Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:6](C)[C:5]=2[N:4]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=1.Cl[CH2:39]Cl>FC(F)(F)C(O)=O>[CH3:39][O:11][C:9]1[CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[CH:14][CH:13]=2)[N:6]=[C:5]2[N:4]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: ClCCl
Reactant: Cc1nn(-c2ccccc2)c2c1c(=O)cc(-c1ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc1)n2C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc(N3CCNCC3)cc2)nc2c1c(C)nn2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of tert-butyl 4-(4-(3,7-dimethyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate (270 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (6 mL), trifluoroacetic acid (3 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to about 9-10 with sodium bicarbonate. The resulting solution was extracted with of ethyl acetate (3×10 mL), the organic layers combined and dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with methanol:CH2Cl2 (1:30) to yield 4-methoxy-3-methyl-1-phenyl-6-(4-piperazin-1-yl-phenyl)-1H-pyrazolo[3,4-b]pyridine as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.S(Cl)([Cl:23])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(CO)c3)ccc21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(-c3cncc(CCl)c3)ccc21
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
At 0° C., 6-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (190 mg, 0.7 mmol) in DCM (15 mL) was treated slowly with thionyl chloride (0.32 mL, 4.0 mmol). After the addition, the reaction mixture was allowed to stir at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give title compound (190 mg, 93.5%) as yellow oil. MS: 287.1 (M+H+).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:36]3[CH:37]=[N:38]N[CH:40]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1.N1C=CC(B(O)O)=[CH:42]1.CC1(C)C(C)(C)OB(C2C=NN(C(OC(C)(C)C)=O)C=2)O1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:24][CH2:25][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:36]3[CH:40]=[CH:42][NH:38][CH:37]=3)[CH2:27][CH2:28]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc[nH]c1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cn[nH]c1
Agent: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cc[nH]c1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine of using (1H-pyrrol-3-yl)boronic acid instead tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate. LC-MS: (M+1=555, obsd.=555).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc2ccoc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1)OCC2

Procedure:
6-Methylbenzofuran (15 g) was dissolved in methanol (200 ml) containing 0.5 g of 10% palladium on carbon. This solution was shaken on a Paar hydrogenator under hydrogen at 40 psi. When hydrogen uptake was complete, the solution was filtered through Celite and the ethanol evaporated to yield 6-methyl-2,3-dihydrobenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Fc1ccccc1S
Reactant: C=C(C(=O)OCC)c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CSc1ccccc1F)c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
The crude product from Step A (3.9 g, 20 mmole) was taken up in 20 ml of ethanol. To this solution, being stirred at room temperature, was added 2-fluorothiophenol (2.5 g, 20 mmole) and 50 mg of solid sodium ethoxide. After stirring for eight hours the ethanol was concentrated and the residue taken up in ether. The ether mixture was washed twice with 15% NaOH solution, dried (MgSO4) and concentrated to a colorless oil (5.3 g, 82% yield).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 64 mg (0.08 mmol) of (R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 52) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shaken for 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered, the solvent was evaporated down i.vac., the residue was combined with acetonitrile and water and lyophilised.
Reaction SMILES: [CH2:1]([S:3]([Cl:6])(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.Cl.Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C@@H:32]3[CH:37]4[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]4)[CH2:33]3)=[O:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CN(C=O)C>[ClH:6].[CH2:1]([S:3]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30]([C@@H:32]3[CH:37]4[CH2:36][CH2:35][N:34]([CH2:39][CH2:38]4)[CH2:33]3)=[O:31])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
39.1 mg (0.30 mmol) of ethanesulfonyl chloride and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated, mixed with 2 ml of a 1:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 26 mg (35.2% of theory) of the title compound are obtained.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:22]2[CH:23]=[C:18]([C:14]3[CH:13]=[C:12]4[C:17](=[N:16][CH:15]=3)[NH:8][CH2:9][CH2:10][CH2:11]4)[CH:19]=[N:20][CH:21]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(COc4ccc(F)cc4)c3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(OCc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Reaction time: 16 h
Yield: 102.5 %

Procedure:
6-[5-(4-Fluoro-phenoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (42 mg, 0.096 mmol) is dissolved in 1.0 mL of DCM and trifluoroacetic acid (0.3 mL) is added. The mixture is stirred for 16 hrs and then the solvent is removed. The residue is dissolved in MeOH and filtered through Varian PL-HCO3 MP resin catridge to give 33 mg of 6-[5-(4-Fluoro-phenoxymethyl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidin-4-ol (59.0 mg, 0.59 mmol). The title compound was obtained as a solid (45.0 mg, 19% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.06 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 4.75 (1H, m), 4.07 (2H, m), 3.87 (1H, m), 3.66 (2H, m), 3.13 (1H, m), 2.98 (1H, m), 1.71 (2H, m), 1.23 (2H, m). MS m/z: 489.31, 491.26 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:23]([O:25]C)=[O:24])=[N:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[N:4]=1.[OH-].[K+].CO.COCCOC>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[N:6]=1
Reactant: COC(=O)c1nc(N2CCCC2)ccc1Oc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc(N3CCCC3)nc2C(=O)O)n1
Yield: 94 %

