Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (5.44 g, 20 mmol) in diethylamine (75 mL) was added PdCl2(PPh3)2 (280 mg, 0.4 mmol), trimethylsilylacetylene (2.36 g, 24.0 mmol) and copper(I)iodide (20 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 24 h, filtered and evaporated. The residue was purified by column chromatography using heptane:ethyl acetate (8:2) as eluent. The desired (3,5-dichloro-phenylethynyl)-trimethylsilane product was isolated in 4.85 g yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCN(C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-methylpiperazine (10.0 mg, 0.1 mmol). The title compound was obtained as a solid (26.5 mg, 61% yield). MS m/z: 433 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH3:12][C:13]1C=[CH:17][C:16](S(OCCCCC#C)(=O)=O)=[CH:15][CH:14]=1>>[CH2:17]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:16][CH2:15][CH2:14][C:13]#[CH:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Product: C#CCCCCOc1cc(C=O)ccc1OC
Yield: 57 %

Procedure:
Isovanillin (0.78 g, 5.2 mmol) was alkylated using hex-5-ynyl 4-methylbenzenesulfonate (1.95 g, 7.73 mmol according to Procedure 4. The crude product was recystallised from EtOAc/petrol to provide 3-(hex-5-ynyloxy)-4-methoxybenzaldehyde (0.68 g, 57%) as a colourless crystalline solid; mp 66-67° C.; δH (400 MHz, CDCl3) 1.74 (p, J=7.2 Hz, 2H, CH2), 1.96-2.0 (m, 3H, CH2, C≡CH), 2.30 (td, J=7.2, 2.8 Hz, 2H, CH2C≡CH), 3.95 (s, 3H, OCH3), 4.11 (t, J=7.2 Hz, 2H, OCH2), 6.97 (d, J5,6=8.0 Hz, 1H, H5), 7.40 (d, J2,6=1.6 Hz, 1H, H2), 7.44 (dd, J5,6=8.0 Hz, J2,6=1.6 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 18.1, 25.0, 28.0, 56.2, 68.4, 68.7, 83.9, 110.3, 110.6, 126.7, 130.1, 149.0, 154.9, 190.9; vmax 1018, 1263, 1582, 1679, 2933, 3238 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1.[CH3:28][CH:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1C(=O)CCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:36][C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:28])[N:15]=1
Reactant: CC(N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Solvent: CO
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1)c1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
To a solution of 2-(2-chlorobenzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.10 g, 0.26 mmol) in NMP (2 mL) is added alpha-methyl benzyl amine (0.10 mL, 0.78 mmol). After stirring 1.5 hours at 90° C., the reaction mixture is diluted with methanol (to 5 mL) and purified by reversed phase liquid chromatography (CH3CN/water/1% TFA) to afford 27 mg (23%) of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=5.1 Hz, 1H), 7.38-7.12 (m, 9H), 6.52 (d, J=5.1 Hz, 1H), 5.06 (q, br, 1H), 4.07-3.95 (m, 4H), 4.02 (s, 2H), 2.58-2.45 (m, 2H), 1.58 (d, J=7.0 Hz, 3H); ESI− MS: m/z (rel intensity) 446.0 (100, M+−H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][NH:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[N+:40]([O-:42])=[O:41]>CN(C)C=O>[N+:40]([C:31]1[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:30]=1[N:11]1[N:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([O:3][C:2]([F:1])([F:21])[F:22])[CH:5]=2)=[N:12]1)([O-:42])=[O:41]
Reactant: CCOC(=O)c1n[nH]nc1Oc1cccc(OC(F)(F)F)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 5-[3-(trifluoromethoxy)phenoxy]-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step E, 0.55 g, 1.7 mmol) in N,N-dimethylformamide (5 mL) was added anhydrous potassium carbonate (0.48 g, 3.5 mmol) and 4-fluoro-3-nitrobenzotrifluoride (0.29 mL, 2.1 mmol). The mixture was heated to 80° C. with stirring for 90 min. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with ethyl acetate (30 mL, 15 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude material was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to obtain the title compound (0.76 g) as a pale yellow oil.
Reaction SMILES: [CH3:1]SC.B.[NH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[O:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[N:22]=4)[N:17]=[CH:16][C:15]=3[NH:14][C:13]2=O)[CH2:8][CH2:7]1>O1CCCC1>[CH3:27][O:26][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]1[N:14]([CH3:1])[CH2:13][CH:12]([C@H:9]3[CH2:8][CH2:7][C@H:6]([NH2:5])[CH2:11][CH2:10]3)[O:25][C:24]2=1
Reactant: CSC
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)C(=O)N3
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3C
Temperature: 0 °C

