Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([CH:10]=1)[NH2:9].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([CH:10]=1)[N:9]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: Nc1cc(Br)ccc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 5.07 g (126.93 mmol, 60%) of sodium hydride were suspended in 150 ml of THF, and the mixture was cooled to 0° C. 10.70 g (51.81 mmol) of 5-bromo-2-chloroaniline dissolved in 10 ml of THF were then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 25 g (124.34 mmol) of 4-methoxybenzyl chloride were then added to the reaction mixture, and the mixture was subsequently warmed to room temperature. The mixture was stirred at RT for 2 h and then slowly poured onto 150 ml of ice-water. The organic phase was separated off, and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically [column: Kromasil Si 6012, 350 mm×30 mm; mobile phase A: isohexane, mobile phase B: ethyl acetate; gradient: 0 min 98% A→4.65 min 98% A→13 min 87% A→13.01 min 98% A→13.28 min 98% A; flow rate: 70 ml/min; temperature: 20° C.; UV detection: 265 nm]. This gave 12.37 g (27.69 mmol, 57% of theory) of the title compound.
Reaction SMILES: Br[CH:2]([CH3:18])[CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:18][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:22][CH:21]=1
Reactant: CC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N(CCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[(2-bromo-propyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02180, 146 mg, 0.50 mmol), 4-hydroxy-thiophenol (240 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMF (10 mL) was stirred for 48 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.31) to give an yellow oil, which was crystallised from methanol. Yield: 211 mg (60%). 1H-NMR (400 MHz, d6-DMSO) δ=1.64 (tt, J=7.0, 7.0 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 3.92 (t, J=7.0 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 7.20 (d, J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz, 2H), 8.96 (s,2H), 9.59 (s, 1H, —OH). LRMS (FAB+): 352.1 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:22]=1.C(N(C(C)C)CC)(C)C.[SH2:32]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH2:21])=[S:32])[CH2:17][CH2:18]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:22]=1
Reactant: S
Reactant: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=S)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1

Procedure:
A suspension of [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile (1.2 g, 3.2 mmol) is heated with diisopropylethylamine (0.65 g, 5.0 mmol) in a solution of ethanol saturated with hydrogen sulfide gas for 4 hours. The reaction is cooled, filtered and washed with cold ethanol to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-thioacetamide. 1H NMR (300 MHz, DMSO-d6) δ9.71 (bs, 1H), 9.01 (bs, 1H), 8.35 (d, 1H), 8.21 (s, 1H), 8.08 (d, 1H), 7.59 (dd, 1H), 4.15 (s, 2H), 3.73 (s, 2H), 3.43 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCc1ccccc1)CC3
Yield: 27.5 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (1.5 g, 6.5 mmol), potassium carbonate (0.50 g, 4.7 mmol), and (2-bromethyl)benzene (1.0 mL, 1.4 g, 7.3 mmol) in 10 mL of N,N-dimethylformamide is heated at 900 for 18 hours. The cooled reaction mixture is added to 300 mL of water and 150 mL of ethyl ether. The insoluble material is filtered and washed with fresh ethyl ether. Recrystallization of the solid from aqueous 2-propanol gives 0.60 g (27%) of product; mp 135°-136° C.
Reaction SMILES: Cl.[C:2]1(CN[C@@](C)([C@@H](O)C)CO)[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C1(C=O)C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.NC(C)(COC)CO.[CH3:53][S:54]([O:57][CH2:58][C:59]([CH3:81])([NH:63][CH2:64]C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1)[CH2:60][O:61][CH3:62])(=[O:56])=[O:55]>>[CH3:53][S:54]([O:57][CH2:58][C:59]([CH3:81])([NH:63][CH2:64][C:3]1[CH:4]=[C:5]2[C:16]3=[C:17]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]4=[CH:13][CH:14]=[C:15]3[CH:2]=1)[CH:7]=[CH:6]2)[CH2:60][O:61][CH3:62])(=[O:56])=[O:55]
Reactant: C[C@H](O)[C@@](C)(CO)NCc1ccc2ccc3cccc4ccc1c2c34
Reactant: COCC(C)(COS(C)(=O)=O)NCc1ccc2ccc3cccc4ccc1c2c34
Agent: COCC(C)(N)CO
Agent: Cl
Agent: O=Cc1ccc2ccc3cccc4ccc1c2c34
Product: COCC(C)(COS(C)(=O)=O)NCc1cc2ccc3cccc4ccc(c1)c2c34

