Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=O)OC(C)(C)C)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.CO.C(Cl)Cl>C(#N)C>[CH3:25][C@@H:15]1[N:14]2[C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]=[CH:5][C:4]=3[N:1]=[C:18]2[NH:17][CH2:16]1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H]1CNc2nc3cnc4ccccc4c3n21

Procedure:
The title compound was prepared from tert-butyl (2S)-2-[(3-nitroquinolin-4-yl)amino]propylcarbamate according to the methods of Parts C through G of Example 22 with the following modifications. Part C was carried out in acetonitrile as the solvent. Part D required chromatography (SiO2, 0-6% methanol/CH2Cl2). Following chromatographic purification (SiO2, 20-40% CMA/CHCl3) in Part G, the title compound, (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline (2.14 g), was obtained as an off white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1C1C=CC(C(=O)C)=CC=1.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18].S(=O)(=O)(O)O.[H][H]>C1C=CC=CC=1>[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: CC(=O)c1ccc(-c2ccccc2Cl)cc1
Reactant: [H][H]
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 7 h

Procedure:
The procedure of Example 3 was repeated, except that the 4'-(2-chlorophenyl)acetophenone was replaced with an equal amount of 4'-chlorophenyl)acetophenone, the amount of benzene employed was increased to 200 ml., and the amount of sulfuric acid was reduced to 5 drops. After seven hours, hydrogen pressure had dropped to 35.5 psig. Evaporation of the benzene left a solid which, according to nuclear magnetic resonance analysis, contained only about 67 percent of the desired ethylbenzene. Consequently, the solid was subjected to the hydrogenation procedure again, using 200 ml. of benzene, 2 g. of catalyst, and 1 ml. of concentrated sulfuric acid. The solid obtained upon evaporation of the benzene was recrystallized from hexane, giving 1-ethyl-4-(4-chlorophenyl)benzene, mp 103°-104°. The following elemental analysis was obtained:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CO)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(CO)c1
Temperature: 0 °C
Yield: 74.1 %

Procedure:
To a solution of (3-aminophenyl)methanol (1.87 g, 14.7 mmol) in tetrahydrofuran (10 mL) was added triethylamine (7 mL, 73.5 mmol). The reaction was cooled down to 0° C., acetic anhydride (1.5 mL, 16 mmol) was added dropwise. The reaction was warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The ethyl acetate layer was dried over MgSO4, concentrated, trituated with CH2Cl2 to yield N-(3-(hydroxymethyl)phenyl)acetamide as a yellow solid (1.8 g, 74%). HPLC retention time (Method C)=1.03 min. LC/MS (ESI) (M+H)+=166.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(O[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=2)[CH2:24][CH2:23]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:35][CH:33]([C:30]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=4)=[N:14][CH:13]=3)[CH2:27][CH2:26]2)[O:32][N:31]=1)[CH3:34]
Reactant: CSc1ccc(-c2ccc(O)cn2)cc1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of 6-[4-(methylthio)phenyl]-3-pyridinol (53.2 g, 245 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 74.3 g, 735 mmol), K2CO3 (101.5 g, 735 mmol) and DMF (500 mL) was stirred at 80° C. for 2 h. The mixture was charged with water, allowed to stand for 30 min, and the resulting precipitate was filtered, washed with water, heptane, and air dried to give 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylthio)phenyl]pyridine (93.7 g, 90%) as a tan solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.8 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.61 (d, 1H, J=8.7 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.22 (d, 1H, J=3.0 Hz), 4.30-4.10 (m, 2H), 3.90 (d, 2H, J=6.2 Hz), 3.15-3.05 (m, 2H), 2.92-2.82 (m, 1H), 2.50 (s, 3H), 2.14-1.99 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([C:10]([OH:12])=O)[CH2:9][CH2:8]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: O=C(O)C1(c2cnccn2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cnccn2)CC1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of 1-(pyrazin-2-yl)cyclopropanecarboxylic acid (0.11 g, 0.669 mmol) in anhydrous dichloromethane (15 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (0.3 g, 0.803 mmol) and diisopropylethylamine (0.35 mL, 2 mmol) at room temperature. The mixture was stirred for 10 min and then (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (0.29 g, 0.803 mmol) was added. The reaction mixture was stirred for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-5% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyrazin-2-yl)cyclopropanecarboxamide (100 mg). MS (ES+APCI) (M+H) 436.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.NC1C(C(C2C=C(F)C=CC=2OC)=O)=CN=C(S(CC)(=O)=O)N=1.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>CN1CCCC1=O.O>[C:56]([O:55][C:53]([N:50]1[CH2:51][CH2:52][CH:47]([NH:46][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:48][CH2:49]1)=[O:54])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Agent: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Temperature: 70 °C
Yield: 95 %