Procedure:
Borane dimethyl sulfide complex (2M solution in tetrahydrofuran, 60.0 mL, 120.0 mmol, 24.5 eq) is added at room temperature to a stirred solution of 3-(trans-4-amino-cyclohexyl)-6-methoxy-1H-4-oxa-1,5,9-triaza-phenanthren-2-one (1.67 g, 4.88 mmol, 1.0 eq) in tetrahydrofuran (600 mL). The reaction mixture is heated to reflux for 3 hours, cooled down to 0° C. and cautiously quenched with methanol (100 mL) and then evaporated to give crude trans-4-(6-methoxy-1-methyl-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine that is directly engaged in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([C:11](OCC)=[O:12])[CH3:10])[C:5]([N+:22]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:22][C:11](=[O:12])[CH:9]([CH3:10])[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)[C@H](C)N(c1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1C(=O)Nc2cnc(Cl)nc2N1c1ccccc1
Temperature: 70 °C
Yield: 75 %

Procedure:
To a stirred solution of ethyl N-(2-chloro-5-nitropyrimidin-4-yl)-N-phenylalaninate (1.6 g, 4.56 mmol) in glacial acetic acid (35 mL) was added iron powder (1.6 g, 28.57 mmol). The resulting mixture was heated at 70° C. for 2 h. The insoluble material was then filtered off celite to give a clear solution. The bulk of solvent was evaporated to give a crude residue, which was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to afford desired product (75%). 1HNMR (300 MHz, DMSOd6): δ 1.29 (d, J=6.6 Hz, 3H), 4.58-4.60 (m, 1H), 7.36-7.50 (m, 5H), 7.70 (s, 1H) and 10.94 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1>>[CH3:16][C@H:17]1[NH:18][CH2:19][CH2:20][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][CH:10]=[N:11]3)=[O:4])[CH2:22]1
Reactant: O=C(CCl)Nc1cccc2ncccc12
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(CC(=O)Nc2cccc3ncccc23)CCN1

Procedure:
The subtitle compound was prepared from 2-chloro-N-(quinolin-5-yl)acetamide (1 g) (J Indian Chem Soc, 1940, 17, 619-621) and (R)-2-methylpiperazine (0.5 g) by the method of Example 58 step (i) as a white solid. Yield: 1.4 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][NH2:60])=[CH:54][CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:60][CH2:59][CH2:58][C:55]3[CH:56]=[CH:57][C:52]([CH2:51][N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)=[CH:53][CH:54]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: NCCc1ccc(CN2CCCC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(CN4CCCC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AC using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (76 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), TEA (0.030 mL, 0.22 mmol) and 2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethanamine (40 mg, 0.20 mmol) in DMF (5 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: N#N.[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[O:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][OH:19])[O:16][CH:17]=2)[CH2:11][CH2:12]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=O)OC1(c2coc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OC1(c2coc(CO)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-4-yl)cyclopropyl pivalate (450 mg, 1.27 mmol) in THF (13.0 mL) at 0° C. was treated with TBAF (2.55 ml of a 1M solution in THF, 2.55 mmol) and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with EA (30 mL), the layers were separated and the org. layer was washed sequentially with sat. aq. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:1 hept-EA)=0.29. LC-MS-conditions 06: tR=0.69 min, [M+H]+=240.11.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N:12]([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
A solution of 3,4-dimethylbenzoic acid (40 g) in concentrated sulphuric acid (250 ml) was cooled to 0° C., treated with a solution of potassium nitrite (27 g) in sulphuric acid (100 ml) dropwise over a period of 1 h, and stirred for 2 h. The reaction mixture was quenched with ice cooled water (100 ml). The solid precipitated was filtered, dissolved in water (2 l), basified with 2N aqueous sodium hydroxide. The solution was acidified to pH 4 with 2N aqueous hydrochloric acid and filtered to get 3,4-dimethyl-5-nitrobenzoic acid (II) (25 g) as colorless solid. The filtrate was further acidified to pH 3 and filtered get 3,4-dimethyl-2-nitrobenzoic acid (I) (13 g) as colorless solid.
Reaction SMILES: [I-].[CH3:2][C:3]1[N:10]2[C:6](=[N+:7]([CH3:19])[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=32)[S:5][CH:4]=1.[CH3:20][O-:21].[Na+]>CO>[CH3:19][N:7]1[C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][C:9]=2[N:10](/[C:3](/[CH3:2])=[CH:4]\[S:5][CH3:6])[C:20]1=[O:21]
Reactant: C[O-]
Reactant: Cc1csc2n1c1cc(C(F)(F)F)ccc1[n+]2C
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(C)c2ccc(C(F)(F)F)cc21
Yield: 85 %

