Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[S:13](=[O:15])(=[O:14])[N:12]([CH3:16])[C:11]([C:17]([O:19]C)=O)=[C:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[S:13](=[O:14])(=[O:15])[N:12]([CH3:16])[C:11]([C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])=[C:10]([OH:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(O)CN(Cc2ccccc2)S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccccc2)=C(O)CN(Cc2ccccc2)S1(=O)=O
Yield: 54 %

Procedure:
The synthesis is effected analogously to Example 1 using in each case 1 equivalent of methyl 6-benzyl-5,6-dihydro-4-hydroxy-2-methyl-1,1-dioxo-2H-1,2,6-thia-diazine-3-carboxylate and aniline. Recrystallisation from a diisopropyl ether/acetone mixture gives the title compound in a yield of 54%.
Reaction SMILES: [NH3:1].[Cl:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:4]>O1CCCC1>[Cl:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:1])(=[O:13])=[O:12])[CH3:4]
Reactant: CC(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CC(Cl)c1ccccc1S(N)(=O)=O

Procedure:
A solution of ammonia (1.2 ml) in tetrahydrofuran (100 ml) at -70° was contacted rapidly with a solution of 2-(1-chloroethyl)benzenesulfonyl chloride (4.32 g, 18.1 mmol) in tetrahydrofuran (50 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and washed with a small volume of water and brine. The dried (MgSO4) solution was evaporated to give 4.7 g of off white solid which was recrystallized from chloroform to give 3.13 g, m.p. 121°-122°. 1H nmr δ(CD3)2COTMS 8.25-7.30 (m), 6.93 (brds), 6.25 (q, J=7 Hz), 3.17 (s), 1.98 (d, J=7 Hz).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:5]1[N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:2]=[CH:3][CH:4]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C#N)cc2)ccc1=O
Solvent: CO
Product: N#Cc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 4.6 %

Procedure:
To a solution of 4-{3-[3-(dimethylamino)prop-2-enoyl]-4-oxopyridazin-1(4H)-yl}benzonitrile (crude, 340 mg, 1.16 mmol) in 20 mL of methanol was added phenylhydrazine (500 mg, 4.62 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 4-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]benzonitrile (18 mg, 4% for two steps) as a yellow solid.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:9])[O:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25]1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
In a 50 ml sealed tube was added 2-biphenylylisocyanate (8 g, 41 mmol) in anhydrous acetonitrile (40 mL). To this solution was added N-benzyl-4-piperidinol (9.8 g, 51.25 mmol) and the tube was partially immersed in a silicon oil bath and heated to 85° C. After 16 h, the reaction mixture was cooled and concentrated in vacuo to give a 1-benzyl-4-piperidyl N-(2-biphenylyl)carbamate which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[C:23]([C:24]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[N:4]=[CH:5][C:6]=3[CH2:12]2)=[O:25])[CH:27]=1)(=[O:18])=[O:17]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1ncc2c(n1)CCNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ncc2C1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (CA [74737-17-7]; WO2004069162) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): 498.4 (M+H+).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[C:16]([CH2:17][CH:18]=C)=[CH:15][C:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1)=[O:10]>O.C1COCC1.[Os](=O)(=O)(=O)=O>[CH3:7][O:8][C:9]([C:11]1[C:16]([CH2:17][CH:18]=[O:2])=[CH:15][C:14]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][N:12]=1)=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1cc(COc2ccccc2)cnc1C(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ncc(COc2ccccc2)cc1CC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 123 %

Procedure:
Sodium metaperiodate (304 mg, 1.42 mmol) was added to a stirred solution of 3-allyl-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (161 mg, 0.57 mmol) and osmium tetraoxide (0.37 mL, 0.028 mmol; 2.5% in tert-butanol) in H2O (3 mL) and THF (6 mL) at 0° C. The mixture was stirred at RT for 2 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 3-(2-oxo-ethyl)-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (200 mg, 60% purity, 74%) as a black residue which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]4=[O:33])=[CH:23][C:22]=3[F:34])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(Cc1csc(NC(=O)c2ccc(Cl)cc2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 4-chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide, using general procedure B. Off-white solid. MS 483.3 ([M+H]+)
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]2[CH:11]=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[K+].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(OC(=O)C)(=O)C>CO>[C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([C:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CC(=O)Nc1ccc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Yield: 58.9 %

Procedure:
A solution of 0.477 gm (2.7 mMol) of the 5-(N-acetylamino)pyrrolo[3,2-b]pyridine, 0.54 mg (9.5 mMol) potassium hydroxide, and 0.43 mL (3.5 mMol) 1-methyl-4-piperidone in 15 mL methanol was heated at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue dissolved in pyridine. To this solution was added 0.20 mL (2.2 mMol) acetic anhydride and the resultant mixture stirred for 1 hour. This reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of ethyl acetate (2-40% methanol). Fractions containing product were combined and concentrated under reduced pressure to provide 0.43 gm (59%) 5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine as an ivory foam. A portion was recrystallized from methanol/ethyl acetate to provide an analytical sample.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]3[N:14]=[C:13]([Cl:15])[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]3[N:7]=2)[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[Cl:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:6]2[N:7]=[C:8]3[C:4]([CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH:10]=[CH:9]3)=[C:5]2[N:14]=1
Reactant: Clc1nc2c3cc(Br)ccc3nn2cc1-c1ccccc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2ccc3nn4cc(-c5ccccc5)c(Cl)nc4c3c2)cc1

