Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[S:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]2[N:6]([CH2:5][CH:2]3[CH2:3][CH2:4]3)[CH2:7][CH2:8][S:20]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: ClCC[NH2+]CC1CC1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CC2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C@H:15]([CH3:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Reaction time: 15 h
Yield: 86.3 %

Procedure:
To a solution of compound 1.7a (3 g, 7 mmol) in EtOAc (60 mL) was added 10% Pd/C (300 mg, 10% wt/wt), and the resulting slurry was hydrogenated in a Parr apparatus (70 psi) for 14-16 h. At this point the reaction was determined to be complete by TLC (10% ethyl acetate in hexanes). The mixture was filtered through a small plug of Celite® and the solvent was removed under vacuum, affording compound 1.8a (2.6 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3Cl)[CH:24]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:24]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCCN1CCOCC1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide by a procedure analogous to Example 1C. MS: 436 (MH+); HPLC Rf: 3.45 min.; HPLC purity 94%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[O:11][C:12]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:13]=1N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OCCC(C)C)=O.[ClH:45]>[Cu](Cl)Cl.C(#N)C>[Cl:45][C:13]1[CH:15]=[C:16]([F:32])[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:18][C:12]=1[O:11][C:10]1[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
To a mixture of 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 2.45 g of copper chloride (I), 5.04 g of copper chloride (II) and 90 ml of acetonitrile was added dropwise 4.46 g of isoamyl nitrite at room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into 2% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica-gel column chromatography to give 4.6 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]#[N:6].C(=O)([O-])[O-:20].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][N:12]=1)[C:5]([NH2:6])=[O:20]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Combine 3-bromo-4-(5-formyl-pyridin-2-yloxy)-benzonitrile (1.60 g, 5.28 mmol) and potassium carbonate (365 mg, 2.64 mmol) in DMSO (40 mL). Cool the reaction mixture at 0° C. Add hydrogen peroxide (1.59 mL, 5.28 mmol) dropwise and let the reaction stir at room temperature for 2 h. Pour into water and triturate to a white solid with stirring. Filter the white solid and dry to give (852 mg, 82%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:42])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[C:37]([N:39]([CH3:40])[CH3:41])[N:36]=[CH:35][N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:42])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CN(C)c1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(N(C)C)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (103 mg, 0.4 mmol) and 3-[3-(6-dimethylamino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K55) (150 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (109 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18]([N:22]([CH2:33][CH2:34][CH2:35][N:36]2C(=O)C3C(=CC=CC=3)C2=O)[C:23](=[O:32])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([F:31])[CH:25]=2)[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[NH2:36][CH2:35][CH2:34][CH2:33][N:22]([CH:18]([C:9]1[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH:19]([CH3:21])[CH3:20])[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([F:31])[CH:25]=1
Reactant: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3ccccc3cc2Cc2ccccc2)C(C)C)cc1F
Agent: NN
Solvent: CCO
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3ccccc3cc2Cc2ccccc2)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-3-fluoro-N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-methylbenzamide 19 (19 mg, 1 eq) in ethanol (1 ml), was added hydrazine (3 μl, 3 eq). The reaction was stirred at room temperature for 2 h then heated to 40° C. for another hour. The precipitate was filtered through a PTFE filter and washed with CH2Cl2. The filtrate was concentrated and purified by flash chromatography to yield 2 mg of N-(3-aminopropyl)-N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-3-fluoro-4-methylbenzamide 2 as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[S:24][C:25]([CH3:28])=[N:26][N:27]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[S:24][C:25]([CH3:28])=[N:26][N:27]=1)=[O:19]
Reactant: Cc1nnc(N)s1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: Cc1nnc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)s1
Yield: 65 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methyl-1,3,4-thiadiazole with a yield of 65% of theory.
Reaction SMILES: [OH:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3]1.[C:13](=O)([O-])[O-].[K+].[K+].CI.CO>CN(C=O)C>[CH3:13][O:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3]1
Reactant: COC(=O)c1ccc(=O)n(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(OC)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (0.75 g, 4.43 mmol) in 5 mL DMF at 23° C., were added potassium carbonate (1.8 g, 13.3 mmol) and MeI (1.5 g, 11 mmol). The resulting mixture was stirred overnight and then MeOH (6 mL) was added and the resulting mixture was stirred for 2 h. The volatiles were removed under vacuum, and the resulting residue was dissolved in EtOAc (75 mL), washed with water (2×50 mL), brine (50 mL), dried (MgSO4), and concentrated to give methyl 1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a brown oil.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1cccc(Cl)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-chlorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11ClN4, 296. Found, 295, 297.
Reaction SMILES: [O:1]1[CH:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]1[C:3]([O:5]C)=[O:4].[OH-].[Na+]>C1(C)C=CC=CC=1>[O:1]1[C@H:7]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C1OC1C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)[C@H]1O[C@@H]1C1CCCCC1
Reaction time: 48 h

