Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].[CH:40](B1OB(C=C)OB(C=C)O1)=[CH2:41].N1C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O.C1(C)C=CC=CC=1>[CH3:14][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[C:7](=[O:15])[N:6]([CH3:16])[C:5]1[CH:17]=[C:18]([O:19][CH2:20][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:22][CH:23]([CH3:24])[CH3:25])[C:2]([CH:40]=[CH2:41])=[CH:3][C:4]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=Cc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To the solution of (S)-tert-butyl (1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (300 mg, 0.579 mmol), prepared as described in Example 3, Part A, in the solvent mixture toluene (10 mL), water (0.5 mL) and ethanol (2 mL) was added sodium carbonate (184 mg, 1.736 mmol), tetrakis(triphenylphosphine)palladium (33.4 mg, 0.029 mmol) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane with pyridine (1:1) (167 mg, 0.694 mmol). The reaction mixture was degassed for 30 min. Then the reaction mixture was allowed to stir at 90° C. for 16 h. After cooling to room temperature the mixture was filtered through diatomaceous earth (Celite®) eluting with EtOAc. The filtrate was concentrated under reduced pressure. The residue was taken up in EtOAc and water. The solution was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% Ethyl acetate in hexane) to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (300 mg, 0.110 mmol, 19% yield) as a pale yellow semi solid. LC/MS, (ESI) m/z 466.5 [(M+H)+, calcd for C27H36N3O4 466.3]; LC/MS retention time (method E): tR=1.18 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:23])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH:20]([CH3:21])[CH3:22])[C:16](=[O:23])[CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]
Reactant: CC(C)N1CCN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1=O
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 120 °C
Yield: 43.9 %

Procedure:
A mixture of 4-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-1-isopropylpiperazin-2-one (51 mg, 0.12 mmol), 2-ethylbenzimidazole (20 mg, 0.13 mmol), Pd2(dba)3 (2.8 mg, 2.5 mol %), Xphos (5.8 mg, 10 mol %) and Cs2CO3 (59 mg, 0.18 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 20-98%) to give 493 (28 mg, 44%) as an off white solid. LCMS: (Method I): RT 2.75 min; [M+H]+ 532.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1H), 7.80-7.76 (m, 1 H), 7.28 (m, 2 H), 4.91-4.82 (m, 1 H), 4.5-4.21 (m, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 3.77 (s, 3 H), 3.37 (q, J=7.5 Hz, 2 H), 3.29 (s, 2 H), 3.26 (t, J=5.4 Hz, 2 H), 3.08-3.01 (m, 2 H), 3.00-2.93 (m, 2 H), 2.81 (t, J=5.4 Hz, 2 H), 1.45 (t, J=7.5 Hz, 3 H), 1.14 (d, J=6.9 Hz, 6 H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[NH:44][CH:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OCc5nc(=O)c(O)c[nH]5)c5csc(N)n5)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (65 mg) (0.11 mmol), 22.5 mg (0.143 mol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 27 mg (0.143 mmol) of p-toluenesulphonic acid hydrate are dissolved in 2 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed in a high vacuum and the residue is treated with water. The precipitated product is filtered off and washed in succession with water and diethyl ether. After drying in a high vacuum there are obtained 55 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrimidinyl)methoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[H-].[Na+].[C:14](OCC)(=O)[CH2:15][CH2:16][CH3:17].Cl>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:14]([CH2:15][CH2:16][CH3:17])=[CH:10][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: CCCC(=O)OCC
Reactant: CC(=O)c1cc(F)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(=O)c2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2'-hydroxy-5'-fluoroacetophenone (2 gm) in tetrahydrofuran (10 mL) was added dropwise to sodium hydride (600 mg), then ethyl butyrate (10 mL) was added. After 30 minutes, aqueous 1N HCl (50 mL) was added, and the mixture extracted with ethyl acetate, and the extracts washed with H2O, saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The residue was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (7 mL) added, and after stirring overnight at room temperature, dichloromethane and saturated aqueous NaHCO3 were added, and the layers separated. The organic layer was washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield 6-fluoro-2-propyl-4H-1-benzopyran-4-one (2.4 gm, Rf=0.4 1:1 diethyl ether/hexanes). This compound (9 gm) was dissolved in ethanol (250 mL) and sodium borohydride (1.6 gm) added, and the mixture heated under reflux. After 3.5 hours additional sodium borohydride (1.6 gm) added, and after 7 hours a further addition of sodium borohydride (1.6 gm) was made. After 10 hours more sodium borohydride (0.8 gm) was added and after 23 hours total reaction time the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated to yield 4-hydroxy-2,3-dihydro-6-fluoro-2-propyl-4H-1-benzopyran-4-one (Rf=0.4 1:1 diethyl ether/hexanes). This material (10.8 gm) was dissolved in acetic acid (45 mL) and a solution of chromium trioxide (7.8 gm) in acetic acid (45 mL)/H2O (10 mL) was added dropwise. After one hour, the mixture was poured into ice/H2O (1L) and extracted with ethyl acetate. The extracts were washed with H2O, saturated NaHCO3, dried (Na2SO4), filtered and evaporated to yield the title compound (7.4 g, Rf=0.7, 1:1 diethyl ether/hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[I:13]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:6][C:7]=1[I:13]