Procedure:
90 mg (0.23 mmol) of 3,9-dimethyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a][3,1]benzimidazol-9-ium iodide 6a were solubilised in MeOH (20 mL). NaOMe was added (8 eq, 100 mg) and the solution stirred under reflux for 2 h. The solvent was then evaporated and water was added (15 mL). The resulting mixture was extracted 3×15 mL of CH2Cl2, the organic layer dried with MgSO4 and evaporated under reduced pressure to yield 1-methyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one 7a (58 mg, orange oil, 85%). 1H NMR (300 MHz, CDCl3) δ=2.14 (3H, d, J=1.2, CH3), 2.27 (3H, s, SCH3), 3.47 (3H, s, NCH3), 6.29 (1H, q, J=1.2, H5), 7.03-7.10 (2H, m, Ar), 7.38-7.42 (1H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=16.90, 20.33, 27.36, 106.06 (q, J=4), 107.28, 119.02 (q, J=4), 123.69 (q, J=33), 124.55 (q, J=271), 125.83, 127.36, 128.53, 132.82, 152.50; HRMS m/z C13H14F3N2OS [M+H]+ calcd: 303.0773, found: 303.0775.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1.[Br:16]N1C(=O)CCC1=O.[NH4+].[OH-]>CCCCCCC>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][N:7]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCCC
Product: Brc1cccc2cnccc12
Temperature: -10 °C

Procedure:
Concentrated H2SO4 (260 mL) was cooled to −25° C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0° C. After the addition was complete, the red solution was recooled to −25° C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed −20° C. The reaction mixture was stirred for 5 hours keeping the temperature between −30° C. and −18° C. The reaction mixture was then allowed to warm to −10° C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3×600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2×200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78°-80° C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:5]1[CH:6]=[CH:7][C:2]([O:1][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
To a solution of 4-hydroxypyridine (4.42 g, 45.8 mmol) and 1-fluoro-4-nitrobenzene (4.89 mL, 45.8 mmol) in anhydrous DMF (50 mL) was added anhydrous K2CO3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temperature with stirring for 24 h, cooled to room temperature and poured in water (300 mL). The solid that separated was filtered, washed with water and dried well under high vacuum to yield 8.9 g (90%) of desired product, 4-(4-pyridinyloxy)-1-nitrobenzene. 1H NMR (CDCl3, 300 MHz): δ 8.36 (d, 2H, J=9.0 Hz), 8.11 (d, 2H, J=8.1 Hz), 7.83 (d, 2H, J=9.0 Hz), 6.27 (d, 2H, J=7.8 Hz); LCMS (m/z): 217 (MH+).
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:23][CH:24]=[CH:25][N:26]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:23][CH:24]=[CH:25][N:26]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1coc([C@@H]2CCCN2)n1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1c1ncco1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and 2-(S)-pyrrolidin-2-yl-oxazole A-5 (synthesis is described in Procedure E) according to General Procedure B.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:15]=4)=[CH:5][C:4]=1[CH3:31])=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>C(Cl)Cl>[CH3:31][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:15]=4)[CH:7]=[CH:8][C:3]=1[CH2:1][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3c2)ccc1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(4-formyl-3-methylphenyl)-7-morpholino-9H-carbazole-1-carboxamide (20 mg, 0.034 mmol), morpholine (0.05 mL, 0.574 mmol), sodium triacetoxyborohydride (100 mg, 0.472 mmol) were mixed with THF (5 mL) and CH2Cl2 (2 mL) in a sealed microwave vial. The mixture was stirred for 3 hr at r.t. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 485.25 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.10 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J=8.6), 7.67 (s, 1H), 7.62 (d, 1H, J=8.0), 7.47(s, 1H), 7.33 (d, 1H, J=7.6), 7.24 (s, 1H), 6.93 (dd, 1H, J=8.6, 1.9), 3.8 (t, 4H, J=4.7), 3.58 (bs, 4H), 3.49 (s, 2H). 3.19 (t, 4H, J=4.6), 2.45 (s, 3H), 2.4 (bs, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[N:11][NH:7]2)=[CH:4][C:3]=1[Cl:10]
Reactant: Cc1cc(Cl)c(Br)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1cc2cn[nH]c2cc1Br
Yield: 63.8 %