Procedure:
500 ml of toluene containing 100 g of racemic methyl 2,3-epoxy-3-cyclohexylpropionate, was added to 500 ml of a 1M tris-HCl buffer solution (pH 8.0) containing lipase type VII (derived from Candida rugosa, prepared by Sigma Co., U.S.A.) in a concentration of 5 g/l, and asymmetric hydrolysis reaction was carried out at 30° C. for 48 hours at a stirring speed of 600 rpm. After the reaction, a 1N sodium hydroxide aqueous solution was added to the reaction solution to adjust the pH of the aqueous phase to 10, whereupon the aqueous phase was separated. The aqueous phase was then adjusted to pH 2 with a 1N hydrochloric acid solution and then extracted twice with 300 ml of t-butyl methyl ether, and the organic layer was concentrated under reduced pressure to obtain 38.5 g of (2S,3R)-2,3-epoxy-3-cyclohexylpropionic acid as crude crystals. The crude crystals were dissolved in 200 ml of a solution of toluene/n-heptane=1/2 (v/v) and heated and dissolved for 20 minutes with stirring at 60° C. The solution was gradually cooled from 60° C. to 20° C. and then cooled with ice for 30 minutes, whereupon precipitated crystals were collected by filtration to obtain 34.2 g of crystals of (2S,3R)-2,3-epoxy-3-cyclohexylpropionic acid (99.1% ee [α]D20 =+20.8 (c 1.04, CHCl3)).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:32]1([CH2:38]/[CH:39]=[CH:40]/[CH2:41]I)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:31])[C@H:27]([CH:28]([CH3:29])[CH3:30])[CH2:41]/[CH:40]=[CH:39]/[CH2:38][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: IC/C=C/CC1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)[C@H](C/C=C/CC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
The chloride (B) (38.6 g) was added to a solution of sodium iodide (55.7 g) in acetone (1 litre) and the solution was allowed to stand overnight. Hexane (500 ml) was added and the precipitated solid was removed by filtration. The filtrate was concentrated and the residue partitioned between water (500 ml) and hexane (500 ml). The organic phase was separated, washed with saturated sodium thiosulphate solution (500 ml) and saturated sodium chloride solution (2×500 ml), and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under vacuum to give (2E)-4-cyclohexyl-1-iodobut-2-ene (C) as a dark liquid (44.9 g), b.p. 80°-85° C. at 0.15 mm Hg; NMR: 0.8-1.8(complex m, 11H), 1.9(t, 2H), 3.9(m, 2H), 5.7(m, 2H). (iii) A 1.6M solution of butyllithium in hexane (93.9 ml) was added dropwise over 30 minutes to a stirred solution of diisopropylamine (21.9 ml) in dry tetrahydrofuran (THF) (200 ml) at 0° C. under an atmosphere of argon. The temperature was maintained at 0° C. for 30 minutes and then the solution was cooled to -40° C. A solution of (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (31.3 g) (obtained as described in Tetrahedron. 1987, 44, 5525) in dry THF (70 ml) was added dropwise over 30 minutes. The solution was kept at -40° C. for 30 minutes and then the temperature was allowed to rise to 0° C. A solution of iodide (C) (39.0 g) in dry THF (75 ml) was added dropwise over 30 minutes, and then the solution was stirred at 0° C. for 1 hour. Saturated sodium chloride solution (250 ml) was added and the mixture was extracted with ether (3×250 ml). The extracts were washed with saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (8:92 v/v), to give (4s)-4-benzyl-3-[(2S,4E)-6-cyclohexyl-2-isopropylhex-4-enoyl]oxazolidin-2-one (A) (34.5 g) as a clear oil; NMR: 0.8 -1.2(complex m, 12H), 1.6(m, 6H), 1.85(t, 1H), 2.0(m, 2H), 2.35(m, 2H), 2.6(m, 1H), 3.3(dt, 1H), 3.8(m, 1H), 4.1(d, 1H), 4.7(m, 1H), 5.4(m, 2H), 7.3(m, 5H); mass spectrum (+ve FAB), 398 (M+H+); 22 [α]436 +45.8 (c, 1.04, CHCl3). ##STR1##
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[C:8](Cl)[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CCCCC1Cc2cccc(Cl)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: CCCCC1Cc2cccc(-c3ccccc3)c2C1=O
Temperature: 125 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
Using a method similar to Example 16d), 10.02 g (0.045 mol) of 2-butyl-7-chloro-1-indanone, 6.58 g (0.054 mol) of phenylboronic acid and 11.9 g (0.122 mol) of sodium carbonate were placed in 135 ml of ethylene glycol/27 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 5 mg (0.022 mmol) of palladium acetate and 0.051 g (0.09 mmol) of TMSPP, the reaction mixture was stirred for 5 hours at 125° C. After addition of 120 ml of water, the aqueous phase was extracted 4 times with 100 ml each time of ether, the combined ether phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 12.0 g of (33) as an oil.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][O:13][CH2:14][C:15](=[O:17])[CH3:16].S(=O)(=O)(O)O>C(O)C>[CH3:12][O:13][CH2:14][C:15](=[O:17])[CH2:16][C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere sodium (1.61 g, 70.0 mmol) was dissolved in small pieces in a flask containing dry ethanol (150 ml). Diethyl oxalate (8.15 ml, 60 mmol) and methoxyacetone (5.52 ml, 60.0 mmol) were added with a syringe. The resulting mixture was stirred at RT for 1 h. The flask was put in an ice bath and into it a mixture of sulphuric acid and ice water was added dropwise. The resulting precipitate was filtered and washed with DCM. The ethanol/DCM filtrate was evaporated. The residue was dissolved in DCM, extracted with brine and the DCM phase dried with Na2SO4, filtered and evaporated. The product was purified with flash chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.28 (t, 3H), 3.34 (s, 3H), 4.19-4.23 (m, 2H), 4.27 (q, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16](C3C=CC=CC=3)[CH2:15][C:14]3=[N:23][NH:24][CH:25]=[C:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:26]1([CH2:32]C2CC(=O)CCN2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:32]([CH:16]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][C:13]2[CH:25]=[N:24][NH:23][C:14]=2[CH2:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CCNC(Cc2ccccc2)C1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1Cc2c[nH]nc2CC1c1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cn[nH]c2CC1Cc1ccccc1