Reactant: ClI
Reactant: CNC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
4-Amino-N-methyl-benzeneacetamide (6) (6.56 g, 0.04 mol) was dissolved in CH3CN (200 mL) and ICl (7.14 g dissolved in 60 mL of CH3CN, 0.044 mol) was added dropwise with vigorous stirring. After stirring at RT for 3 h, saturated aqueous Na2CO3 (50 mL) was added and the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and extracted with saturated aqueous Na2CO3. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product (7) (7.38 g, 63.6%) was isolated from the concentrate by trituration with CH2Cl2 /EtOAc and washing with Et2O. This material was found to be pure by NMR analysis.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20]([NH2:22])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:33]=[O:34]>O1CCCC1>[CH2:35]([NH:32][C:33]([NH:22][C:20]1[N:19]([CH3:23])[C:18]2[CH:24]=[CH:25][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]=2[N:21]=1)=[O:34])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN=C=O
Reactant: Cn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A mixture of 4.1 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-amine, 1 part of 1-isocyanatobutane and 180 parts of tetrahydrofuran is stirred and refluxed over week-end. After cooling to room temperature, the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol. The product is filtered off, washed with ethanol and with 2,2'-oxybispropane, and dried, yielding 3.4 parts (66.7%) of N-butyl-N'-{5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-yl}urea; mp. 195.8° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][CH2:4][NH:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:14][CH3:15])=[CH:9][C:8]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]1.[C:29]([O:33][C:34](=[O:48])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([N:44]=[C:45]=S)[C:38]=1[Cl:47])([CH3:32])([CH3:31])[CH3:30].CC(C)N=C=NC(C)C>CN(C=O)C>[F:28][C:2]([F:1])([F:27])[CH2:3][CH2:4][NH:5][C:6]([C:7]1[C:8]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([F:23])([F:24])[F:25])[CH2:18][CH2:17]2)=[CH:9][C:10]2[N:14]([CH3:15])[C:45]([NH:44][C:39]3[C:40]([Cl:43])=[CH:41][CH:42]=[C:37]([CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:48])[C:38]=3[Cl:47])=[N:13][C:11]=2[CH:12]=1)=[O:26]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)OC(C)(C)C)c2Cl)nc2cc(C(=O)NCCC(F)(F)F)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound is prepared in analogy to 1e from N-(3,3,3-trifluoro-propyl)-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-amino-benzoic acid amide (2.3 g, 5.6 mmol), (2,4-dichloro-3-isothiocyanato-benzyl)-carbamic acid tert.-butyl ester (compound B; 1.85 g, 5.6 mmol), DIC (1.0 mL) and DMF (10 mL).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:8]=2[C:9]=1[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:7]2[O:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:21][CH:22]=3)=[O:11])[C:8]=2[CH:23]=1
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCCO)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCO)cc1
Yield: 90.7 %

Procedure:
180 g (0.453 mol) of 3-{4-[(2-butyl-5-nitro-1-benzofuran-3-yl) carbonyl]phenoxy}propan-1-ol (formula(II)) dissolved in 1800 ml of methanol are loaded in a glass Buchi autoclave. Subsequently 9 g of Pd/C 10% (50% H2O) are added and H2 is loaded at a pressure of 4 bars. The mixture is left under stirring maintaining the temperature below 40° C. Once the consumption of hydrogen is complete, the reaction is left under stirring for approximately one further hour until it reaches 25° C. The catalyst is filtered on a Celite panel and the alcoholic solution containing the product is concentrated to residue. The crude product is crystallised, recovering it with 400 ml of toluene and the product is dried under a vacuum at 40° C. for 6-7 hours. 151 g of the product in the title are obtained.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]2[S:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]#[N:18]>>[CH:1]1(/[CH:7]=[CH:8]/[C:9]2[S:13][CH:12]=[C:11]([CH:14]([OH:15])[CH2:16][C:17]#[N:18])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1csc(/C=C/C2CCCCC2)c1
Reactant: CC#N
Product: N#CCC(O)c1csc(/C=C/C2CCCCC2)c1

Procedure:
Addition of CH3CN to (E)-5-(2-cyclohexylvinyl)thiophene-3-carbaldehyde following the method used in Example 3 gave (E)-3-(5-(2-cyclohexylvinyl)thiophen-3-yl)-3-hydroxypropanenitrile as a yellow oil which was used in the next step without further purification. Yield (0.47 g, quant.).
