Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Br:56]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:56][CH2:2][C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)=[O:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)c1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of Example 100 in THF (5 mL) was cooled to −78° C. and treated with diisopropylethyl amine (0.424 mL, 2.57 mmol) followed by trimethylsilyltriflate (0.421 mL, 2.177 mmol). The reaction was allowed to warm to rt over 30 min, then cooled again to −78° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (62 mg, 0.218 mmol). The reaction was allowed to stir for 1 h at −78 C, then warmed to rt and quenched with methanol (200 uL) and diluted with ethyl acetate and 1N sodium sulfite solution. The organic layer was separated, washed with 1 N bisulfate buffer (pH 2), dried with sodium sulfate and passed thru a silica plug. Evaporation of the solvent gave a yellow solid which was triturated with Et2O:hexanes (1:1) to provide the title compound as a yellow solid (154 mg, 70% Yield). 1H-NMR (DMSO-d6) δ 9.18 (s, 1H), 8.45 to 8.48 (m, 1H), 8.02 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.27 (s, 1H), 7.20 to 7.37 (m, 4H), 4.77 (s, 2H). MS [M+H]+=551.2; LCMS RT=3.63.
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].P(Cl)(Cl)([Cl:14])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:3][C:2]1[N:4]=[C:5]2[C:9]([NH:8][CH:7]=[N:6]2)=[C:10]([Cl:14])[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]cnc2n1
Reaction time: 1.17 h
Yield: 39 %

Procedure:
4.5 g (0.03 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.), 7.5 g (0.045 mol) of tetraethylammonium chloride and 27.1 g (0.177 mol) of phosphorus oxychloride were added to 60 ml of acetonitrile, followed by stirring for 70 minutes under heating refluxing conditions. After cooling, the crystal was collected by filtration and suspended in 50 ml of water. This suspension was made alkaline with a 30% aqueous solution of sodium hydroxide and then adjusted to a pH of 7 with 1N hydrochloric acid. The resulting crystal was collected by filtration and dissolved in 50 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure to yield 2.0 g (0.012 mol) of a precipitating crystal of 2-amino-6-chloropurine (yield 39%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH:9]([CH:12](Br)[C:13]([F:16])([F:15])[F:14])[C:10]#[N:11]>O1CCCC1>[Br:8]/[C:9](=[CH:12]\[C:13]([F:16])([F:15])[F:14])/[C:10]#[N:11]
Reactant: N#CC(Br)C(Br)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#C/C(Br)=C/C(F)(F)F
Reaction time: 1 h
Yield: 67.4 %

Procedure:
Triethylamine (317 g, 0.037 mol) is added dropwise to a solution of 2,3-dibromo-4,4,4-trifluorobutyronitrile (5.32 g, 0.023 mol) and tetrahydrofuran (100 mL). A voluminous white precipitate forms during the addition. Stirring is continued for 1 hour, then the solid is filtered off and washed with tetrahydrofuran. The tetrahydrofuran is distilled off to give a dark brown oil. Bulb to bulb distillation (15 mm, 24° C.) of the oil yields the title product as a clear colorless liquid (3.1 g, 82%). NMR spectral analyses identifies a 6:1 mixture of E:Z.
