Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11]C>Br.CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloro-5-nitroanisole (310 g, 1.7 mol) was taken up in a mixture of 48% HBr (1.5 L) and AcOH (1.2 L) and heated at reflux for 3 days. The dark solution was allowed to cool to room temperature, poured into ice water (10 L), and let stand for 3 h. The resultant dull yellow solid was filtered, washed with water, and dried in vacuo (230 g, 79%): mp 115–117° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11]C)[N:5]=[C:4]([O:13]C)[N:3]=1>Cl.CO>[Cl:1][C:2]1[NH:3][C:4](=[O:13])[NH:5][C:6](=[O:11])[C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Agent: Cl
Solvent: CO
Product: CC(C)c1c(Cl)[nH]c(=O)[nH]c1=O
Yield: 700.4 %

Procedure:
4-Chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (40 g, 18.47 mmol) was dissolved in 150 mL of conc. HCl-methanol (1:2) and refluxed for 6 hr. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, chloroform:methanol (from 95:5 to 90:10)) to give 24.4 g (70%) of 6-chloro-5-isopropyl-1H-pyrimidine-2,4-dione as a white solid. m.p. 250-251° C.; 1H-NMR (200 MHz, CDCl3) δ 1.25 (6H, d, J=7.1 Hz), 3.13 (1H, m); m/z (EI) 188 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[CH:4][CH:3]=1.[Li]CCCC.[F:20][C:21]([F:30])([F:29])[C:22](N1C=CN=C1)=[O:23].[Cl-].[NH4+].[OH-].[NH4+]>C1COCC1.CCCCCC.Cl.C(OCC)(=O)C>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:22](=[O:23])[C:21]([F:30])([F:29])[F:20]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reactant: O=C(n1ccnc1)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 14.9 %

Procedure:
To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (6.7 g, 30 mmol) in anhydrous THF (100 mL) under nitrogen at 0° C. was added a solution of n-BuLi (2.5M, 30 mL, 70 mmol) in hexane in a dropwise fashion. After addition, the solution was kept stirring at 0° C. for 40 minutes and treated with a solution of 1-(trifluoroacetyl)imidazole (9 mL, 78 mmol) in anhydrous THF (10 mL). The reaction mixture was warmed to ambient temperature and kept for 18 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (50 mL) followed by addition of ethyl acetate (100 mL). The organic layer was separated and the solvent was removed in vacuo. The residue obtained was suspended in 3N aqueous hydrochloride solution (50 mL) and heated at reflux overnight. The reaction solution was cooled to room temperature and treated with a cold ammonium hydroxide solution to a pH above 8. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1) to afford the title compound as a yellow solid (1 g, 15%): mp 93-94° C.; 1H-NMR (CDCl3) δ7.70 (m, 1H), 7.33 (dd, 1H, J=9.0, 2.3 Hz), 6.70 (d, 1H, J=9.1 Hz), 6.45 (bs, 2H); MS (ESI) m/z 222(M−H, 100%), 224(M−H, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[NH:27][C:28]2[S:29][CH2:30][C:31](=[O:33])[N:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:30]3/[C:31](=[O:33])[N:32]=[C:28]([NH:27][C@@H:25]4[CH2:26][C@H:24]4[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:29]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2]
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12
Temperature: 150 °C
Yield: 26.5 %