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2].C(#[N:24])C.N>O>[CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([NH2:24])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: CC#N
Reactant: CCCCC(CC)COC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: N
Solvent: O
Product: CCCCC(CC)COC(=O)c1cccc(S(N)(=O)=O)c1
Temperature: 0 °C
Yield: 77 %

Procedure:
An ice-cooled solution of 460 g of 3-(2-ethylhexyloxycarbonyl)phenylsulfonyl chloride and 0.7 L of acetonitrile was added dropwise to 0.7 L of a 28% ammonia solution. The resultant mixture was stirred for 2 hours at room temperature. Thereafter, 0.7 L of water and 35 g of common salt were added thereto, followed by extraction with 1.0 L of ethyl acetate. The extract was washed with 0.5 L of diluted hydrochloric acid and 0.5 L of saturated brine and was then decolored with 20 g of active carbon. The active carbon was removed with Celite, and then the solvent was distilled off. 0.6 L of hexane was added and crystallized by cooling, and thus 338 g (1.08 mol, yield 77%) of 3-(2-ethylhexyloxycarbonyl)phenylsulfonamide was obtained m.p. 40° C. to 42° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][C:14]([CH3:18])=[CH:15][CH:16]=O>C1(C)C=CC=CC=1>[CH3:18][C:14](=[CH2:13])[CH:15]=[CH:16][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: CC(C)=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C)C=CN1CCOCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Anhydrous potassium carbonate (43.5 mmol; 6 g) and morpholine (308 mmol; 26.8 g) were introduced into a 100-ml Erlenmeyer equipped with a dropping funnel,under an inert atmosphere. When the reaction medium had been cooled to 0° C., prenal (150 mmol) in toluene (20 ml) was added dropwise. The temperature was allowed to rise to 20° C. and stirring was continued for 4 hours. The potassium carbonate was separated by filtration. The toluene was removed at atmospheric pressure, which permits cracking of the aminal. Under reduced pressure, the excess morpholine was distilled first, and then the expected dienamine (b.p. 108-110.C at 20 mm Hg) was distilled.
