Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:6]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[C:6]([Cl:14])=[C:7]([C:10]([F:13])([F:12])[F:11])[N:8]([CH2:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[O:24])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1[nH]nc(C(F)(F)F)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C(F)(F)F)c1Cl

Procedure:
Protocol T was followed using 5-tert-Butyl-4-chloro-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.22 (m, 2H), 6.84–6.92 (m, 2H), 5.3 (s, 2H), 3.68–3.8 (m, 2H), 3.6–3.68 (m, 2H), 3.04–3.2 (m, 4H), 1.4 (s, 9H). 13C NMR (400 MHz, CDCl3): 164.8, 119, 118.4, 118.2, 116.2, 116, 54, 51, 50.8, 45.4, 42.2, 30, 29, 27.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[CH3:31][C@@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[C@H:32]([CH3:31])[CH2:36][O:35][C:34]4=[O:37])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 39 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (184 mg) described in Preparation Example 127 and (R)-4-methyloxazolidin-2-one (47.8 mg) described in Preparation Example 25, the title compound (82.6 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[CH:15]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:15](/[CH:14]=[CH:13]/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][O:44][C:41]2[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=2)[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCBr)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(F)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 392 mg (0.72 mmol) of methyl 4-[(4E)-5-[2-(4-bromobutoxy)phenyl]-3-(4-cyanobenzyl)pent-4-en-1-yl]benzoate in 10 ml of dry acetonitrile is mixed with 120 mg (1.08 mmol) of 4-fluorophenol and 148 mg (1.08 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is subsequently filtered, and the filtrate is evaporated to dryness. 445 mg (0.71 mmol, purity 93%, 99% of theory) of a yellowish oil are isolated.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:26]([C:20]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])(=[O:28])=[O:27])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Nc1ccc2[nH]nc(N)c2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1n[nH]c2ccc(NS(=O)(=O)c3c(F)cccc3F)cc12
Yield: 8.4 %

Procedure:
N-(3-Amino-1H-indazol-5-yl)-2,6-difluorobenzenesulfonamide can be obtained as described in Example 39 from 1 g of 3,5-diamino-1H-indazole, 10 ml of pyridine, 10 ml of tetrahydrofuran and 1.4 g of 2,6-difluorobenzenesulfonyl chloride. 179 mg of N-(3-amino-1H-indazol-5-yl)-2,6-difluorobenzenesulfonamide are thus obtained in the form of a gray solid melting at 241° C. (analysis C13H10F2N4O2S % calculated C, 48.15; H, 3.11; F, 11.72; N, 17.28; O, 9.87; S, 9.89. % found C, 47.81; H, 3.18; F, 11.64; N, 17.00; S, 9.67).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(-c2ccccc2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(-c2ccccc2)c(F)c1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
2-Fluoro-biphenyl-4-carbaldehyde (1 gm, 5 mmole), NaBH4 were dissolved in ethanol stirred for 2 hrs, NaOH 10% was added, ethanol was evaporated, the reaction mixture was extracted with ethyl acetate, the ethyl acetate extract was dried with Na2SO4 and evaporated to produce white solid (0.8 gm, 80%). H1-NMR INOVA-500 (CDCl3) δ 2.266 (s, 1H), 4.683 (s, 2H), 7.142-7.168 (m, 2H), 7.339-7.442 (m, 4H), 7.519-7.535 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:20]=[C:19]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:32]=3[N:31]=[C:30]2[CH:40]([F:42])[F:41])[N:18]=1.N>C1COCC1.O.C(O)(=O)C>[F:42][CH:40]([F:41])[C:30]1[N:29]([C:19]2[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=[C:17]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:18]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:32]=2[N:31]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: N
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Yield: 72.6 %