Procedure:
A solution composed of a 9:1 mixture of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone and (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (11.6 g, 36 mmol, Example 163) and 4-amino-1-N-Boc-piperidine (Astatech Inc.) (10.8 g, 54 mmol) in 1-methyl-2-pyrrolidinone (50 mL, Aldrich) was heated at 70° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The dried (Na2SO4) organic solution was evaporated and the residue was triturated with ethyl ether/hexane to give 95% yield of 4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid, mp 122–124 dec. Mass Spectrum (LR-ES) M+: 445.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13](=[O:18])[CH2:14][C:15]([OH:17])=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH:55]1[CH2:60][CH2:59][N:58]([C:15](=[O:17])[CH2:14][C:13]([NH:12][C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)=[O:18])[CH2:57][CH2:56]1
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ncc(-c2ccccc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Cl)CC1)Nc1ncc(-c2ccccc2)s1
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a stirred solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid (0.075 g, 0.00028 mole) in DMF (2 mL) was added DIPEA (0.11 g, 0.00085 mole), HOBt (0.038 g, 0.00028 mole) and EDCI.HCl (0.065 g, 0.00034 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (0.078 g, 0.00031 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.031 g (24%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(5-phenyl-thiazol-2-yl)-propionamide. LC-MS purity: 456.11 (M+1)+, 93.27%, 1H NMR (CDCl3): δ 11.6 (s, 1H), 7.9 (d, 2H), 7.44 (t, 3H), 7.3 (d, 1H), 7.22 (d, 1H), 7.14 (s, 1H), 6.92 (d, 2H), 4.7 (s, 1H), 4.1 (m, 1H), 3.8 (m, 1H), 3.7-3.5 (m, 4H), 2.0 (d, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[CH:4][C:3]=1[F:9]
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(Br)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(OCCN2CCOCC2)ccc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.9 %

Procedure:
A flask was charged with 4-bromo-3-fluorophenol (4.999 g, 26.2 mmol) and triphenylphosphine (10.298 g, 39.3 mmol). Methylene chloride (120 mL) was added followed by 2-morpholinoethanol (4 mL, 33.0 mmol) and the solution was stirred on an ice water bath to cool. After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added over 6 to 8 minutes. The reaction was left stirring on the cold bath to slowly warm to room temperature overnight. The reaction was concentrated and the residue purified by flash chromatography (25% to 100% EtOAc in hexanes) to provide the product as a colorless oil (2.621 g, 33%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:24](=[O:25])[N:23]([N:26]=[C:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:22]4[CH:33]=[CH:34][S:35][C:21]=4[C:20]=3[OH:36])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:24](=[O:25])[N:23]([NH:26][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:22]4[CH:33]=[CH:34][S:35][C:21]=4[C:20]=3[OH:36])=[N:15][S:16](=[O:17])(=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc2n1N=C1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc2n1NC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
The product of Example 324C (0.167 g, 0.30 mmol) in tetrahydrofuran (6 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was reacted with lithium borohydride (2.0 M solution in tetrahydrofuran, 0.250 mL, 0.50 mmol). The reaction was stirred at 25° C. for 1.5 hour, acidified to pH 2 with 1 M aqueous hydrochloric acid and diluted with water (25 mL). The resulting precipitate was collected by filtration and dried to constant weight to give the title compound (0.114 g, 69%). MS (APCI+) m/z 551 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (m, 10 H) 5.25 (s, 2 H) 6.50 (s, 1 H) 7.43 (m, 8 H) 7.69 (d, J=8.82 Hz, 1 H) 8.29 (d, J=5.15 Hz, 1 H) 14.10 (s, 1 H) 14.87 (s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:11][CH:10]=1.C(O)C.[C:22]1([C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH:14]([NH:15][CH2:30][CH:29]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(N)Cc1ccc(OCc2ccccn2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(OCc2ccccn2)cc1)NCC=C(c1ccccc1)c1ccccc1