Procedure:
To the suspension of 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e) (68 mg, 0.3 mmol) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f, 70 mg, 0.3 mmol) in toluene (2 mL) was added benzolic acid (3.5 mg, 0.03 mmol) and piperidine (35 uL, 0.03 mmol). The mixture was heated to 150° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with toluene and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 4-ethoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (35 mg, 27%) as a light yellow solid: LC-MS m/e 441 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][C@@H:17]([CH3:20])[C@@H:16]([N:21]3[C:25]4=[C:26]5[CH:32]=[CH:31][NH:30][C:27]5=[N:28][CH:29]=[C:24]4[NH:23][C:22]3=[O:33])[CH2:15]2)=[CH:12][CH:13]=1)=[O:6].O1CCCC1.CC([O-])(C)C.[K+].C(Cl)(Cl)Cl>O>[CH3:20][C@@H:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][N:10]=2)[CH2:15][C@@H:16]1[N:21]1[C:25]2=[C:26]3[CH:32]=[CH:31][NH:30][C:27]3=[N:28][CH:29]=[C:24]2[NH:23][C:22]1=[O:33]
Reactant: C[C@@H]1CCN(c2ccc(NC(=O)CCCCl)cn2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCN(c2ccc(N3CCCC3=O)cn2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of rel-4-chloro-N-{6-[(3R,4R)—4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]pyridin-3-yl}butanamide (72 mg) and tetrahydrofuran (2.2 mL) was added potassium 2-methylpropan-2-olate (138 mg) at ambient temperature. The mixture was stirred for 0.5 hour then chloroform (10 mL) and H2O (4 mL) were added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to give rel-1-{(3R,4R)-4-methyl-1-[5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]piperidin-3-yl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (66 mg) as a colorless solid.
Reaction SMILES: BrC1CN(C(CC)C(N)=O)C(=O)C1C#C.Br[C:17](Br)=[CH:18][CH:19]1[CH2:23][N:22]([CH:24]([CH2:28][CH3:29])[C:25]([NH2:27])=[O:26])[C:21](=[O:30])[CH2:20]1.[K]>C1COCC1>[C:18]([CH:19]1[CH2:23][N:22]([CH:24]([CH2:28][CH3:29])[C:25]([NH2:27])=[O:26])[C:21](=[O:30])[CH2:20]1)#[CH:17]
Reactant: CCC(C(N)=O)N1CC(C=C(Br)Br)CC1=O
Agent: C#CC1C(=O)N(C(CC)C(N)=O)CC1Br
Agent: [K]
Solvent: C1CCOC1
Product: C#CC1CC(=O)N(C(CC)C(N)=O)C1

Procedure:
Alternatively, 2-(4-bromo-ethynyl-2-oxo-1-pyrrolidinyl)butanamide 267 is obtained by reacting 2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide 47 with two equivalent of potassium tertbutoxyde in THF at low temperature (−50° C. to 0° C.).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH2:20]1[O:30][C:29]2[C:22](=[CH:23][C:24]([N+:31]([O-:33])=[O:32])=[C:25]([CH:28]=2)[CH:26]=[O:27])[O:21]1.C(O)(=O)C>O1CCCC1.O>[OH:27][CH:26]([C:25]1[CH:28]=[C:29]2[O:30][CH2:20][O:21][C:22]2=[CH:23][C:24]=1[N+:31]([O-:33])=[O:32])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reaction time: 1 h
Yield: 119 %