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.C1(=O)N(OC(N(C)C)=[N+](C)C)C(=O)CC1.C(N(CC)C(C)C)(C)C.[NH2:45][CH:46]([CH2:48][CH2:49][CH2:50][N:51]([CH2:54][CH3:55])[CH2:52][CH3:53])[CH3:47]>CN(C=O)C>[CH2:54]([N:51]([CH2:52][CH3:53])[CH2:50][CH2:49][CH2:48][CH:46]([NH:45][C:13](=[O:15])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:47])[CH3:55]
Reactant: O=C(O)CCN1CCCc2ccccc21
Reactant: CCN(CC)CCCC(C)N
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21

Procedure:
The procedure was carried out as described previously in step (b) of Example 8 with Compound 7 (1.9 g, 9.3 mmol), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (3.4 g, 11.2 mmol), N,N-diisopropyl ethylamine (3.4 mL, 19.5 mmol), 2-amino-5-diethylaminopentane (2.2 g, 13.9 mmol) and DMF (40 mL). Compound 10 was obtained (2.64 g) as a viscous liquid and used without any further purification. The structure of Compound 10 is given below:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](Cl)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[C:16]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)(=[O:18])[CH3:17]
Reactant: Brc1ccc2ccccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a cold (10° C.) mixture of 44.0 g (0.212 mol) of 2-bromonaphthalene and 34.0 g (0.255 mol) of aluminum chloride in 400 ml of nitrobenzene was added 21.0 g (267 mmol) of acetyl chloride. The mechanically stirred reaction mixture was warmed to room temperature, and heated to 40° C. for 18 hours. After cooling to 0° C. in an ice bath, the reaction was quenched by the addition of 12M HCl (70 ml). The layers were separated and the organic phase was washed with water and dilute aqueous Na2CO3. Kugelrohr distillation, followed by recrystallization from 10% EtOAc-hexane yielded 23 g of the title compound as a tan solid. 1H NMR (CDCl3): δ8.44 (1H, br s), 8.04-8.10 (2H, m), 7.85 (1H, d, J=8.5 Hz), 7.82 (1H, d, J=8.8 Hz), 7.64 (1H, d, J=8.8 Hz), 2.73 (3H, s).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1ccc2oc3ccccc3c2c1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc3oc4ccccc4c3c2)c1

Procedure:
Acid (18) (50 mg, 0.24 mmol) was coupled to aniline (2) (54 mg, 0.28 mmol) using Method D, except that DMF (1 mL) was used. The product was further purified by trituration in DCM/heptane to give the title compound. Yield: 46 mg, 51%; LC-MS tr 1.70 min; HPLC Purity: 97-100%; MS (ES+) m/z 386 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][C:38](=O)[CH3:39])[CH:33]=[CH:34][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:38]([CH3:39])[CH2:37][CH2:36][C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:41])[F:42])[CH:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42]([OH:44])=O)[N:38]=[N:37]1.[CH3:45][NH:46][C:47]1[CH:52]=[CH:51][N:50]=[N:49][CH:48]=1>CN(C=O)C>[CH3:32][O:33][CH2:34][CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42]([N:46]([CH3:45])[C:47]2[CH:52]=[CH:51][N:50]=[N:49][CH:48]=2)=[O:44])[N:38]=[N:37]1
Reactant: CNc1ccnnc1
Reactant: COCCn1nnc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCn1nnc(C(=O)N(C)c2ccnnc2)c1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphat (HATU; 1.23 g, 3.24 mmol, 3.00 eq) and N-methylmorpholine (0.71 ml, 0.66 g, 6.5 mmol, 6.0 eq) was added to a solution of 1-(2-methoxyethyl)-5-methyltriazole-4-carboxylic acid (200 mg, 1.08 mmol) and N-methylpyridazin-4-amine (118 mg, 1.08 mmol, 1.00 eq) in DMF (2.5 ml) and the mixture was stirred at room temperature for 4 d. After removal of the solvent, the residue was dissolved in dichloromethane, washed twice with sat. aq. NaHCO3 sol. and once with brine and dried over Na2SO4. Removal of the solvent under vacuum and chromatographic purification (CH:EtOAc) gave the title compound as a brown oil (200 mg, 64%, 95% purity).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:49])[CH2:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[S:36][CH:37]=[C:38]([CH2:40][O:41]C3CCCCO3)[N:39]=2)[CH:30]=1)(C)(C)C>C1(C)C=CC=CC=1>[OH:41][CH2:40][C:38]1[N:39]=[C:35]([C:31]2[CH:30]=[C:29]([C:28]3[CH2:27][C:26](=[O:49])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[S:36][CH:37]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (0.145 g) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert.-butyl ester (Example K19) (0.23 g) in toluene (2 mL) was heated to 100° C. for 5 h. The mixture was cooled and evaporated in vacuum. A solution of the residue in a mixture of CH2Cl2 (2 mL) and TFA (2 mL) was stirred for 0.5 h at 20° C. The mixture was evaporated in vacuum, the residual oil was dissolved in AcOEt and the solution was washed with saturated NaHCO3 solution and with brine, dried over Na2SO4 and evaporated in vacuum. The residue was crystallized from CH2Cl2/hexane to give the title compound (0.04 g) as light-brown crystals.