Procedure:
Using the reductive amination procedure outlined in 20G, pyrene-1-carbaldehyde (Aldrich) and 2-amino-3-methoxy-2-methyl-1-propanol (22C) gave after workup using the procedure outlined in 1B 3-methoxy-2-methyl-2-((1-pyrenylmethyl)amino)-1-propanol methanesulfonate.1/3H2O mp 158°-160°, (EtOH/Et2O), (C, H, N, S).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][OH:19]>>[CH2:20]([C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH2:18][OH:19])[CH2:22][CH3:23])[CH3:21]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CCC(N)(CC)CO
Product: CCC(CC)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-ethyl-1-butanol (CAN 19792-52-0) as starting materials and isolated (22 mg, 67% as colorless oil; LC-MS (UV peak area, m/z) 98%, 327.1470 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[CH3:41][C@H:42]1[C@H:47]([NH2:48])[CH2:46][C@@H:45]2[CH2:49][C@H:43]1[C:44]2([CH3:51])[CH3:50]>>[CH3:41][C@H:42]1[C@H:47]([NH:48][C:30]([CH:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])[CH2:46][C@@H:45]2[CH2:49][C@H:43]1[C:44]2([CH3:50])[CH3:51]
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: C[C@H]1[C@H](N)C[C@@H]2C[C@H]1C2(C)C
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N[C@@H]4C[C@@H]5C[C@H]([C@H]4C)C5(C)C)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 69.1 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.089 g, 0.148 mmol) was reacted with (1R,2R,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 30 μL, 0.179 mmol) to form 2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1R,2R,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.075 g, 68%). m/z=733 (M+1); HRMS: calcd for C39H59ClFN4O4S. Calc [M+H+] 733.3924. found 733.3920.
Reaction SMILES: [C-]#[C-].[Li+:3].[Li+].C[O:6]CCl.BrC[C:11]1ON=[C:13]([O:16]C)[CH:12]=1.[C:18]1(C(C2C=CC=CC=2)OC2C(CI)=NSN=2)C=CC=C[CH:19]=1.C(=O)=O>O1CCCC1>[C:13]([OH:16])(=[O:6])[C:12]#[CH:11].[C-:18]#[C-:19].[Li+:3].[Li+:3]
Reactant: COc1cc(CBr)on1
Reactant: COCCl
Reactant: ICc1nsnc1OC(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#CC(=O)O

Procedure:
Dibromoolefin intermediate XIX is then converted to ethynyl intermediate XX. Treatment of the dibromoolefin intermediate with about two equivalents of n-butyllithium produces the lithium acetylide XX, wherein R13 is Li. This transformation is typically carried out in a polar organic solvent, such as tetrahydrofuran, at a temperature of about -78° C. to about 25° C. The lithium acetylide is reacted with electrophiles, such as methoxymethyl chloride, 5-bromomethyl-3-methoxyisoxazole, 3-diphenylmethoxy-4-iodomethyl-1,2,5-thiadiazole, carbon dioxide, tetrazole disulfide, and the like, to prepare the formula I compounds. In a typical example, the lithium acetylide is treated with solid CO2 at a temperature of about -78° C. to about -60° C. to produce propargylic acid intermediate XX wherein R13 is CO2H. This compound may be further modified as described herein.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:26])[CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:34]([O:36][CH2:37][CH:38]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35].O>C(Cl)Cl.O1CCOCC1>[CH:1]1([O:6][C:7](=[O:26])[CH2:8][N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:15][CH:16]=2)[C:34]([O:36][CH2:37][CH:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=3[C:45]3[C:50]2=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNCC(=O)OC2CCCC2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CN(CC(=O)OC2CCCC2)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To a solution of [4-(tert-Butoxycarbonylamino-methyl)-benzylamino]-acetic acid cyclopentyl ester (0.2 g, 0.55 mmol) and 1 M Na2CO3 (1.1 mL, 1.1 mmol) in DCM (2 mL), was added slowly with stirring and ice bath cooling, a solution of 9-Fluorenylmethyl chloroformate (0.14 g, 0.55 mmol) in dioxane (1.4 mL). The mixture was stirred in the ice bath for 4 h and at room temperature overnight. The mixture was poured into water (90 mL) and extracted with diethyl ether. The organic extracts were combined, dried (MgSO4) and evaporated to dryness to afford the desired product (0.32 g, 100%). m/z 607 [M++Na]+
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](I)[CH3:41]>O>[CH2:40]([O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)[CH3:41].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCI
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 g of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1=BOC, R2=R3=H) is added to dimethylformamide (80 ml). Cesium carbonate (69 g) is then added. Ethyl iodide (13.6 g) is then added and the mixture is stirred overnight at room temperature. Water (200 ml) is added to the mixture and the mixture is then extracted with isopropyl acetate (2×200 ml). The combined organic phases are washed with brine, dried (MgSO4) and concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (3-a, R1=BOC, R2=H, R3=Et) (56 g). 1H NMR (DMSO): 1.12 (3H), 1.19 (3H), 1.36 (9H), 1.53 (1H), 1.84 (1H), 2.55 (1H), 2.75 (2H), 3.74 (1H), 4.05 (2H), 6.04 (1H), 7.23 (2H), 7.30 (1H), 7.41 (2H), 7.50 (2H), 7.57 (2H). m/z (ES+): 412 ([MH]+, 100%), 356 (63), 312 (73).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)[CH2:4]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>CN(C=O)C>[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[N:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=3)[CH2:4]2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCNC2)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of ethyl (2E)-3-{6-[(3R)-3-piperidinylamino]-3-pyridinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (4 mL) were added triethylamine (349 mg, 3.45 mmol) and 4-chlorobenzoyl chloride (181 mg, 1.03 mmol) at 0° C. under nitrogen and the mixture was stirred at same temperature for 1 hr and at ambient temperature for 2 hrs. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (hexane-EtOAc=1-1) to give ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-piperidinyl]amino}-3-pyridinyl)acrylate (270 mg, 76%) as an amorphous powder.
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1([F:34])[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:8][CH2:7]1.O[N:36]1C(=O)CCC1=O.N>CN(C=O)C>[F:5][C:6]1([F:34])[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([NH2:36])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Temperature: 25 °C

