 0.52 mol) over 1 hour. After stirring at −60° C. for 1 hour a solution of DMF (39.7 ml) in THF (50 ml) was added dropwise over 1 hour. The reaction was stirred at −60° C. for 1 hour before being allowed to warm to room temperature. After 1 hour the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted into ethyl acetate. The organic phase was then dried (Na2SO4), concentrated in vacuo and the residue purified by silica gel chromatography, to give the title compound (57 g, 65%) as a yellow solid; 1H NMR (CDCl3) 10.0 (1H, s), 7.83–7.73 (3H, m), 4.02 (3H, s), 3.10 (2H, m), 2.92 (2H, m).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]([C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:15])[N:14]=1)[NH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:8][NH:7][C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:13]([CH3:15])[N:14]=1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NNc1nnc(-c2ccccc2)c(C)n1
Yield: 64.8 %

Procedure:
A solution of ethyl chloroformate (1.98 g) in methylene chloride (5 ml) was added dropwise to a stirred solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.68 g) in methylene chloride (40 ml) under ice cooling in 15 minutes, and the reaction mixture was treated with a solution of triethylamine (1.8 g) in methylene chloride (10 ml) under ice cooling. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate after addition of water. The extract was washed with 5% hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was pulverized with diisopropyl ether. The resulting precipitates were collected by filtration, washed with water and dried to give 3-(2-ethoxycarbonylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (3.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C[Al](C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:32](=[O:33])[O:31][CH2:30][CH2:29][C:27]=3[N:28]=2)=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:32]([C:26]1[S:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[N:28][C:27]=1[CH2:29][CH2:30][OH:31])=[O:33]
Reactant: O=C1OCCc2nc(-c3ccc(Cl)cc3)sc21
Reactant: COc1ccc(CN)c(OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)c(OC)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.7 %

Procedure:
Dissolve 2,4-dimethoxybenzylamine (22.4 g, 134.0 mmol) in CH2Cl2 (300 mL) and cool to 0° C. To the above solution, slowly add a solution of trimethylaluminum (110 mL, 220 mmol; 2 M in toluene) over 35 min while keeping the temperature below 10° C. Stir the resulting solution at room temperature for 45 min and then re-cool to 0° C. Add 2-(4-chloro-phenyl)-6,7-dihydro-pyrano[4,3-d]thiazol-4-one (52.2 g, 120.6 mmol), then allow the resulting slurry to warm to room temperature and stir overnight. Cool the reaction and carefully quench with saturated Rochelle's salt solution (300 mL) over 30 min. Add CH2Cl2 (750 mL), water (400 mL) and diatomaceous earth (100 g) and stir the mixture at room temperature for 30 min, then filter. Collect the solids and triturate with CH2Cl2 (1 L) at 35° C. for 3 h, then filter. Concentrate the filtrate to obtain the title compound (32.2 g). Repeat the trituration step with the second solid cake and obtain an additional 20 g of title compound (90% total yield). 1H NMR (400 MHz, DMSO-d6) δ9.01 (br s, 1H), 7.96 (d, 2H, J=8.5), 7.57 (d, 2H, J=8.5), 7.15 (d, 1H, J=7.9), 6.57 (d, 1H, J=2.6), 6.48 (dd, 1H, J=2.6, 8.5), 5.34 (t, 1H, J=4.3), 4.34 (d, 2H, J=6.6), 3.81 (s, 3H), 3.79 (m, 2H), 3.75 (s, 3H), 3.11 (t, 3H, J=6.6).
Reaction SMILES: [CH2:1]([N:3](C)[CH2:4][CH2:5][CH2:6]O)[CH3:2].[CH2:9]([NH:11][C:12]([NH:14][CH3:15])=[S:13])[CH3:10].Br>>[CH2:9]([NH:11][C:12](=[N:14][CH3:15])[S:13][CH2:6][CH2:5][CH2:4][NH:3][CH2:1][CH3:2])[CH3:10]
Reactant: CCNC(=S)NC
Reactant: CCN(C)CCCO
Agent: Br
Product: CCNCCCSC(=NC)NCC

