Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[NH:26][CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:41][CH:42]([F:44])[F:43])(=O)=O>CN(C=O)C.CCOC(C)=O.O.[Cl-].[Na+].O>[F:43][CH:42]([F:44])[CH2:41][N:26]1[C:14]2[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])=[N:16][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12][C:13]=2[N:28]=[CH:27]1
Reactant: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3ncn(CC(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reaction time: 0.67 h

Procedure:
To a solution of crude (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09 (ca. 0.13 mmol) in DMF (1 mL) was added Cs2CO3 (114 mg, 0.35 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (36 mg, 0.17 mmol). After 40 min, an additional portion of 2,2-difluoroethyl trifluoromethanesulfonate (7 mg, 0.03 mmol) was added. After an additional 30 min, the reaction mixture was diluted with EtOAc (20 mL), water (10 mL), and brine (10 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0% to 10% MeOH in DCM) to afford (R)-4-((R)-1-(3-(2,2-difluoroethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.12.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](Cl)=[O:16].[CH3:18][C:19]([NH:28][CH:29]([CH3:33])[C:30](=[O:32])[CH3:31])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:20].O>ClCCl>[CH3:20][C:19]([N:28]([CH:29]([CH3:33])[C:30](=[O:32])[CH3:31])[C:15](=[O:16])[CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH3:18]
Reactant: CC(=O)C(C)NC(C)(C)c1cccc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(C)N(C(=O)Cc1ccccc1F)C(C)(C)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
In 30 ml of dichloromethane containing 4.0 g of pyridine, 5.0 g of 2-(2-fluorophenyl)acetyl chloride was added dropwise to 3.2 g of N-[1-methyl-1-(3-chlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine at 20° to 30° C. After stirring for 1 hour, the solution was poured into water, and then extracted with dichloromethane. Next, the solution was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated by an evaporator, and then subjected to column chromatography to obtain 2.4 g of N-[1-methyl-1-(3chlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)-2-(2-fluorophenyl)acetamide.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([S:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[N:22][C:21]=2[CH:25]=1)([F:15])[F:14].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:15][C:13]([F:12])([F:14])[S:16]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][CH:23]=[N:22][C:21]=2[CH:25]=1)=[O:6]
Reactant: FC(F)(F)Sc1ccc2ocnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(c1ccc2ocnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.3 %

Procedure:
0.71 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.50 g of 5-trifluoromethylsulfanylbenzoxazole and 3 ml of chloroform under ice cooling, and then the mixture was stirred at room temperature for 1 day. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.20 g of 5-trifluoromethylsulfinylbenzoxazole.
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[NH:23][C:22](=O)[C:21]=2[CH:31]=1.[OH-].[NH4+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(C)C.C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[N:23]=[C:22]([N:13]3[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]3)[C:21]=2[CH:31]=1
Reactant: O=C1Nc2cscc2Nc2ccc(Cl)cc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CN1CCN(C2=Nc3cscc3Nc3ccc(Cl)cc32)CC1
Reaction time: 8 h

Procedure:
To a solution of 7 ml. of anisole, 3.8 ml. of titanium tetrachloride and 1.5 g. of methylpiperazine in 67 ml. of toluene is added a mixture of 6.7 g. of 7-chloro-4H-thieno-[3,4-b][1,4]benzodiazepin-9(10H)-one and 7.6 g. of methylpiperazine in 7 ml. of toluene. The mixture is refluxed with stirring overnight, cooled and 10 ml. of isopropyl alcohol, 5 g. of diatomaceous earth and 10 ml. of ammonium hydroxide are added. The mixture is filtered and washed with toluene. The toluene is washed with water and then extracted with three 150 ml. portions of 3 N hydrochloric acid. The acid extracts are made alkaline with ammonium hydroxide and extracted with dichloromethane. This extract is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is crystallized from dichloromethane-hexane giving the desired product, m.p. 191°-194° C.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>O1CCCC1.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>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][C:4]([C:31]2[S:30][CH:29]=[CH:33][CH:32]=2)=[C:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCCCCCc1c(Br)sc(Br)c1CCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCc1c(-c2cccs2)sc(-c2cccs2)c1CCCCCCCC
Yield: 145.7 %