Procedure:
The starting material is prepared as follows: The mixture of 12.1 g of dl-4-(2-pyridylmethoxy)-amphetamine, 400 ml of absolute ethanol and 10.4 g of β-phenylcinnamaldehyde is treated dropwise under stirring with the solution of 3.5 g of sodium borohydride in 10 ml of water. The whole is then stirred and refluxed overnight, concentrated and the concentrate diluted with water. It is extracted with ethyl acetate, the organic layer washed with saturated aqueous sodium chloride, dried and evaporated to yield the dl-1-[4-(2-pyridylmethoxy)-phenyl]-2-(3,3-diphenylallylamino)-propane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[C:18](=[O:27])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[NH:39]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=6[Cl:26])[C:18](=[O:27])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH:41]=[N:40]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n1-c1ccccc1Cl

Procedure:
Following the procedure of Example 44, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-(2-chlorophenyl)-1H-1,2,4-triazol-5(4H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 277. MS: (ESI+) 462.1
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>O1CCCC1.C(OCC)(=O)C>[C:14]1([S:20]([CH2:23][CH2:24][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CCn1c2ccccc2c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.8 g 9H-carbazole and 9.8 g phenylvinylsulphone are suspended in 3 ml of tetrahydrofuran, cooled to 0° C., combined with 60 μl benzyltrimethylammonium hydroxide (40% solution in water) and stirred for 20 minutes. Then the mixture is heated to 115° C. for 7 hours. Then it is divided between ethyl acetate and 1 N hydrochloric acid, the organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([C:14]2[N:15]=[C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[S:17][CH:18]=2)[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[Ca+2].[C:29](Cl)(Cl)=[S:30].[NH3:33]>C(Cl)(Cl)(Cl)Cl.O.C(Cl)Cl.O>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:16]1[S:17][CH:18]=[C:14]([C@@H:12]([NH:13][C:29]([NH2:33])=[S:30])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:15]=1
Reactant: S=C(Cl)Cl
Reactant: N
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=S)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-(4-nitrophenyl)-1-(thiophen-2-ylthiazol-4-yl)ethanamine hydrobromide salt, 8, (1.23 g, 2.98 mmol) and CaCO3 (0.597 g, 5.96 mmol) in CCl4/water (10 mL/5 mL) is added thiophosgene (0.412 g, 3.58 mmol). The reaction is stirred at room temperature for 18 hours then diluted with CH2Cl2 and water. The layers are separated and the aqueous layer extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated in vacuo to a residue which is subsequently treated with ammonia (0.5M in 1,4-dioxane, 29.4 mL, 14.7 mmol) which is purified over silica to afford 0.490 g of the desired product as a red-brown solid. ESI+ MS 399 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:13]([CH:14]=O)=[C:12]([Cl:16])[N:11]=[C:10]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:25])=[O:24].[CH:46]1C=CC=C[CH:47]=1>>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:13]([CH:14]=[CH:26][C:23]([O:25][CH2:46][CH3:47])=[O:24])=[C:12]([Cl:16])[N:11]=[C:10]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: c1ccccc1
Product: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1.2 g of 1-(4-nitrobenzyl)-2-butyl-4-chloroimidazole-5-aldehyde and 1.5 g of (carboxymethylene)triphenylphosphorane in 50 mL of benzene was refluxed for 2 hours. The reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (Hexane: EtOAc=3:1 elution). The major product, the E isomer, was eluted first and was obtained as a thick oil initially which solidified to give an amorphous solid, 1.2 g. The minor product, the Z isomer was eluted next and was isolated as a thick liquid, 85 mg. E isomer: NMR (200 MHz, CDCl3): 7.3 and 6.53 (d, 2H, 5=16 Hz); 5.3 (s, 2H); 2.62 (t, 2H, J=7.3 Hz); 1.69 (m, 2H); 1.28 (m, 5H); 0.89 (t, 3H, J=7.3 Hz). Z isomer: NMR (200 MHz, CDCl3): (key peaks only) δ 6.45 and 6.02 (d, 2H, J=11.8 Hz); 5.17 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]([NH:12][C:13](=[O:16])[CH2:14][Cl:15])([CH3:11])[CH2:9][OH:10])[CH:7]=1.[K].CCSC([N:24](CC(C)C)CC(C)C)=O>[Pd]>[ClH:15].[NH2:24][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:7]=1
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)ccc1F
Reactant: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [Pd]
Agent: [K]
Product: C[C@@]1(c2cc(N)ccc2F)COCC(=O)N1
Product: Cl