Procedure:
A mixture of 3-(ethylmethylamino)propanol, N-ethyl-N'-methylthiourea and aqueous hydrobromic acid is boiled under reflux to give the dihydrobromide salt of the title compound.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:14]1[CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[N:13]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: COc1nccnc1OC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
A solution of 14.6 gm of N-bromosuccinamide, 32 ml of dry DMF was added to a stirred solution of 11 gm (0.078 mol) of 2,3-dimethoxypyrazine in 14 ml of DMF at 0° C. whereupon the reaction was warmed to 25° C. and stirred for 16 hours. The reaction mixture was then cooled in an ice bath and to it was added aqueous Na2SO3 to remove the bromine and this was poured into ice water. The resulting crystalline solid was filtered, triturated with water and dried to give 10.48 gm of the title compound. NMR (CDCl3)δ4.0, 4.02(2s, 6H, OCH3), 7.70(s,1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[F:25][C:26]1[CH:52]=[CH:51][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][N:47]=[N+]=[N-])=[CH:40][CH:39]=3)[C:34](=[O:50])[CH:33]=2)=[CH:28][CH:27]=1.Cl>O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][NH2:47])=[CH:40][CH:39]=3)[C:34](=[O:50])[CH:33]=2)=[CH:51][CH:52]=1
Reactant: [N-]=[N+]=NCCOc1ccc(-n2ccc(OCc3ccc(F)cc3)cc2=O)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1ccc(-n2ccc(OCc3ccc(F)cc3)cc2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
Triphenylphosphine (50 mg) was added to THF (5 mL)-water (1 mL) solution of 4-(4-fluorobenzyloxy)-1-[4-(2-azidoethoxy)phenyl]-1H-pyridin-2-one (50 mg), and stirred at 80° C. for 2 hours. Allowing the reaction liquid to cool off, 1N hydrochloric acid was added, followed by washing with diethyl ether. The aqueous layer was rendered basic by addition of 1N aqueous sodium hydroxide, extracted with chloroform and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was reprecipitated from diethyl ether-hexane to provide the title compound (9.8 mg, 21%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C(CN)c2cccc(Br)c2)cc1
Reaction time: 16 h
Yield: 68.4 %

Procedure:
3-Bromophenylethylamine hydrochloride (9.44 g) was added to THF (60 ml) containing triethylamine (12.24 ml) and stirred-under argon at 5° C. during the portionwise addition over 15 minutes of 4-methylphenylsulphonyl chloride (11.44 g). The slurry was diluted with THF (50 ml) and stirred for 16 h. The solid was filtered off, washed with THF and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, brine and dried (MgSO4). Chromatography on flash silica, eluting with 0 to 25% ethyl acetate in isohexane gave the product (9.67 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][NH:39][C:40]2=[O:45].[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[CH2:56][CH2:57]O>C1COCC1.O>[Br:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][N:39]([CH2:57][CH2:56][C:47]1[CH:48]=[CH:49][C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:46]=1)[C:40]2=[O:45]
Reactant: O=c1[nH]ncc2c(Br)cccc12
Reactant: OCCc1ccc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2cccc(Br)c2cnn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of PPh3 (699 mg, 2.67 mmol) in THF (50 mL) and DIAD (198 mg, 0.98 mmol), 5-bromo-2H-phthalazin-1-one (300 mg, 1.33 mmol) and then 2-quinolin-2-yl-ethanol from example a1 (254 mg, 1.46 mmol) were added dropwise at 15° C. under nitrogen. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with HCl (1 N). The aqueous phase was basified and extracted with DCM. The organic phase was washed with a NaHCO3-solution, dried over Na2SO4, filtered and concentrated. The crude product was recrystallized from EA and dried to give the title compound as bright beige solid (300 mg, 59.2% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)Cl>[CH3:18][NH:19][C:20](=[O:21])[NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) was dissolved in methylene chloride (10 ml) and a solution of methyl isocyanate (0.24 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 1-(2-(3-methylureido)ethyl)-3-tert-butoxycarbonylaminomethylpyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[N:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12].O.[BH4-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Temperature: 25 °C