Procedure:
In a dry box under an inert atmosphere, Pd(PPh3)2Cl2 (0.15 gram, 0.2 mmol) was added to a mixture of 2,5-dibromo-3,4-dioctylthiophene (4.2 grams, 9 mmol) and 2-(tributylstannyl)-thiophene (7.4 grams, 19.8 mmol) in anhydrous tetrahydrofuran (50 milliliters) in a 250 milliliter round bottom flask. The mixture was then refluxed for 12 hours and the solvent was removed by evaporation. The crude product thus obtained was purified by flash chromatography on silica gel using hexane as eluent to provide 3.1 grams of 2,5-bis(2-thienyl)-3,4-dioctylthiophene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](=[O:42])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[CH:38][CH:39]=[CH:40][C:27]3=4)=[O:25])=[CH:20][C:19]=2[CH3:41])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43].O1CCOCC1>>[ClH:43].[CH3:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:15](=[O:42])[CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)CC1CCNCC1
Yield: 97 %

Procedure:
A solution of 4-{[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylcarbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Compound number 1067) (156 mg, 0.27 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (135 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][Si](C(C)(C)C)(C)C)[CH:8]=[CH:7]1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[OH:15])[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cccc(O[Si](C)(C)C(C)(C)C)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOC(=O)Cn1ccc2cccc(O)c21

Procedure:
In analogy to the procedure described in example 6 c], [7-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester was treated with tetrabutylammonium fluoride hydrate to give the title compound as colorless solid.
Reaction SMILES: Br.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:11]=1)[C:4]([NH2:6])=[NH:5]>[OH-].[Na+]>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:7](=[N:3][C:4]#[N:5])[S:8][CH3:9])[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N=C(N)Nc1nc(CCCCCN)cs1
Agent: Br
Agent: Cl
Agent: [Na+]
Product: CSC(=NC#N)NCCCCCc1csc(NC(=N)N)n1

Procedure:
To 2-guanidino-4-(5-aminopentyl)thiazole hydrochloride hydrobromide (1.2 g.) was added dilute aqueous sodium hydroxide solution (10 ml.). The mixture was stirred briefly, and the white precipitate (0.588 g.) filtered off. This material was dissolved in ethanol (10 ml.) and dimethyl (cyanoimido)dithiocarbonate (0.4 g.) added. The mixture was stirred 2.5 hours to give a solution of 2-guanidino-4-[5-(3-cyano-2-methylisothioureido)pentyl]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:9]2)=[CH:5][CH:4]=1.[C:15](O)(=O)[C@H:16]([C@@H:18]([C:20](O)=[O:21])O)O.C(N)(=O)CCC.CCCC(Cl)=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH2:12][CH2:13][NH:14][C:20](=[O:21])[CH2:18][CH2:16][CH3:15])[CH2:8][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CCC2CCN
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CCCC(=O)Cl
Agent: CCCC(N)=O
Product: CCCC(=O)NCCC1CCc2cc(OC)ccc21

Procedure:
N-[2-(2-,3-dihydro-6-methoxy-1H-inden-3-yl)ethyl]amine was resolved with D-tartaric acid using the resolution technique described. The 1:1 amine: D-tartaric acid complex was shown to have an enantiomeric excess of ≤90 by 1H NMR. The resolved amine was converted into the butanamide using n-butyryl chloride according to General Procedure A. The resulting white solid was purified by recrytallization from EtOAc/Hexane and shown to be product. m.p. 79°-80° C.; 1H NMR (300 MHz, CDCl3) δ7.08 (d, J=8Hz, 1H), 6.72-6.67 (M, 2H), 5.57 (bs, 1H), 3.76 (s, 3H), 3.86-3.66 (bm, 2H), 3.08 (bm, 1H), 2.89-2.69 (bm, 2H), 2.35-2.27 (m, 1H), 2.13 (t, J=7.5 Hz, 2H), 2.06-2.00 (m, 2H), 1.7-1.5 (bm, 4H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ172.0, 158.8, 148.11, 135.8, 124.9, 112.27, 109.18, 55.48, 42.67, 38.71, 37.98, 34.83, 32.47, 30.55, 19.21, 13.76; IR (KBr) 1632, 1546, 1290 cm-1 ; MS (DCI) 276m/e (MH); Analysis calc'd for C16H21NO1 : C, 78.97; H, 8.70; N, 5.76; found: C, 78.73; H, 8.90; N, 5.76.Analysis calc'd for C16H23N1O2 : C, 73.53; H, 8.87; N, 5.36; found: C, 73.47; H, 8.77; N, 5.13; [α] (25° C., 589 nm, CHCl3)=-5.26
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=2[C:5]=1[C:13]([O:15]C)=O)=[C:2]=[S:3].[CH3:17][C:18]1[N:19]=[CH:20][N:21]([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=1>>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([CH2:23][CH2:24][CH2:25][N:26]2[C:13](=[O:15])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCC2
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCCC4)cn1