Procedure:
300 mg (0.84 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole, (intermediate example Int-1-2), 128.7 mg (0.92 mmol) (4-fluorophenyl)boronic acid, 68.3 mg (0.084 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 1.5 mL aqueous sodium carbonate solution (10%) in 10 mL dimethoxyethane were heated in the microwave oven for 45′ at 110° C. The reaction mixture was poured on water/dichloromethane and stirred vigorously for 30′. The organic phase was separated and washed twice with brine. After drying and filtration the solvent was evaporated and the residue (194 mg), a mixture (according to UPLC/MS) of the title compound, the regioisomer 9-bromo-2-(4-fluorophenyl)-3-phenyl-pyrimido[1,2-b]indazole and the bisproduct 2,9-bis-(4-fluorophenyl)-3-phenyl-pyrimido[1,2-b]indazole, was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CC2)COc2ccccc2C3)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2c(c1)CC1(CCNCC1)CO2
Yield: 91.1 %

Procedure:
1′-benzyl-4H-spiro[chromene-3,4′-piperidine] (800 mg, 2.7 mmol) was dissolved in methanol (100 mL). Acetic acid (5 mL) and palladium on activated charcoal (cat amount, 10%) was added. Reaction in a Parr apparatus at 35 psi for 18 hrs, followed by filtration, evaporation and HPLC purification on C18 (acetonitrile/water) yielded 500 mg (92%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[C:24]=1[CH2:25][N:26]1[C:31]([CH3:32])=[C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]3[O:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=3)[CH2:35][CH2:34]2)[C:29](=[O:49])[NH:28][C:27]1=[O:50].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([Si:5]([CH3:20])([CH3:21])[O:6][C@H:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:8][N:28]1[C:29](=[O:49])[C:30]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]3[O:41][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:43][CH:44]=3)[CH2:37][CH2:38]2)=[C:31]([CH3:32])[N:26]([CH2:25][C:24]2[C:51]([C:55]([F:57])([F:58])[F:56])=[CH:52][CH:53]=[CH:54][C:23]=2[F:22])[C:27]1=[O:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](COS(C)(=O)=O)c1ccccc1
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethanol (85 mg, 0.337 mmol) in dichloromethane (2 mL) were added triethylamine (61 μl, 0.44 mmol) and methanesulfonyl chloride (27 μl, 0.35 mmol) in the order, followed by stirring at room temperature for 20 min. The solution was washed with an aqueous saturated sodium bicarbonate solution to separate an organic layer. The organic layer was dried over sodium sulfate and filtrated. The filtrate was concentrated and dried for 30 min in a vacuum to give methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester. Methanesulfonic acid (R)-2-(tert-butyl-dimethyl-silanyloxy)-2-phenyl-ethyl ester, 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (5-3) (60 mg, 0.112 mmol) and potassium carbonate (77 mg, 0.560 mmol) were dissolved at 70° C. for 12 hrs in DMF (1 ml) in a nitrogen atmosphere with stirring. The solution was cooled to room temperature, washed with an aqueous saturated sodium bicarbonate solution and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 5/1) and dried in a vacuum to afford 83 mg of the compound as a white solid (yield 97%). 1H NMR (300 MHz, CDCl3) δ −0.23 (3H, s), −0.11 (3H, s), 0.80 (9H, s), 2.25 (2H, m), 2.33 (3H, s), 2.47 (2H, m), 2.80 (2H, m), 3.50-3.70 (2H, m), 3.62 (2H, s), 3.83 (1H, dd), 4.36 (1H, dd), 5.13 (1H, dd), 5.26-5.50 (2H, m), 6.30 (1H, d), 6.73 (1H, m), 7.16-7.43 (7H, m), 7.53 (1H, d)
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:34][S:35]([CH:38]=[CH2:39])(=[O:37])=[O:36]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: C=CS(C)(=O)=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CCS(C)(=O)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and methylvinylsulfone were reacted to give 544. LCMS m/z: 553.3 (MH+)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].[CH3:8][Si:9]([CH3:24])([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]1[CH2:17][O:16]1>C(O)C>[CH3:24][Si:9]([CH3:8])([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:16])[CH2:17][NH:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1
Reactant: NCC1CCCO1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CNCC1CCCO1
Temperature: 70 °C

Procedure:
C-(Tetrahydro-furan-2-yl)-methylamine (3.68 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess C-(Tetrahydro-furan-2-yl)-methylamine.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1)=[O:13]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:15]=1)=[O:13]
Reactant: COC(=O)c1ccnc(S(C)(=O)=O)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Oc2ccccc2)n1
Reaction time: 12 h
Yield: 25 %