Procedure:
Prepared as described for compound 55 in Example 1 using 2-(phenylmethyl)-4-piperidinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16](CC3C=CC=CC=3)[CH:10]([CH2:11][C:12](=[O:24])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][C:12](=[O:24])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2
Reaction time: 48 h
Yield: 99.7 %

Procedure:
9-Benzyl-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (16.6 g, 50.5 mmol) was dissolved in methanol (40 mL) and added to a suspension of palladium hydroxide (1 g) in methanol (10 mL) in a Parr bottle. The Parr bottle was filled with hydrogen (40 psi) and evacuated three times. The Parr bottle was refilled with hydrogen (40 psi) and shook for 48 h. The suspension was filtered through Celite and concentrated under vacuum to give 12.1 g (quantitative yield) of 7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=0.531, method [1], MS(ESI) 481.3 (2M+H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Li+].[OH-]>C1COCC1.O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
methyl 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate (3.5 g, 10.8 mmol) and LiOH (0.52 g, 21.7 mmol) were dissolved in a mixture of THF:H2O (1:1, 150 mL). After the resulting mixture was stirred at 70° C. for 2 h, the water phase of the reaction mixture was separated, adjusted to pH 4.0 and extracted with EtOAc (100 mL×4). The organic phase was pooled and concentrated to give product (3.0 g, 90.5%). LCMS (ESI): m/z 310.6 (M+H+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:3]2=[C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:7]=1
Reactant: Cc1cc(Cl)c2oc(-c3ccccc3)cc2n1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCCC2)c2oc(-c3ccccc3)cc2n1
Temperature: 120 °C
Reaction time: 26 h
Yield: 68.4 %

Procedure:
To a mixture of 7-chloro-5-methyl-2-phenylfurano[3,2-b]pyridine (Example 228 (c)) (365 mg, 1.50 mmol) and piperidine (5 mL, 50.5 mmol) was added DMF (2 mL). Mixture stirred at 120° C. under N2 for 26 h. After cooling, the reaction mixture was concentrated. The residue was diluted with H2O (70 mL) and Et2O (50 mL). The mixture was transferred to a separatory funnel and the organic solution was collected. The aqueous solution was washed with Et2O (2×40 mL). The organic solutions were combined, washed with H2O (50 mL), saturated NaCl (70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 50:50 EtOAc:hexanes as elutant to give 300 mg (68%) of 5-methyl-2-phenyl-7-piperidylfurano[3,2-b]pyridine as a cream colored solid. This material (298 mg, 1.02 mmol) was dissolved in EtOAc (20 mL) and heated to boiling. To the hot solution was added 1M etheral HCl (1.00 mL, 1.00 mmol). The solution was left to cool to 25° C. The resulting solid was collected by filtration, washed with EtOAc (2×5 mL), Et2O (3×5 mL) and dried under vacuum at 25° C. to give 290 mg (59%) of the title compound as a white colored powder. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.67 (br s, 6), 2.49 (s, 3), 3.94 (br s, 4), 6.93 (s, 1), 7.46-7.54 (m, 4), 7.98 (dd, 2, J=1.5, 7.6), 14.14 (s, 1). MS m/z: 293 (M+1 for free base). Anal. Calcd for C19H20N2O.HCl.0.25H2O: C, 68.46; H, 6.50; N, 8.41; Cl, 10.64. Found C, 68.60; H, 6.44; N, 8.43; Cl, 10.56.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:7]=3[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)ccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.96 g, 5.58 mmol) was dissolved in DMF (20 mL), and sodium hydride (60% weight dispersion in mineral oil, 330 mg, 8.37 mmol) was added. After 30 minutes, methyl iodide (0.52 mL, 8.4 mmol) was added, and the reaction stirred for a further 2 h. The mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (1.75 g, 86%) as a white powder: 1H NMR (500 MHz, CD3OD) δ 7.41 (d, J=1.5 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 4.60 (br s, 2H), 3.73 (br s, 2H), 3.59 (s, 3H), 2.76 (br s, 2H), 1.50 (s, 9H).