Procedure:
1.44 g (4 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate and 0.67 g (12 mmol) of potassium hydroxide were added to 30 ml of methanol, 30 ml of 1,2-dimethoxyethane and 10 ml of water, and the mixture was reacted at 40° C. for 4 hours. The solvent was distilled off, and water was added to the residue. The mixture was acidified (pH=4) by 10% hydrochloric acid, then extracted with chloroform and ethyl acetate, dried and concentrated, and then crystallized from diisopropyl ether to obtain the desired product.
Reaction SMILES: [NH2:1][C:2](=[O:25])[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:5]1=2.C(C(O)=O)(F)(F)F.[ClH:33]>C(Cl)Cl.CCOC(C)=O.CCOCC>[ClH:33].[CH2:13]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]([CH2:3][C:2]([NH2:1])=[O:25])[C:5]=2[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(N)=O)c3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cn1c2c(c3ccccc31)CCNCC2
Reaction time: 0.5 h
Yield: 80 %

Procedure:
tert-Butyl 6-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0233 g, 0.0678 mmol) was dissolved in CH2Cl2 (2 mL) at rt. CF3CO2H (0.8 mL) was added, then the reaction mixture was stirred for 30 min. The reaction mixture was concentrated to give a crude product (0.0288 g). The crude product was dissolved in EtOAc (1 mL), 1 N HCl in Et2O (2 mL) was added, and the precipitated salt was collected by filtration. 2-(2,3,4,5-Tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide hydrochloride (0.0151 g) was obtained in 80% yield. 1H NMR (300 MHz, DMF-d7) δ 3.29-3.33, 3.40-3.43, 3.50-3.58, 4.97, 7.07, 7.15, 7.45, 7.53; MS (ESI+) for C14H17N3O m/z 244.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[C:17](I)[CH:16]=3)=[O:11])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[C:17]([C:26]#[C:25][CH2:24][OH:27])[CH:16]=3)=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C#CCO)ccc2c1O
Reaction time: 8 h