Procedure:
0.029 g EDC was added to a mixture of 0.050 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 33.2) and 0.020 g 1-hydroxy-pyrrolidine-2,5-dione in 1 ml DMF and stirred at rt over the weekend. After the addition of 0.327 ml ammonia (7M) the reaction mixture was stirred at rt for further 1.5 hours. The mixture was concentrated and the residue was recrystallized from hot MeOH.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)(=O)C.[CH3:17][NH:18][NH2:19].[OH-].[Na+].Cl>O.C1(C)C=CC=CC=1>[OH:6][C:5]1[N:18]([CH3:17])[N:19]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cn1nc(C(F)(F)F)cc1O
Temperature: 10 °C
Yield: 86.5 %

Procedure:
92.1 g (0.5 mole) of ethyl 4,4,4-trifluoroacetoacetate was dissolved in 60.1 g (1.0 mole) of acetic acid. The solution was cooled to 10° C. or lower with stirring. Thereto was dropwise added, in 1 hour, 65.8 g (0.5 mole) of a 35% aqueous methylhydrazine solution. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and successively at 80° C. for 5 hours to give rise to a reaction. After the reaction, the mixture was cooled to room temperature. Thereto were added 150 ml of toluene, 600 ml of water and 48 g (1.2 moles) of sodium hydroxide. After phase separation, 154 g (1.5 moles) of 35% hydrochloric acid was added to the aqueous layer. The resulting crystals were collected by filtration, washed with 50 ml of water twice, and dried in a hot-air drier, to obtain 71.8 g (yield: 86.5%) of a title compound as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[NH:15][C:16]4[C:21]([C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[NH:29][N:30]=[CH:31][C:24]=12>CS(C)=O.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[NH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]=3[CH2:12][CH2:11][N:10]2[C:23]2[N:28]=[CH:27][N:26]=[C:25]3[NH:29][N:30]=[CH:31][C:24]=23)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2c3[nH]c4ccccc4c3CCN2c2ncnc3[nH]ncc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole from step 1 in dimethylsulfoxide (2.4 ml) and N,N-diisopropylethylamine (175 μl) was added a 0.25 M solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine in dimethylsulfoxide (800 μl). The mixture was shaken at room temperature for 24 hours. The mixture was evaporated to dryness and the residue shaken at 50° C. in a mixture of ethyl acetate (3 ml) and water (2 ml) for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2 ml). The combined organic layers were evaporated to dryness and the residue dissolved in dimethylsulfoxide (1.6 ml) at 50° C. then purified by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95acetonitrile/water gradient using 0.1% TFA as modifier to yield 1-(4-methoxyphenyl)-2-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,3,4,9-tetrahydro-1H-beta-carboline. LCMS m/e 397 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(Cl)CCl.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:21][CH:20]=1>>[CH3:5][O:4][N:3]([CH3:2])[C:27](=[O:29])[CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCC(=O)O)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CCC(=O)N(C)OC)cc1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (5.41 g, 55.5 mmol), EDC (12.77 g, 66.6 mmol), followed by triethylamine (17 mL, 122 mmol) were added to a cooled 0° C. solution of 3-(4-methoxyphenyl)propionic acid (10 g, 55.5 mmol). The reaction mixture was stirred for 15 h under N2 and then concentrated. The residue was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by silica gel chromatography (40% EtOAc in hexanes) to give a clear oil (10.6 g, 85%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH:38]1([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CO.C(Cl)(Cl)Cl>[CH:38]1([N:44]2[CH2:49][CH2:48][N:47]([C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]4)=[O:3])[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N1CCN(C2CCCCC2)CC1
Reaction time: 5 h
Yield: 49.8 %

Procedure:
Into 200 ml of chloroform were added 5 g of 6-(3-carboxypropoxy)carbostyril and 3.2 g DBU. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 2.8 g of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation, the reaction mixture was further stirred for 1 hour, then 3.7 g of N-cyclohexylpiperazine was added dropwise at a room temperature, and the reaction was continued for 5 hours. After the reaction was completed, the reaction mixture was washed with 1% NaOH aqueous solution and water, then dried with anhydrous sodium sulfate. The drying agent was removed by filtration and the mother liquor was concentrated. The residue thus obtained was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=30:1) to obtain elute. The elute was concentrated and the residue was recrystallized from water-containing methanol to obtain 4 g of 6-[3-(4-cyclohexyl-1-piperazylcarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals. Melting point: 184.5°-186° C.