Procedure:
To a solution of diisopropylamine (6.8 ml, 49.0 mol) in tetrahydrofuran (80 ml) was added, at -78° C. under an argon atmosphere, a 1.5 N butyllithium (30.7 ml, 46.0 mmol). The mixture was stirred for one hr. Ethyl propiolate (3.9 ml, 38.4 mmol) and a solution of 4,5-methylenedioxy-2-nitrobenzaldehyde (5.0 g, 25.6 mmol) in tetrahydrofuran (50 ml) were added in that order to the reaction mixture, and the mixture was stirred at -78° C. for additional 1.5 hr. A solution of acetic acid (8.0 ml, 139 mmol) in tetrahydrofuran (20 ml) was then added to the reaction mixture, water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order. It was then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4,5-methylenedioxy-2-nitrophenyl)-2-butynoate as an oil (8.93 g). Ethyl 4-hydroxy-4-(4,5-methylenedioxy-2-nitrophenyl)-2-butynoate thus prepared was dissolved in toluene (75 ml), 4-methoxybenzylazide (14.9 g, 91.1 mmol) was added to the solution, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give a 1:1 mixture of ethyl 4-(1-hydroxy-(4,5-methylenedioxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and ethyl 5-(1-hydroxy-(4,5-methylenedioxy-2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2: high polar product (MP)) (6.42 g, 55%).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(C(OC)=O)C=C(NCC2CCCC2)N=1.[NH2:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][OH:45])=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:39][C:40]3[CH:47]=[CH:46][C:43]([CH2:44][OH:45])=[CH:42][CH:41]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(CO)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Agent: COC(=O)c1cc(NCC2CCCC2)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CO)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A solution of 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13, 1.00 g; 3.63 mmol) in dry DMF (100 ml) was treated with polymer-supported Mukaiyama reagent, prepared as described in “S. Crosignani et al. Org. Lett. 2004, 6(24), 4579-4582” (2 987 mg; 6.54 mmol), 4-aminobenzyl alcohol (Fluka, 492 mg; 3.99 mmol) and triethylamine (1.52 ml; 10.9 mmol). The reaction mixture was then stirred at room temperature for 18 hours. DCM was added and the product was filtered through an SPE column (Isolute NH2, 10 g) and the column washed with DCM. The mixture was concentrated then rediluted in AcOEt. The organic phase was washed 5 times with brine, dried over MgSO4 and the solvent removed under vacuum to give the title compound (990 mg, 72%).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[C:33]([O:32][C@@H:9]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a stirred solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethyl pivalate (5.6 mg, 0.011 mmol) in THF and methanol (1.5 mL/0.5 mL) was added 2 M NaOH solution (0.5 mL, excess) at 0° C. The mixture was stirred at 50° C. for 3 hours, diluted with water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide the desired product (3.0 mg, 64%). LCMS-ESI+ (m/z): 427.3, 429.2 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([C@H:12]([NH2:35])[C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[C@H:17]1[O:21][C@@H:20]([N:22]2[C:28](=[O:29])[NH:27][C:25](=[O:26])[CH:24]=[CH:23]2)[C@H:19]([OH:30])[C@@H:18]1[OH:31])=[O:14])[C@H:3]([OH:11])[C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][N:9]=1>O>[CH3:1][C@@H:2]([C@H:12]([NH2:35])[C:13]([NH:15][C@H:16]([C:32]([OH:34])=[O:33])[C@H:17]1[O:21][CH:20]([N:22]2[C:28]([OH:29])=[N:27][C:24]([CH:25]=[O:26])=[CH:23]2)[C@H:19]([OH:30])[C@@H:18]1[OH:31])=[O:14])[C@H:3]([OH:11])[C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][N:9]=1
Reactant: C[C@@H]([C@H](N)C(=O)N[C@H](C(=O)O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O)[C@H](O)c1ccc(O)cn1
Solvent: O
Product: C[C@@H]([C@H](N)C(=O)N[C@H](C(=O)O)[C@H]1OC(n2cc(C=O)nc2O)[C@H](O)[C@@H]1O)[C@H](O)c1ccc(O)cn1
Reaction time: 24 h

Procedure:
19 g of nikkomicin were dissolved in 75 ml of H2O, and 9 g of Alkylamine/CPG-1350 (Pierce Chem. Comp.) were added. After degassing the mixture in vacuo, it was left to stand at room temperature for 24 hours. The support material was filtered off, washed out with 800 ml of H2O and treated with 100 ml of 5% strength acetic acid at room temperature for 30 minutes. The filtrate was lyophilized. 116 mg of a residue, which was subsequently chromatographed on LiChroprep RP-8 using methanol/H2O (30:70), were obtained. Yield of X (after lyophilization): 18 mg.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCCBr
Reactant: CCOC(=O)CCCOc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1OCCCBr
Temperature: 0 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of ethyl 4-(2-hydroxyphenoxy)butanoate (5.61 g, 25 mmol) in DMF (25 mL) at 0° C. was slowly added sodium hydride (0.6 g, 25 mmol) and then the solution was left stirring at 0° C. for 4 hours. To a stirred solution at 65-70° C. was added 1,3-dibromopropane (3.80 mL, 37.5 mmol). The resulting solution was continued to stir at 65-70° C. for 3 hours. Normal work-up and purification by silica gel column chromatography gave bromo-compound as a white solid in 60% yield (5.18 g, m.p. 31-32.6° C., CH2Cl2/hexane). 1H NMR (400 MHz, CDCl3): 1.25 (3H, t, J=7.1 Hz), 2.13 (2H, m), 2.34 (2H, m), 2.54 (2H, t, J=7.3 Hz), 3.64 (2H, t, J=6.4 Hz), 4.04 (2H, t, J=6.2 Hz), 4.10-4.15 (4H, m), 6.99-6.93 (4H, m).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[N:28][CH:29]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Clc1ccc(Br)nc1
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: C1COCCO1
Solvent: O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(Cl)cn3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (1 g, 2.74 mmol) in dry 1,4 dioxane (15 ml), polymer supported Pd(PPh3)4 (54 mg, 0.5 mmol/g, 0.027 mmol) was added along with 2-bromo-5-chloropyridine (1.05 g, 5.48 mmol) and 3.5 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCl and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 682 mg of title compound were recovered as whitish solid (71%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:34][CH2:33][O:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:36])=[O:24])[CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3ccccc32)s1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccc(Cl)s3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D), starting with 4.21 mmol (13 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)-3-piperidin-4-yl-1H-indole and 3.6 g (17 mmol) of of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After the standard work-up, 2.47 g of the corresponding acid was obtained. The crude mixture was purified by flash chromatography over silica gel affording 1.2 g (17% of yield) of the pure acid.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:18]1([S:24]([CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:5][N:6]([CH2:30][CH2:29][CH2:28][CH2:27][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:26])[CH2:7][CH2:8]1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Reactant: COC1(CNC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1(CNC(=O)OC(C)(C)C)CCN(CCCCS(=O)(=O)c2ccccc2)CC1
Yield: 100.1 %