Procedure:
To 5-bromo-4-chloro-2-methylaniline (1 g, 4.54 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (0.329 g, 4.76 mmol) in water (1 mL). The mixture was heated at reflux for 2 hours and was subsequently cooled and concentrated. The residue was partitioned in water and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give the title compound as a red-brown solid (0.67 g, 64%). ESI-MS m/z [M+H]+ 232.2.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:15][C:16]#[N:17]>>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:15][C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: OC1(c2ccccc2)CCNCC1
Product: N#CCN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Hydroxy-4-phenyl-piperidine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=217.2: AtRet=1.51.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][C:26]2=[O:35])[CH2:21][CH2:20]1>>[CH3:13][CH:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH2:28][O:27][C:26]3=[O:35])[CH2:23][CH2:24]2)=[C:3]([N+:15]([O-:17])=[O:16])[CH:4]=1)(=[O:10])=[O:9])[CH3:14]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: CC(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: CC(C)NS(=O)(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from the product of step (i) (0.14 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.1 g) using the method of example 115 step (ii). Yield 0.037 g.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1[C:12]#[C:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17].[O:19]([CH2:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([O:9][C:27](=[O:28])[CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH3:10])([CH3:11])[C:3]=1[C:12]#[C:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17]
Reactant: CC(C#CC1=C(C)C(=O)[C@@H](O)CC1(C)C)=CC=O
Reactant: O=C(Cl)COc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C#CC1=C(C)C(=O)[C@@H](OC(=O)COc2ccccc2)CC1(C)C)=CC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.5 g of the ketoaldehyde of formula XII obtained in Example 20 are dissolved in 100 ml of pyridine. 10 g of phenoxyacetic acid chloride are added dropwise to the solution at 0° C. The mixture is stirred for 1 hour at 0° C. and then poured into water and extracted with diethyl ether. The ether extract is washed with 5% strength aqueous sulfuric acid and then with water. The 5-[2,6,6-trimethyl-3-oxo-4(S)-(phenoxyacetoxy)-cyclohex-1-en-1-yl]-3-methyl-penta-2-en-4-yn-1-al (XIV) isolated from the extract is further reacted as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[NH:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]=3[N:24]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Br)[CH3:29]>C1COCC1>[CH2:28]([N:18]1[C:19](=[O:25])[CH2:20][CH2:21][CH2:22][C:23]2[N:24]=[C:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:13][CH2:12]3)[N:15]=[CH:16][C:17]1=2)[CH3:29]
Reactant: CCBr
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
Added to 30 ml of THF were 0.65 g (1.84 mmol, Referential Example 51) of 2-(4-benzylpiperazino)-6-oxo-6,7,8,9-tetrahydro(5H)pyrimido[5,4-b]azepine and 0.15 g (3.75 mmol) of 60% NaH. The resultant mixture was stirred at 20° C. for 30 minutes. Thereafter, 3 g (27.8 mmol) of ethyl bromide was added and the reaction mixture was heated to 60° C. at which the reaction was conducted for 5 hours. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 0.65 g of a colorless oil (yield: 92%).