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid (2-amino-5-bromo-phenyl)-(4-chloro-phenyl)-methyleneamide (6.82 g, 0.02 mmol) dissolved in THF (196 mL) and H2O (4 mL) is added NaBH4 (1.57 g, 0.04 mol) at 0° C. The mixture is stirred at RT. The mixture is quenched with MeOH and H2O, MeOH and THF is removed. The mixture is extracted with ethyl acetate, dried over NaSO4 and concentrated. This provides the desired compound which is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C@H:13]1[CH2:17][O:16][C@:15]2([CH2:23][CH2:22][C@@H:21]3[NH:24][C@@:18]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:19][C@H:20]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:14]1.N(C(OCC)=O)=N[C:42](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1>[CH3:42][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]=1[C@H:13]1[CH2:17][O:16][C@:15]2([CH2:23][CH2:22][C@@H:21]3[NH:24][C@@:18]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:19][C@H:20]3[S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:14]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2O)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (1R*,2R*,4S*,5S*,6R*)-2′,3′,4′,5′-tetrahydro-4′-(2-hydroxy-5-trifluoromethoxyphenyl)-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Example 10; 60 mg, 0.11 mmol), diethyl azodicarboxylate (0.04 ml, 0.25 mmol), triphenylphosphine (68 mg, 0.26 mmol), methanol (0.2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature overnight then concentrated in vacuo and treated with methanol (2 ml) followed by 4M aqueous Na
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.CC(=O)CC>C(OCC)(=O)C>[Br:1][C:2]1[N:6]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Brc1ccn[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2nccc2Br)cc1
Yield: 63.7 %

Procedure:
5-bromo-1H-pyrazole (146 mg, 1 mmol), methyl 4-(bromomethyl)benzoate (242 mg, 2 mmol) and K2C03 (276 mg, 2 mmol) were placed in a 100-mL flask with 2-butanone (20 mL) and heated at reflux temperature for 17 h. The mixture was cooled, filtered and evaporated in vacuuo leaving a residue which was dissolved in ethyl acetate and washed with water. The separated organic layer was dried and concentrated to give desired product as an oil (188 mg, 100% yield). This crude material was used without further purification. LCMS (m/z): 295.1 [M+H]+
Reaction SMILES: CS(Cl)(=O)=O.OCC[N:9](CCO)[S:10]([C:13]1[CH:18]=[CH:17][C:16](C)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>ClCCl>[C:13]1([S:10]([NH2:9])(=[O:12])=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1
Yield: 85.7 %

Procedure:
A solution of 11.4 g (0.1 mole) of methanesulfonyl chloride in 17.1 ml of dichloromethane is cooled to 5° C. A solution of 13 g (0.05 mole) of N,N-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide and 10.1 g (0.1 mole) of triethylamine in 52 ml of dichloromethane is then added dropwise with stirring. The resulting mixture is allowed to return to ambient temperature and stirred for a further 3 hours. The reaction mixture is then extracted three times with 40 ml water. The organic phase is dried over sodium sulfate, filtered and concentrated in a rotating evaporator. The resulting oil is then crystallized from ethanol. 17.8 g of 4-methyl-N,N-bis[2-methylsulfonyloxy)ethyl]benzenesulfonamide are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:45]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: COC1(Cc2ccccc2F)CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC1(Cc2ccccc2F)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.025 mmol, 12.4 mg), HCl salt of 3-(2-fluorobenzyl)-3-methoxycyclohexanamine (0.025 mmol, 6.8 mg), HATU (0.025 mmol, 9.5 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-methoxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([SH:37])([C:33]([F:36])([F:35])[F:34])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[OH-].[K+].[NH2:40]OS(O)(=O)=O>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:33]([F:34])([F:36])[F:35])[S:37][NH:40][C:12]([C:14]3[CH:15]=[C:16]4[CH2:17][O:18][C:19]5([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]5)[C:20]4=[CH:21][CH:22]=3)([OH:13])[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NOS(=O)(=O)O
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(S)(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3(O)CC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)SN3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of Intermediate 6 (530 mg) in a solution of potassium hydroxide (182 mg) in water (9 mL) was added a solution of hydroxylamine-O-sulfonic acid (183 mg, 2 eq) in a solution of potassium hydroxide (273 mg) in water (18 mL) and the resulting mixture was stirred at room temperature for 30 min under nitrogen. The mixture was diluted with ethyl acetate and washed with brine. The organic extract was concentrated and subjected to silica gel column chromatography (0 to 30% ethyl acetate in heptane) to yield 150 mg of Intermediate 7 as a mixture of diastereomers.