Procedure:
The compound was synthesized starting from methyl 4,5,6,7-tetrahydro-2-isothiocyanatobenzo[b]thiophene-3-carboxylate (0.109 g. 0.43 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.060 g, 0.43 mmol) as described above.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.Br[C:19]1C=CC(C(O)=O)=CC=1OC1CCCCO1.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CC(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: O=C(O)c1ccc(Br)c(OC2CCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To flask containing 26.1 (2.15 g, 7.14 mmol) and cesium carbonate (3.95 g, 12.1 mmol) in acetone (50 mL), was added iodomethane (0.667 mL, 10.7 mmol). The resulting mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/Hexanes) to provide methyl 26.2 (2.25 g, 99% yield).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1)=[O:6])=[N+]=[N-].[ClH:17]>CO.[Pd]>[ClH:17].[NH2:1][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Yield: 96 %

Procedure:
6-(2-Azidoethanoyl)-1,3-dihydrobenzimidazol-2-one (1.0 g, 4.6 mmol) and Pd—C (5%, 0.3g) in methanol (150 mL) and concentrated HCl (2mL), were subjected to hydrogenation at 25 psi and 27° C. for 1 hour. The catalyst was removed by filtration through a ‘filter aid’ and the solvent removed to give 6-(2-aminoethanoyl)-1,3-dihydrobenzimidazol-2-one hydrochloride (1.01 g, 96%) as a brown solid:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9]2)=[O:4].[N+:20]([O-])([O-:22])=[O:21].[Na+]>S(=O)(=O)(O)O>[F:19][C:2]([F:1])([F:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21])[NH:12][C:11](=[O:16])[C:10](=[O:17])[NH:9]2)=[O:4]
Reactant: O=C(Nc1ccc2[nH]c(=O)c(=O)[nH]c2c1)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 39 g (0.14 mol) of 6-trifluoroacetamidoquinoxaline -2,3(1H,4H)-dione in 500 ml of concentrated sulfuric acid was cooled to 0° C., 12.1 g (0.14 mol) of sodium nitrate were added in portions, and the mixture was stirred at room temperature for 30 minutes. It was subsequently poured into ice-water and the crude product was filtered off and worked up by conventional methods. Yield: 95%. Melting point >320° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@@H:9]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[CH2:11][CH2:10]1
Reactant: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Agent: [Pd]
Solvent: CO
Product: CN1C[C@@H](N)CCC1=O
Reaction time: 16 h
Yield: 101.6 %

Procedure:
0.450 g (S)-5-dibenzylamino-1-methylpiperidin-2-one are suspended in 25 ml of methanol and hydrogenated with 0.150 g Pd/C 10% at a pressure of 3 bar and a temperature of 60° C. After 16 hours the catalyst is suction filtered and the filtrate is evaporated to dryness. 0.190 g of the product are obtained as an oil. 1H NMR (400 MHz, DMSO): 2.76 (3H, s).
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C:21]23[CH2:28][CH:27]2[CH2:26][O:25][CH2:24][C:23](=O)[NH:22]3)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:40]2)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:30])=[C:19]([C:21]23[CH2:28][CH:27]2[CH2:26][O:25][CH2:24][C:23](=[S:40])[NH:22]3)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCC2CC2(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(N=C(c2ccccc2)c2ccccc2)cc1C12CC1COCC(=S)N2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (1SR,7RS)-1-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-oxa-2-aza-bicyclo[5.1.0]octan-3-one (intermediate B11A) (460 mg, 1.15 mmol) in dioxane (3 ml) at 23° C. was added 2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (292 mg, 0.72 mmol) and the mixture was stirred at 80° C. for 2 h. The green solution was poured on sat. NaHCO3 solution, extracted with ethyl acetate, washed the organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left the title compound as a green oil (600 mg, ca. 80% pure, 100%), which was used in the next step without further purification. MS (ISP): m/z=417.3 [(M+H)+].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>CC(O)=O>[OH:5][C:6]1[CH:14]=[C:13]([OH:15])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)cc1O
Solvent: CC(=O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cold stirred solution of nitric acid (70%, 28 mL) and AcOH (30 mL), is added portionwise 2,4-dihydroxybenzoic acid (7.7 g, 49.9 mmol). The mixture is stirred at 0° C. for 15 min and then slowly warmed to room temperature. The reaction becomes very exothermic and is cooled again in an ice bath to keep the mixture at approximately room temperature. The mixture is stirred at room temperature for 18 h. The resulting precipitate is filtered, washed with water, air dried, then washed with DCM and dried under reduced pressure to afford 2,4-dihydroxy-5-nitrobenzoic acid as a solid: (M−H)−=198.1.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[CH3:12][N:13](C=O)C>[Ar].[Zn].[C-]#N.[C-]#N.[Zn+2].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.[Fe+2].Cl[Pd]Cl>[Cl:8][C:7]1[C:2]([C:12]#[N:13])=[N:3][CH:4]=[C:5]([CH2:9][O:10][CH3:11])[CH:6]=1
Reactant: CN(C)C=O
Reactant: COCc1cnc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Ar]
Product: COCc1cnc(C#N)c(Cl)c1
Temperature: 145 °C