Procedure:
To a solution of 3-aminopyridine (1.88 g, 20 mmol) in 100 mL THF was added LDA (10 mL, 2 M in THF; 20 mmol) and to the resulting suspension was added 1.99 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole at room temperature. After 5 min. the reaction was neutralized with acetic acid and diluted with water. After the pH was made slightly alkaline with aq. NH3, the precipitate was collected, washed with hot water, and dried. Recrystallization from EtOH (using CH2Cl2 to aid initial solubility) gave 1.65 g (73% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp 221-223° C.; 1H NMR (CDCl3) δ 8.86 (br, 1H), 8.42 (d, J=2.0 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.48 (br t, JHF=53.6 Hz, 1H), 7.35-7.31 (m, 2H), 7.22 (m, exchangeable with D2O, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.04 (s, 3H), 3.92 (m, 4H), 3.81 (m, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.4%.
Reaction SMILES: C(OC(OCC)C1C=C(C2C(C3C=CC=CC=3)C(=O)C3C(C(OC)=O)=CC=CC=3N2)C=CC=1)C.[CH2:35]([O:37][CH:38]([O:67][CH2:68][CH3:69])[C:39]1[CH:40]=[C:41]([CH:45]2[CH:54]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:53](=O)[C:52]3[C:51]([C:62]([O:64]CC)=O)=[CH:50][CH:49]=[CH:48][C:47]=3[NH:46]2)[CH:42]=[CH:43][CH:44]=1)[CH3:36].O.[NH2:71][NH2:72]>CO>[CH2:68]([O:67][CH:38]([O:37][CH2:35][CH3:36])[C:39]1[CH:40]=[C:41]([CH:45]2[NH:46][C:47]3[C:52]4[C:53](=[N:71][NH:72][C:62](=[O:64])[C:51]=4[CH:50]=[CH:49][CH:48]=3)[CH:54]2[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:42]=[CH:43][CH:44]=1)[CH3:69]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1cccc(C(OCC)OCC)c1)N2
Reactant: NN
Agent: CCOC(OCC)c1cccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccccc2)c1
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of methyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2-(3-(diethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (160 mg, 0.36 mmol) in 85% hydrazine monohydrate (4 mL) and methanol (3 mL) was stirred at 25° C. for overnight. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the 8-(3-(diethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, yield 58%) as a yellow solid. LC-MS (ESI) m/z: 442(M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C

Procedure:
The solution of 32.7 g of 2-methyl-5-hydroxy-pyridine in 300 ml of dimethylformamide is added to a suspension of 12.8 g of sodium hydride (57% mineral oil dispersion) in 150 ml of dimethylformamide, with stirring. Then the mixture is heated to 100° and maintained at 100° for 18 hours. After that, the mixture is cooled to room temperature and to the cooled mixture is added a solution of 49.8 g of benzyl chloride in 100 ml of dimethylformamide over a period of 30 minutes. The mixture is then refluxed for 7 hours, cooled and then evaporated to a residue. The residue is partitioned between water and ether, the layers are separated and the water layer extracted with ether. The ether layer is combined with ether extract, dried over sodium sulfate, filtered and the ethereal filtrate is distilled off. The residue is distilled to yield 5-benzyloxy-2-methyl-pyridine, boiling at 100°-102°/0.02 mm/Hg.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]([F:41])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:36]([F:41])=[CH:37][CH:38]=[C:39]([CH3:40])[C:32]=3[Cl:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Cc1ccc(F)c(CBr)c1Cl
Product: Cc1ccc(F)c(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)c1Cl

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-chloro-6-fluoro-3-methylbenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.40 (m, 1 H), 7.26-7.17 (m, 2 H), 7.02-6.88 (m, 3 H), 6.20-6.12 (m, 1 H), 5.73-5.66 (m, 1 H), 5.66-5.55 (m, 2 H), 4.30-4.24 (m, 2 H), 2.92-2.78 (m, 2 H), 2.74 (s, 3 H), 2.38 (s, 3 H), 2.12-2.06 (m, 2 H), 1.01-0.92 (s, 9 H); LC/MS (m/z) ES+=551.36 (M+1).
Reaction SMILES: [Mg].C1C[O:5][CH2:4]C1.Br[C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CN(C=O)C>[CH2:23]([CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:4]=[O:5])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C1CCOC1
Reactant: CCCCCCCCC(CCCCCC)Cc1ccsc1Br
Agent: Cl
Agent: [Mg]
Solvent: CN(C)C=O
Product: CCCCCCCCC(CCCCCC)Cc1ccsc1C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Magnesium (345 mg, 14.2 mmol) was added to a flask and put under a nitrogen atmosphere after sufficient deaeration. THF (10 ml) was added, and 2-bromo-3-(2-hexyldecyl)thiophene (A2) (5 g, 12.9 mmol) was dropped while refluxing THF. After the dropping, refluxing was similarly performed for three hours. THF (40 ml) was then added, and the flask was cooled to 0° C. DMF (10 ml) was dropped, and the temperature was increased to room temperature. The mixture was then stirred overnight. To the reaction solution, 1N hydrochloric acid (20 ml) was added, followed by extraction with chloroform. An organic layer was then washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and chloroform was used as a mobile phase, 3-(2-hexyldecyl)-2thiophenaldehyde (A3) was obtained as clear oil (3.0 g, 69% yield). The product (A3) obtained was identified using a 1H-NMR method. 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.03 (s, 1 H), 7.64 (d, J=4.9 Hz, 1 H), 6.97 (d, J=4.9 Hz, 1 H), 2.88 (d, J=7.3 Hz, 2 H), 1.25 (m, 25 H), 0.88 (m, 6 H)
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>C1COCC1>[F:8][C:9]([F:16])([F:15])[C:10]([N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4])=[O:11]
Reactant: OC[C@@H]1CCCN1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(N1CCC[C@H]1CO)C(F)(F)F
Reaction time: 12 h
Yield: 97 %