Procedure:
NaH (3.5 g of a 60% suspension, 87.4 mmol) is added to a solution of phenol (8.23 g, 87.4 mmol) in THF (100 mL) at room temperature. 2-Methanesulfonyl-pyrimidine-4-carboxylic acid methyl ester, 15, (6.3 g, 29.1 mmol) is dissolved in THF (60 mL) and added dropwise to the solution of phenol. The reaction is allowed to stir for 12 hours then quenched by the addition of saturated aqueous NH4Cl. The aqueous phase is extracted with methylene chloride and the combined organic layers are dried, filtered, and concentrated in vacuo to afford a crude oil which is purified over silica (ethyl acetate/hexane 2:3) to afford 1.72 g (25% yield) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.[C:35]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1=O)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([NH:8][CH:45]2[CH2:46][CH2:47][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:43][CH2:44]2)[C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
0.41 g of N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea is dissolved in 4 ml of dichloromethane under N2 in the presence of 0.17 g of N-BOC-piperidone and of 0.23 g of sodium triacetoxyborohydride, and the mixture is stirred at ambient temperature for 16 h. After evaporation and hydrolysis, extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. Drying over MgSO4 and concentration to dryness are carried out. The crude is chromatographed on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and methanol. 0.37 g of tert-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo-[3.2.1]oct-8-yl)-2-oxoethyl]amino}piperidine-1-carboxylate is then obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>COCCOC>[OH:36][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:24]
Reactant: COc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COCCOC
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
According to the procedure in the literature [J. Chem. Soc. Perkin Trans. I, 1992, 2409-2417], dissolve 292 ml (2.08 mol) diisopropylamine in 3.6 litre 1,2-dimethoxyethane and cool to −78° C. Add 826 ml n-butyllithium solution (2.5 M in n-hexane, 2.066 mol) at a temperature below −60° C. Stir the mixture for a further 15 min at <−60° C. and then add a solution of 442 g (1.877 mol) (4-methoxyphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.41 litre 1,2-dimethoxyethane dropwise at <−60° C. After further stirring for 30 min at −60° C., add a solution of 199.3 g (1.878 mol) benzaldehyde in 1.4 litre 1,2-dimethoxyethane in the space of 20 min at −60° C. Next, heat the reaction mixture slowly to RT in 4 h. Add 7 litre saturated ammonium chloride solution and extract with ethyl acetate. Wash the organic phase with saturated ammonium chloride solution, dry, and concentrate under vacuum. Take up the residue in 7 litre dioxan and 5 litre methanol, and add 6 litre 1 N hydrochloric acid. Stir the mixture for 3 h at RT, then add 3 litre saturated sodium chloride solution and extract the mixture with 6.5 litre ethyl acetate. Wash the organic phase with 1.0 litre 1 N sodium hydroxide solution and with saturated sodium chloride solution, dry, and concentrate under vacuum. Take up the residue in 2 litre diisopropyl ether, decant from the insoluble matter and seed with crystals. Stir the resultant suspension for 2 h at RT and then filter off the crystals with suction. Wash with 300 ml diisopropyl ether and petroleum ether and dry under vacuum. 236.8 g (47.8% of theor.) of the target compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O>O1CCCC1>[Br:12][C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc2[nH]ccc2c1
Solvent: C1CCOC1
Product: COc1cnc2[nH]cc(Br)c2c1
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (0.439 g, 2.96 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (0.527 g, 2.96 mmol) at 0° C. After 90 minutes at 0° C., the reaction was quenched with 30% Na2S2O3 and extracted with EtOAc (2×). The combined organic layers were washed with water, dried and concentrated. The residue was triturated with EtOAc/diethyl ether (1:1) to give 0.375 g of the title compound.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-])=O)=[C:14]([S:16]([NH:19][CH3:20])(=[O:18])=[O:17])[CH:15]=1)[CH2:3][CH2:2]2.[H][H]>N.CO.[Pd]>[NH2:21][C:13]1[CH:12]=[CH:11][C:10]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[CH:15][C:14]=1[S:16]([NH:19][CH3:20])(=[O:17])=[O:18]
Reactant: [H][H]
Reactant: CNS(=O)(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CO
Product: CNS(=O)(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Yield: 95.2 %

Procedure:
5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-2-nitrobenzenesulfonamide (Intermediate 17A) (1.0 g, 2.94 mmol) was dissolved in 2M ammonia in methanol (110 mL). The resulting solution was hydrogenated using the H-cube at 40° C. under 30 bar pressure of hydrogen, with a flow rate of 1 mL per minute through a 10% palladium on charcoal cartridge. The reaction mixture was purified by SCX and evaporated to afford 2-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methylbenzenesulfonamide, (868 mg, 2.8 mmol). 1H NMR; δ (ppm)(CHCl3-d): 7.17 (1H, d, J=3.01 Hz), 6.88 (1H, dd, J=9.04, 3.01 Hz), 6.72 (1H, d, J=9.04 Hz), 4.82 (1H, bs), 4.31 (2H, bs), 3.88-3.87 (1H, m), 3.42-3.39 (2H, m), 3.13-2.97 (6H, m), 2.57 (3H, d, J=3.51 Hz), 2.11-2.04 (2H, m), 1.76-1.68 (2H, m).