Procedure:
4-Methoxy-4-tert-butoxycarbonylaminomethylpiperidine (1.43 g), 4-phenylsulfonylbutyl bromide (1.7 g) and potassium carbonate (1.6 g) were reacted and treated in the same manner as in Preparation Example 138(1) to give 2.58 g of 4-methoxy-1-(4-phenylsulfonylbutyl)-4-tert-butoxycarbonylaminomethylpiperidine.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 58034.5 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (50 mg, 0.165 mmol) and 5-fluoro-1,3-dihydro-indol-2-one (22.4 mg, 0.15 mmol) were dissolved in 0.3 ml of ethanol under stirring, and added with piperidine (0.05 ml, 0.5 mmol) to the solution at room temperature. Upon completion of the addition, the mixture was stirred at 40˜50° C. in an oil bath for 5 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered to obtain yellow solid. The solid was dissolved in ethanol (2 ml), heated to reflux for 30 minutes, cooled down to room temperature and filtered to obtain the title compound (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 32 (38 g, yield 58%) as a yellow solid.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:37]([NH2:40])[CH2:38][CH3:39]>CN(C)C=O.O.C(Cl)(Cl)Cl>[C:13]1([C:4]2[N:3]=[C:2]([NH:40][CH2:37][CH2:38][CH3:39])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCN
Reactant: CCOC(=O)c1cnc(-c2ccccc2)[nH]c1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNc1nc(-c2ccccc2)ncc1C(=O)OCC
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
A mixture of ethyl 3,4-dihydro-4-oxo-2-phenylpyrimidine-5-carboxylate (9.8 g), triethylamine (10.1 g) and dimethylformamide (20 ml) is added dropwise a solution of p-toluenesulfonyl chloride (8.4 g) in dimethylformamide (20 ml) at room temperature, and the mixture is stirred at the same temperature for 10 minutes. To the reaction mixture is added dropwise a solution of propylamine (2.8 g) in dimethylformamide (20 ml), and the mixture is stirred at room temperature for one hour. To the reaction mixture are added chloroform and water, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude ethyl 2-phenyl-4-propylaminopyrimidine-5-carboxylate (11 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:30])=[C:16]([C:25](OCC)=[O:26])[C:17](=[O:24])[C:18]2([CH2:22][CH3:23])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:32]([O:36][C:37](=[O:40])[CH2:38][NH2:39])([CH3:35])([CH3:34])[CH3:33]>O1CCOCC1>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:30])=[C:16]([C:25]([NH:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])=[O:26])[C:17](=[O:24])[C:18]2([CH2:22][CH3:23])[CH3:21])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(CC)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 85.4 %

Procedure:
DIPEA (0.253 mL, 1.45 mmol, 1.2 eq) was added to a mixture of ethyl 7-chloro-1-ethyl-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (373 mg, 1.21 mmol) and glycine tert-butyl ester hydrochloride (0.243 g, 1.45 mmol) in dioxane (8 mL). The reaction mixture was stirred at 80° C. for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow oil. The crude oil was purified by silica flash chromatography (0-75% DCM/hexane) to give the desired compound as a white solid (407 mg). MS (m/e)=338.1 (M+H-tBu)+.