Procedure:
L-prolinol (2.0 g, 20 mmol) was dissolved in 20 ml of THF. On the other hand, ethyl trifluoroacetate (3.0 g, 21 mmol) was dissolved in 20 ml of THF. Then, the latter THF solution was instilled in the former THF solution containing the L-prolinol, and this was stirred for 12 hours. This reaction solution was vacuum concentrated. Thus, Compound 1 was obtained (3.7 g, yield: 97%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27](=[O:32])[CH2:26]5)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O>C(O)C.N1CCCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27](=[O:32])[C:26]5=[CH:40][C:36]4[NH:35][CH:39]=[CH:38][CH:37]=4)[CH:17]=3)=[O:14])=[CH:33][CH:34]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)C(=Cc4ccc[nH]4)C(=O)N5)c3)cc2)CC1

Procedure:
To a solution of 4-(4-methyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-phenyl]-benzamide (23 mg, 0.05 mmol) in ethanol (2 ml) is added 1H-pyrrole-2-carbaldehyde (16 mg, 0.17 mmol) and 2 drops of piperidine. The reaction is refluxed for 12 hours and then concentrated. The desired compound after HPLC purification: 1H NMR (DMSO-d6) δ 2.44-2.52 (m, 2H), 2.79 (s, 3H), 2.98-3.10 (m, 2H), 3.18-3.22 (m, 2H), 3.38-3.42 (m, 2H), 3.77 (s, 2H), 6.32-6.36 (m, 1H), 6.61-6.69 (m, 111), 6.81-6.82 (m, 2H), 6.92 (dd, 1H, J=8.8 Hz, J2=1.6 Hz), 7.12-7.18, (m, 2H), 7.34 (s, 1H), 7.46 (dd, 2H, J=4.8 Hz, J2=1.6 Hz), 7.48 (s, 2H), 7.69 (s, 1H), 7.93 (d, 2H, J=8.0 Hz), 8.01 (s, 1H), 10.09 (s, 1H), 10.78 (s, 1H), 13.39 (s, 1H); LC-MS: 533.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([Cl:24])=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 0 °C

Procedure:
A suspension of 3-(4-bromophenylsulfonamido)benzoic acid (2.30 g, 6.46 mmol) in DCM (50 mL) was stirred and cooled under argon to 0° C. Oxalyl chloride (676 μL, 7.11 mmol) was then added dropwise via a syringe, followed by DMF (50 μL). The resulting solution was then stirred overnight, allowing the reaction mixture to warm room temperature. The solution was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: CC(Br)C(=O)N(C)C
Reactant: Oc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(Oc1cc(Cl)ccc1Br)C(=O)N(C)C
Reaction time: 8 h

Procedure:
2-Bromo-5-chlorophenol (8 g), 2-bromo-N,N-dimethylpropionamide (6.66 g) and anhydrous potassium carbonate (2.6 g) in methyl iso-butyl ketone (100 ml) were refluxed with stirring overnight. The mixture was cooled to 50° and washed with 5% sodium hydroxide (2×20 ml) and then water (2×50 ml). The organic solution was dried and evaporated under reduced pressure to yield a pale red oil, which solidified on cooling. Recrystallisation from 50% aqueous ethanol gave the title compound, m.p. 76°-77°. Compounds 2, 9, 10 to 13, 17 and 21 were made by a similar procedure.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[F:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1>C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][NH:15][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[N:12][CH:13]=1
Reactant: CC(C)N=C=O
Reactant: NNc1ccc(F)cn1
Solvent: ClCCl
Product: CC(C)NC(=O)NNc1ccc(F)cn1
Yield: 93 %

Procedure:
Isopropyl isocyanate (0.25 mL, 2.60 mmol) was added dropwise, over 2 min, to a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) in dry DCM (10 mL) at RT and stirred for 3 h. The solvent was evaporated and the residue triturated (diethyl ether) and filtered to give the title compound as a colourless solid (464 mg, 93%). LCMS (Method 1): Rt 1.92 min, m/z 213 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16]C)=[N:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccc(OC)nc1)c1cccc(Br)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(c1ccc(=O)[nH]c1)c1cccc(Br)c1
Temperature: 125 °C