Procedure:
To a solution of 2,3-dichloro-5-methoxymethyl-pyridine (CA registry 202395-72-0) (7.5 g, 38 mmol) in DMF (100 ml) was added after degasing with argon Zn-dust (126 mg, 1.91 mmol), Zn(CN)2 (2.27 g, 19.1 mmol) and DPPF PdCl2 (0.997 g, 1.15 mmol) and the reaction mixture was heated for 2 h at 145° C. The reaction mixture was concentrated, the residue redissolved in TBME and 5% aqueous NaHCO3 solution and extracted with TBME. Combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after chromatography on silica gel (hexane-EtOAc 20:1 to EtOAc) as beige crystals: TLC (hexane-EtOAc 1:1): Rf=0.47;
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[O:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][O:18][C:19]=3[CH:24]=2)[CH:8]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and benzo[1,3]dioxole-5-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 4 h. 1H NMR (400 MHz, CDCl3) δ 7.27-6.74 (m, 7H), 5.90 (s, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.62 (t, 2H); MS 328 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.C([Li])CCC.[O:27]=[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:28]3([OH:27])[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:32][CH2:33]3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ccnc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.462 mmol) in tetrahydrofuran (1.5 mL) at −78° C. was added 1.6 M n-butyllithium in hexanes (0.347 mL, 0.555 mmol) under nitrogen. The mixture was stirred for 10 minutes and tert-butyl 4-oxopiperidine-1-carboxylate (111 mg, 0.555 mmol) was added. The mixture was stirred at −78° C. for 1 hour and was slowly warmed to room temperature overnight. The mixture was quenched with water, extracted with ethyl acetate (2×5 mL) and the organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (silica gel, 20-100% ethyl acetate/heptanes) afforded the title compound. MS (ESI+) m/z 506.0 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[NH2:9][C:10]1[C:23]([Br:24])=[CH:22][C:13]2[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][O:16][C:12]=2[CH:11]=1.[C:25]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.[NH4+].[Cl-]>C1COCC1>[NH2:9][C:10]1[C:23]([Br:24])=[CH:22][C:13]2[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([C:25]3([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]3)[O:16][C:12]=2[CH:11]=1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)c1coc2cc(N)c(Br)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C2(O)CCCC2)oc2cc(N)c(Br)cc12
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of LDA (6.32 g, 59.0 mmol) in THF (60 mL) was added dropwise ethyl 6-amino-5-bromobenzofuran-3-carboxylate (5 g, 17.6 mmol) at −78° C. under N2. After the mixture was stirred for 1 hour, cyclopentanone (4.44 g, 52.8 mmol) in THF (40 mL) was added dropwise at −78° C. After the mixture was stirred for 1 h, NH4Cl (a.q.) was added, then the mixture was extracted with EtOAc (100 mL*3) and dried over Na2SO4 After concentration, the residue was purified by column chromatography (PE:EtOAc=10:1) to give the product of ethyl 6-amino-5-bromo-2-(1-hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, yield: 44%). 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 6.86 (s, 1H), 6.07 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.20 (s, 1H), 2.12˜2.17 (m, 4H), 1.99 (t, J=5.6 Hz, 2H), 1.79 (t, J=3.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H). MS (M+H)+: 368/370.