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].C(O)=O.[CH3:8][C@H:9]1[CH2:18][NH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=2)[N:10]1[C:29](=[O:31])[CH3:30]>>[C:29]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[N:17]([CH:1]=[O:3])[CH2:18][C@@H:9]1[CH3:8])(=[O:31])[CH3:30]
Reactant: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2NC[C@@H]1C
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2N(C=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
Sodium formate (14 mg, 0.200 mmol) and formic acid (46 mg, 1.0 mmol) were added to (S)-1-(2-methyl-6-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.2 M in 1,2-dichloroethane, 0.1 mL, 0.02 mmol) and shaken at room temperature for 5 h. The reaction was concentrated and the crude product was purified by mass-triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-4-acetyl-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1 (2H)-carbaldehyde (0.0034 g, 46%). MS (ESI, pos. ion) m/z 373
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][C:27]4([C:37](O)=O)[CH:32]=[CH:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1.O.O[N:43]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl-].[NH4+].CN1CCOCC1>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:18])[CH:15]=[C:16]([Br:17])[C:9]=3[C@@H:8]([CH:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:40])[CH2:26][C:27]4([C:37]#[N:43])[CH:32]=[CH:31][N:30]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:29]=[CH:28]4)[CH2:21][CH2:20]3)[C:5]2=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)N1C=CC(CC(=O)N2CCC([C@H]3c4ncc(Br)cc4CCc4cc(Cl)cc(Br)c43)CC2)(C(=O)O)C=C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)N1C=CC(C#N)(CC(=O)N2CCC([C@H]3c4ncc(Br)cc4CCc4cc(Cl)cc(Br)c43)CC2)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve the title compound from Example 2 (1 mmol) in anhydrous N,N-dimethylformamide (DMF, 10 mL) and add 1-hydroxybenzotriazole hydrate (1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1 mmol), ammonium chloride (1 mmol) and N-methylmorpholine (1 mmol). Stir the resulting mixture at room temperature under nitrogen overnight. Concentrate in vacuo to provide a residue and dilute with dichloromethane, wash with 1M hydrochloric acid and brine, then dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo to afford (+)-4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-[[4-cyano-1-(methylsulfonyl)-4-pyridinyl]acetyl]piperidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:8]C(=O)OC(C)(C)C)[CH3:7].[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[NH2:8][C@H:6]([CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: C[C@H](CCCCO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)CCCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (R)-tert-butyl 6-hydroxyhexan-2-ylcarbamate (0.530 g, 2.44 mmol) in DCM (1.5 mL) was added TFA (1.88 mL, 24.4 mmol). The resulting clear solution was stirred at rt for 1 hr. The reaction was concentrated. The obtained oily residue was dried under vacuum to give (R)-5-aminohexan-1-ol trifluoroacetate as a light brown oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].ClCCl.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(Cl)(Cl)Cl>[N:11]1([CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:4][CH:3]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: c1ccc(OCCCN2CCOCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCCCN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
[3-(Morpholin-4-yl) propoxy] benzene-4-sulfonyl chloride was prepared by chlorosulfonylation of 4-(3-phenoxypropyl)morpholine using chlorosulfonic acid in the presence of dichloromethane or chloroform. For example, to a solution of 2.2 g (10 mmole) of N-(3-phenoxypropyl) morpholine in 20 ml of chloroform, 2 ml of chlorosulfonic acid (30 mmole) was slowly added at −10° C. and stirred for 30 min. The reaction mixture was stirred at room temperature for 5 hr. Chloroform was removed from lower layer. Lower layer was treated with chopped-ice to give solids. To a mixture of ice and solid product, 10 g of sodium phosphate (tribasic) was added and stirred with cooling. Chlorosulfonyl compound was extracted with dichloromethane (300 ml). Dichloromethane extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 1.6 g of [3-(morpholin-4-yl) propoxy]benzene-4-sulfonyl chloride was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:36].[N:37]12[CH2:44][CH2:43][CH:40]([CH2:41][CH2:42]1)[C@@H:39]([NH:45][C:46]([C:48]1[O:49][C:50]3[C:56](Br)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:36].[N:37]12[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44]1)[C@@H:39]([NH:45][C:46]([C:48]1[O:49][C:50]3[C:56]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([N:8]5[CH2:12][CH2:11][CH2:10][CH2:9]5)[CH:3]=4)=[CH:55][CH:54]=[CH:53][C:51]=3[CH:52]=1)=[O:47])[CH2:38]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: Brc1cccc(N2CCCC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(N4CCCC4)c3)c2o1

Procedure:
114.3 mg (0.51 mmol) of 1-(3-bromophenyl)pyrrolidine, 148.1 mg (0.58 mmol) of bis(pinacolato)diboron, 124.1 mg (1.26 mmol) of potassium acetate, 14.2 mg (0.02 mmol) of PdCl2(dppf), 150 mg (0.39 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A), 0.97 ml of 2 M sodium carbonate solution and a further 14.2 mg (0.02 mmol) of PdCl2(dppf) in 2.0 ml of DMF are reacted by general method D. Drying under high vacuum results in 95.6 mg (54.4% of theory) of the title compound.