Procedure:
A sealed tube was charged with 5-[1-(3-bromo-phenyl)-vinyl]-2-methoxy-pyridine (600 mg) and pyridinium hydrochloride (3 g) freshly prepared. The tube was heated at 125° C. for 10 minutes, then the mixture was allowed to cool to room temperature. The crude was dissolved in dichloromethane (15 ml), the solution washed with hydrochloric acid (1N) (2×15 ml), dried over sodium sulphate and evaporated. The crude product was purified by flash chromatography eluting with cyclohexane/ethyl acetate. The 5-[1-(3-bromo-phenyl)-vinyl]-1H-pyridin-2-one was obtained as a colorless oil (366 mg, 64% of theory). MS (ISP): m/z=278 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[C:16]([CH3:32])=[C:17]([NH:21]C(=O)OCC5C=CC=CC=5)[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:12]=[C:11]([C:33](=[O:35])[NH2:34])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.I[Si](C)(C)C.C(OCC)(=O)C.CCCCCC>C(#N)C>[NH2:21][C:17]1[C:16]([CH3:32])=[C:15]([C:14]2[C:6]3[C:5]4[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[NH:8][C:7]=3[C:11]([C:33]([NH2:34])=[O:35])=[N:12][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(Br)ccc3c12
Agent: C[Si](C)(C)I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a solution of benzyl 3-(7-bromo-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.65 g, crude from the previous step) in acetonitrile (80 mL) at 0° C. was added iodotrimethylsilane (0.67 mL, 4.91 mmol) dropwise. The mixture was stirred at room temperature for 1.5 hr, and then concentrated under vacuum. To the residue was added diethylamine (2 mL) and ethyl acetate (150 ml). The mixture was washed with water (2×40 mL) and brine (40 mL), and dried over anhydrous MgSO4. The desired product (0.243 g, 52.6% yield over two steps) was isolated as a beige solid by ISCO (40 g silica gel, solid loading, 40-70% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-:29].[Na+].OO>C(O)C>[O:29]1[C@H:19]2[C:18](=[O:28])[CH:17]=[C:16]3[C@:21]([CH3:22])([C@@H:20]12)[C@@H:23]1[C@H:13]([C@H:12]2[C@:26]([CH3:27])([CH2:25][CH2:24]1)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH2:11]2)[CH:14]=[CH:15]3
Reactant: [OH-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
The trienone from (a) (1 gm) in ethanol (50 mls) at 0° was treated with 10% aqueous sodium hydroxide (0.25 ml) and 30% aqueous H2O2 (2.5 ml). The mixture was stored at 5° overnight and then the resulting epoxide was filtered off, washed with aqueous alcohol and dried to afford the title compound (0.86 mgs). Recrystallization from ethanol gave colourless needles, melting point 107°-109°.
Reaction SMILES: [O-2].[Mg+2:2].[N+:3]([O-:6])([OH:5])=[O:4]>>[N+:3]([O-:6])([O-:5])=[O:4].[Mg+2:2].[N+:3]([O-:6])([O-:5])=[O:4]
Reactant: O=[N+]([O-])O
Agent: [Mg+2]
Agent: [O-2]
Product: O=[N+]([O-])[O-]

Procedure:
This Example was performed according to the procedure of Example 1, except that 19 parts by weight of magnesium oxide dissolved in nitric acid to produce magnesium nitrate was added to the paragraph A solution of Example 1. All other operations were the same as for Example 1. The several samples denoted 6-1 to 6-5, inclusive, were given the corresponding treatments for samples 1-1 to 1-5, respectively.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](Br)([CH3:13])([CH3:12])[CH3:11]>[OH-].[K+]>[C:10]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C1=Cc2ccccc2C1
Reactant: CC(C)(C)Br
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)C1C=Cc2ccccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
42.0 g of indene (technical grade, 94 % by GC, 39.5 g, 340 mmol), 50 % w aqueous KOH (308 g in 308 nL) and 15.8 g of Adogen (Aldrich, 34 mnuol) dissolved in 139.7 g of tert-butylbromide (1019.6 mmol) were introduced in this order, at room temperature, in a 1 L, jacketed glass reactor with mechanical stirrer (Buïchi). The organic phase turns green. The mixture is heated to 60° C. and vigorously stirred for two hours (a pressure build-up to 2.5 bar-g is observed) and then cooled to room temperature. Total reaction time is 3 h. The organic phase is extracted with technical hexane (3×200mL) and analyzed by GC. Conversion: 74.5% w of 3-tert-butyl-indene and 1.8% of 1-tert-butyl-indene, unreacted indene 13.7% w. The solution was evaporated under reduced pressure (rotovac) and the resulting dark brown viscous liquid was distilled at 1 mmHg, collecting the fraction boiling between 70 and 80° C. (40 g, 76.8% of 3-tert-butyl-indene and 19.5% of 1-tert-butyl-indene, no indene).