Reaction SMILES: CN(C)C(=O)C.[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([S:29](O)(=[O:31])=[O:30])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:8].P(Cl)(Cl)([Cl:37])=O>C(#N)C>[CH2:7]([N:9]([CH2:33][CH3:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:20]([S:29]([Cl:37])(=[O:31])=[O:30])[CH:19]=2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)c1ccc(N=Nc2ccc(OCCOC)c(S(=O)(=O)O)c2)cc1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CCN(CC)c1ccc(N=Nc2ccc(OCCOC)c(S(=O)(=O)Cl)c2)cc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
10 ml of N,N-dimethylacetoamide was added dropwise to a mixture of 13 g of N,N-diethyl-4-[4-(2-methoxyethoxy)-3-sulfophenylazo]-aniline prepared in Step (1) described above, 100 ml of acetonitrile and 13 ml of phosphorus oxychloride while the reaction mixture was maintained at a temperature of 30° C. or lower. After completion of the addition, the mixture was allowed to stand with stirring over a period of 3 hours and then, it was poured little by little into 500 ml of ice water. The crystals thus precipitated were recovered by filtration, washed with 200 ml of water and air-dried. Yield 11.0 g, Melting Point 103°-104° C.
Reaction SMILES: N1(C2SC(C(N)=O)=C(OCC3C=CC=CC=3C(F)(F)F)N=2)C2C=CC=CC=2N=C1.Cl[C:31]1[S:32][C:33]([C:48]([NH2:50])=[O:49])=[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:47])([F:46])[F:45])[N:35]=1.[CH3:51][C:52]1[C:60]([CH3:61])=[CH:59][C:55]2[N:56]=[CH:57][NH:58][C:54]=2[CH:53]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:51][C:52]1[C:60]([CH3:61])=[CH:59][C:55]2[N:56]([C:31]3[S:32][C:33]([C:48]([NH2:50])=[O:49])=[C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]([F:47])([F:46])[F:45])[N:35]=3)[CH:57]=[N:58][C:54]=2[CH:53]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Agent: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(-c3nc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cc1C

Procedure:
Following the procedure described above for the preparation of 2-(1H-benzimidazol-1-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide using the following materials: 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.050 g, 0.14 mmol), 5,6-dimethylbenzimidazole (0.012 g, 0.08 mmol), K2CO3(0.011 g, 0.08 mmol) and DMF (4 mL). The title compound was afforded by preparative HPLC. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.70-7.58 (m, 4H), 7.54-7.49 (m, 1H), 6.81 (bs, 1H), 5.82 (s, 2H), 5.60 (bs, 1H), 2.42 (s, 1H), 2.40 (s, 1H). MS m/z 447 (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:19][CH2:18]1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (420 mg, 1.48 mmol) was reacted with tert-butyl trans-4-aminocyclohexylcarbamate (642 mg, 3.00 mmol) to afford the desired product (550 mg, 80%) as an off-white solid: ESI MS m/z 462 [C22H28BrN3O3+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccc(Br)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Cc1ccc(Br)cc1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of (4-bromo-phenyl)-methanesulfonyl chloride (1.4 g, 5.2 mmol) in DCM (20 mL) at room temperature was added pyridine (1.26 mL, 15.6 mmol) followed by 3-chloroaniline (1.1 mL, 10.4 mmol) and the reaction was stirred at room temperature for 3 hours. 1 M aqueous HCl was added and then extracted with DCM, filtered through a separator, concentrated, dry loaded onto silica and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-methanesulfonamide (0.61 g, 1.68 mmol). 1H NMR (300 MHz, CDCl3): δ 7.49 (d, 2H), 7.26 (m, 1H), 7.13-7.15 (m, 4H), 6.96-6.98 (m, 1H), 6.31 (s, 1H), 4.31 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CO[2H]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#Cc1c(N)cccc1OCC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: [2H]OC
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohexylmethoxy)benzonitrile (Example 115b) and ethyl 3-oxobutanoate as a pale yellow solid (47%). 1H NR (400 MHz, MeOD) δ 1.12-1.37 (m, 6H), 1.42 (t, J=4.0 Hz, 3H), 1.73-2.01 (m, 5H), 2.68 (s, 3H), 4.06 (d, J=4.0 Hz, 2H), 4.42 (q, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H). MS 343 (MH+).