Procedure:
In close analogy to the reaction sequence described for the preparation of Building block C, the cyclization of the (R)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide with potassium tent-butylate, followed by the palladium-catalyzed amination, and, finally, by the hydrolysis yielded the (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one hydrochloride as a light yellow solid. Mass (calculated) C11H14ClN2O2 [260.698]; (found) [M+H]+=225.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-:35].[Na+].Cl>O1CCOCC1>[OH:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][CH:15]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4ccc5ccnc(O)c5c4)C3=O)cc2c1

Procedure:
7-Methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.07 g, 0.14 mmol), prepared as described in EXAMPLE 1, Part K, is treated with dioxane (1 mL) and 10% aq. NaOH (3 mL) and heated to reflux for 48 hours. The reaction was cooled, acidified with 1 N HCl and extracted with CH2Cl2. The organic layer is separated, dried and concentrated. The residue is purified by column chromatography eluting with 2.5% MeOH/CH2Cl2. The product fractions are collected, concentrated and precipitated with dilute HCl/ether to yield the title compound (0.041 g, 0.086 mmol).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]#[N:11])=[N:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6]1.[C:22](=[O:25])([O-])[O-].[K+].[K+].Cl.[NH2:29]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[N:29]=[CH:22][O:25][N:11]=2)=[N:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nc(-c2ccccn2)nn1Cc1ccccc1F
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1-c1ncon1
Temperature: 70 °C

Procedure:
To a solution of 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbonitrile (I-33, e.g., about 100 mg, 0.358 mmol) and potassium carbonate (e.g., about 198 mg, 1.43 mmol) in methanol (e.g., about 3.6 mL) is added hydroxylamine hydrochloride (e.g., about 75 mg, 1.1 mmol). The solution is heated to about 70° C. for about 1.25 h, at which point the solution is diluted with ethyl acetate (e.g., about 20 mL) and the solids are filtered off through a cotton plug. The solvent is removed in vacuo and the crude residue is diluted with water (e.g., about 50 mL) and a mixture of dichloromethane and 2-propanol, e.g., a 5:1 mixture of dichloromethane and 2-propanol (e.g., about 50 mL). The layers are separated and the organic layer is washed with water (e.g., about 50 mL), dried, e.g., over sodium sulfate or magnesium sulfate, and the solvent is removed in vacuo. To the resulting crude 1-(2-fluorobenzyl)-N′-hydroxy-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboximidamide is added trimethyl orthorfomate (e.g., about 4.5 mL, 41 mmol) and a catalytic amount of p-toluensulfonic acid monohydrate (e.g., about 3.4 mg, 0.018 mmol). The solution is heated to about 100° C. for about 1.5 h, and the excess orthoformate is removed in vacuo to give the crude product, I-34. Purification by silica gel chromatography (e.g., 20-80% ethyl acetate in hexanes) yields 3-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,2,4-oxadiazole, I-34, as a solid.