Procedure:
To a mixture of the title compound of Example 39 (0.439 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added propargyl alcohol (0.058 mL). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 3% MeOH/CH2Cl2 to yield 0.271 g of the desired product as a tan solid.
Reaction SMILES: Cl.[C:2]([C:4]12[CH2:11][CH2:10][CH2:9][N:8]1[CH2:7][CH2:6][CH2:5]2)#[N:3]>C(O)(=O)C.[Pt]=O>[NH2:3][CH2:2][C:4]12[CH2:11][CH2:10][CH2:9][N:8]1[CH2:7][CH2:6][CH2:5]2
Reactant: N#CC12CCCN1CCC2
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: NCC12CCCN1CCC2
Temperature: 20 °C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
In 8.5 ml of acetic acid introduced therein hydrogen chloride gas (400 mg, 11.0 mmol), 7a-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine (300 mg, 2.20 mmol, obtained in Example 1) and platinum oxide (30 mg) were added to stir under hydrogen gas atmosphere for 24 hours at 20° C. After removal of insoluble matters from the reaction mixture, the filtrate was concentrated, 0.5N NaOH (10 ml) was added to the residue, which was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, concentrated, and distilled in vacuo to afford 188 mg of the desired compound (Yield: 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:28][CH:29]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:30])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:30][CH:29]([NH:31][C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH3:28])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: Oc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-(4-Benzyloxyphenoxy)phenol (1.948 g, 6.66 mmol), 2-tert-butoxycarbonylaminopropyl methanesulfonate (2.0 g, 6.66 mmol) and cesium carbonate (5.43 g, 16.66 mmol) were stirred in 75 ml of DMF at 80° C. for 3 h. Following addition of 2 g of 2-tert-butoxycarbonylaminopropyl methanesulfonate the reaction mixture was stirred at 80° C. for a further 4 h. The reaction mixture was concentrated in vacuo and the residue is taken up in ethyl acetate and water. The organic phase was separated off, concentrated and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 837 mg (28%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:9](=[O:12])[CH2:10][CH3:11])[C:5](=[O:8])[CH2:6][CH3:7].[C:14](=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(OC)(=O)=O>CC#N>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:5](=[O:8])[CH2:6][CH3:7])=[C:9]([O:12][CH3:14])[CH2:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)C(C(=O)CC)C(=O)OC
Agent: COS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Solvent: CC#N
Product: CCC(=O)C(C(=O)OC)=C(CC)OC
Temperature: 2 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
7.50 g (40.3 mmol) of 3-oxo-2-propionyl-pentanoic acid methyl ester were dissolved in 40 ml of MeCN and the mixture cooled to 2° C. While stirring, 13.26 g (40.3 mmol) of caesium carbonate were added in small portions and the reaction then warmed up to RT. 6.86 g=4.73 ml (40.3 mmol) of methyl trifluoromethanesulfonate were then added drop by drop between 22 and 25° C. After 90 min, the reaction mixture was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 7.86 g of crude compound as yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Mg]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])=[CH2:11])=[CH:6][N:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Br)nc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A lanthanum(III) chloride-bis(lithium chloride) complex (0.6 M solution in THF, 16.7 mL, 10 mmol) was added to a solution of 1-(6-bromopyridin-3-yl)ethanone (2 g, 10 mmol) in THF (10 mL), and the mixture was stirred at room temperature for 1 hour. Methyl magnesium bromide (1.12 M solution in THF, 10.7 mL, 12 mmol) was added thereto at 0° C., and the mixture was stirred for 1 hour. A 10% citric acid aqueous solution was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and insoluble matter was filtered off through Celite. After extraction with ethyl acetate twice, combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. An internal salt of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (2.86 g, 12 mmol) was added to a solution of the obtained residue in THF (20 mL), and the mixture was stirred at 60° C. for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=98/2-80/20 (gradient)] to obtain the title compound (1.00 g, yield: 51%).
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-])([OH:8])=[O:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[O:18])=[CH:15][C:16]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
A 2 L, 3 necked round bottomed flask equipped with a mechanical stirrer, thermocouple and ice-bath was charged with concentrated H2SO4(aq) (635 mL) and concentrated HNO3(aq) (62 mL). The flask and its contents were cooled to 0° C. (4-Bromo-phenyl)-(3-nitro-phenyl)-methanone (127 g, 0.42 mol) was added over a period of 1 h and the temperature was kept under 10° C. Thirty minutes later, the reaction was complete by thin layer chromatographic analysis (Hexanes/EtOAc 6:4). The reaction was poured into ice-H2O (2 L). The solids were filtered, washed with H2O (4 L), saturated NaHCO3(aq) (1 L) and an additional portion of H2O (1 L). The product was dried at 45° C., for 48 h yielding (4-Bromo-3-nitro-phenyl)-(3-nitro-phenyl)-methanone in 95% (138.4 g, 0.39 mol).
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13]COC)=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2.Cl>CO>[CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2
Reactant: COCOc1cccc2c1C1CC1(C)CO2
Agent: Cl
Solvent: CO
Product: CC12COc3cccc(O)c3C1C2
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 1a-methyl-7-{[(methyloxy)methyl]oxy}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene (Intermediate 124, 280 mg) in methanol (16 ml) a 2.0 M aqueous solution of HCl (1.271 ml, 2.54 mmol) was added. The reaction mixture was stirred at 50° C. for 2 hours and then at room temperature overnight at which time the reaction still showed some unreacted starting material, therefore more 2.0 M HCl was added (2 eq.) and stirring was continued at 50° C. for 2 hours. The reaction mixture was then quenched with water and diluted and extracted with dichloromethane, washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, with a gradient from pure cyclohexane to cyclohexane/ethyl acetate 5/1) to give the title compound as a white solid (192 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][NH:25][S:24]4(=[O:30])=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:31])[S:24]4(=[O:29])=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNS4(=O)=O)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCN(C)S4(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-2-yl)phenyl]methanone (150 mg) described in Example 271 and methyl iodide (24 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (103 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(C=O)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CO)c2n1
Reaction time: 1 h

Procedure:
To a suspension of 5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (3 g, 9.65 mmol) in ethanol (20 mL) at 0° C. was added sodium borohydride (0.183 g, 4.83 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was recooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was concentrated to remove most of the ethanol. The resulting residue was dissolved in water and extracted with diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated to give 3.3 g (quant.) as a viscous oil. 1H-NMR (CDCl3, 500 MHz) δ 8.04 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 5.67 (s, 2H), 5.04 (d, J=4.9 Hz, 2H), 3.61 (t, J=8.2 Hz, 2H), 3.31 (m, 1H), 0.92 (t, J=8.2 Hz, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 145.9, 132.4, 128.0, 124.7, 122.7, 122.6, 118.3, 81.9, 67.8, 62.3, 17.9, −1.4. Mass spec.: 313.12 (MH)+.