Reaction SMILES: [C-:1]1([C:6]([OH:8])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[C-:1]1([C:6]([Cl:23])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)[c-]1cccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ferrocene carboxylic acid (5.0 g, 21.7 mmol) was suspended in 40 mL of toluene containing a catalytic amount of DMF; oxalyl chloride (3.08 g, 24 mmol) was added dropwise (approx. addition time 30 min.). The resulting mixture was stirred at room temperature for 3 hours, filtered and the resulting solution used as such in Examples 3,4 and 5.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Intermediate (18b) (7.2 g, 15.5 mmol) was dissolved in pyridine (30 mL). Hydroxylamine hydrochloride (4.0 g, 57.9 mmol) was added followed by water (20 mL) and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched with water, extracted with 200 mL EtOAc, washed with 3×100 mL 1M phosphoric acid, 1×100 mL saturated sodium bicarbonate solution, and 2×100 mL saturated aqueous NaCl, then dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18c) as a white solid (7.4 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H30FN3O4, 480.23. found 480.4. 1H-NMR (DMSO-d6) 10.99 (1H, s), 8.21 (1H, s), 7.67 (1H, d), 7.54 (1H, m), 7.44 (1H, s), 7.34 (1H, m), 7.11 (2H, m), 6.81 (2H, m), 5.73 (1H, d), 5.36 (2H, s), 5.10 (1H, d), 1.66 (2H, m), 1.13 (9H, s), 0.85 (4H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21]Br)[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]([F:34])[C:25]=1[C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:20]=[C:19]([CH2:21][O:33][C:32]2[C:24]([F:23])=[C:25]([C:29]([F:34])=[CH:30][CH:31]=2)[C:26]([NH2:28])=[O:27])[S:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: Clc1ccc(-c2nsc(CBr)n2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3OCc3ccccc3)ns2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of 3-(2-(benzyloxy)-4-chlorophenyl)-5-(bromomethyl)-1,2,4-thiadiazole (0.33 g, 0.83 mmol) in DMF (10 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.13 g, 0.75 mmol) and potassium carbonate (0.403 g, 2.92 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 25 ml water and extracted with ethyl acetate (3×25 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 40% EtOAc-Hexane) to get the desired product (0.123 g, 30%).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cu](C#N)[C:25]#[N:26]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7](=[O:23])[C:6]3[C:5]4[C:13](=[CH:14][C:2]([C:25]#[N:26])=[CH:3][CH:4]=4)[NH:12][C:11]=3[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:17]=1
Reactant: N#C[Cu]C#N
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Br)ccc3c1C2=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 170 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml) and stirred at 170° C. for 17 hours. The reaction mixture was suspended in ethyl acetate (500 ml) and distilled water (200 ml). The insoluble matters were filtered off using Celite, and washed with ethyl acetate (300 ml×2). The organic layer was washed once with aqueous solution of disodium EDTA (200 ml) and twice with saturated brine (200 ml) in order, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resultant was suspended and washed with a small amount of CPME to give the title compound as a colorless crystal (6.58 g, 73%).
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.Cl[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][CH2:19][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])[CH3:16])=[CH:11][CH:10]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NEt3 (60 mL) followed by (S)-1-(4-chloro-phenyl)-ethylamine (20.5 g) was added to a solution of 3-chloro-1-phenyl-propan-1-one (23.2 g) in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature overnight. Then, the solution was concentrated, water (100 mL) was added to the residue, and the resulting mixture was extracted with tert-butyl methyl ether. The combined organic extracts were washed with water and brine and dried (MgSO4). The title compound was obtained after removal of the solvent.