Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:23](Br)#[C:24][CH2:25]C>CC(C)=O>[CH2:1]([O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]#[CH:23])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C=Cc1ccc(O)cc1
Reactant: CCC#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=CC(=O)OCCCC)cc1
Temperature: 56 °C

Procedure:
903 g (4.1M) of p-hydroxy cinnamic acid n-butyl ester (see above) are dissolved in 4 liter acetone. 622 g (4.5M) of finely powdered potassium carbonate and 523.5 g (4.4M) freshly distilled butinyl bromide are added. Under stirring the suspension is heated to reflux (temperature in the mixture 56° C.). After refluxing for about 18 hours the starting material is consumed. The yellow suspension is cooled to about 10° C. and filtered. The filtrate is evaporated to dryness in vacuo (about 12 mbar) at 35° C. The yellow oily residue is added with stirring to about 6 liters of water. A white crystalline precipitate is obtained which is isolated by filtration. The solid material is washed with water and dried. It is crystallised from 1 liter of hexane. The product, 805.5 g, is obtained in colourless prisms, mp 38.5° to 39.0° C. From the mother liquor another 183.0 g of product could be isolated. Total yield 988.5 g (93.3% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:38])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:27][CH:26]=2)[C:12](=[O:23])[NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(O[C:50]1[C:55]([F:56])=[C:54]([F:57])[C:53]([F:58])=[C:52]([F:59])[C:51]=1[F:60])=O>CN(C=O)C>[F:56][C:55]1[C:50]([O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([NH:13][C:12]([N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:38])[NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[CH:27][CH:26]=3)=[O:23])[CH:15]=2)=[C:51]([F:60])[C:52]([F:59])=[C:53]([F:58])[C:54]=1[F:57]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)O)c2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}benzoic acid was added a solution of pyridine (500 μL) in DMF (5 mL) followed by pentafluorophenyl trifluoroacetate (850 μL). The mixture was shaken for 4 hours at 25° C., filtered and washed with DMF (2×10 mL), affording the resin bound title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C(#N)C>[C:13]1([C@@H:19]([NH:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C[C@H](N)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In another embodiment, the present invention may utilize ethyl 2-oxocyclohexane carboxylate (6) to prepare (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) as described in FIG. 4 by modification of methods of synthesis using an aprotic solvent to produce an amine [See Xu D et al., Tetrahedron Asymmetry, Vol. 8, No. 9, pp/1445-51, 1997]. The current embodiment may comprise reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of an aprotic solvent including, but not limited to, toluene and acetonitrile, to produce (S)-Ethyl 241-phenylethylamino)cyclohex-1-enecarboxylate (8). The ratio of compound (6) to compound (7) generally ranges from approximately 10:1 to approximately 1:10. In one embodiment, the ratio of compound (6) to compound (7) ranges from approximately 5:1 to approximately 1:5. In another embodiment, the ratio of compound (6) to compound (7) ranges from approximately 2:1 to approximately 1:2. In an additional embodiment, the ratio of compound (6) to compound (7) comprises approximately 1:1.05.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[CH:6][CH:5]=1.[CH3:32][C:33]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[CH:39]=[C:38]([CH3:48])[C:34]=1[C:35](O)=[O:36]>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]([CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:35](=[O:36])[C:34]2[C:38]([CH3:48])=[CH:39][C:40]([C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)=[CH:41][C:33]=2[CH3:32])[CH2:24][CH2:25]1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:31])=[CH:9][CH:8]=1)#[N:19]
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)O
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Product: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (100 mg, 0.24 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (59 mg, 0.26 mmol) followed by general procedure K with the resulting ester afforded 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a white solid (92 mg, 58% over 2 steps).
Reaction SMILES: [C@H:1]1([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5][C@H:4]([C:7]([O-])=[O:8])[CH2:3][CH2:2]1.O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][CH2:7][C@H:4]1[CH2:3][CH2:2][C@H:1]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](CO)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
The compound obtained in Reference Example 85(2) (mono-methyl trans-cyclohexane-1,4-dicarboxylate, 14.3 g) is dissolved in tetrahydrofuran (78 mL) and 1.0M boran-tetrahydrofuran complex solution in tetrahydrofuran (100 mL) is added dropwise thereto at −50° C. under argon gas atmosphere over a period of 1 hour. The mixture is stirred at −10° C. for 1 hour. To the reaction mixture is added water (160 mL) and a saturated sodium hydrogencarbonate solution (160 mL) under ice-cooling and the mixture is extracted with ethyl acetate (×4). The extract is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=20:1) to give methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (13.25 g, yield; quantitative) as an oil. MS (APCI) m/z; 173 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][O:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: COCOCCCON
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCCONc1nc(NC=O)nc(Cl)c1NC=O
Temperature: 100 °C

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.75 g, 7.4 mmol), 3-(methoxymethoxy)propoxyamine (1.0 g, 7.4 mmol) and N,N-diisopropylethylamine (2 g, 15.5 mmol) in dry diglyme was heated to 100° C. for 2 hr. The cooled reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate:hexane (50:50) then ethyl acetate to give the title compound as a yellow oil which was crystallised from ethyl acetate (1.2 g, 50%) mp 136°-8° C. νmax (KBr) 3240, 2920, 2880, 1705, 1640, 1590, 1565, 1495, 14650, 1410, and 1380 cm-1 ; δH [(CD3)2SO]1.85 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.24 (3H, s, OCH3), 3.58 (2H, t, J=6.3 Hz, CH2OCH2OCH3 ), 3.94 (2H, t, J=6.3 Hz, CH2ONH), 4.5 (2H, s, OCH2O), 8.15 (1H, s, NHCHO), 9.26 (1H, d, J=9.6 Hz, collapses to singlet on D2O, NHCHO), 9.4 (1H, s, D2O exchangeable NHOCH2), 10.73 (1H, s, D2O, exchangeable NHCHO), 10.84 (1H, d, J=9.6 Hz, D2O exchangeable, NHCHO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH3:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH:39]([CH3:43])[NH:38]1>>[CH:32]([N:29]1[CH2:28][CH2:27][CH:26]([NH:25][C:24]([C:13]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:38]4[CH:39]([CH3:43])[CH2:40][CH2:41][CH2:42][CH:37]4[CH3:36])=[O:22])[C:15]=3[N:14]=2)=[O:35])[CH2:31][CH2:30]1)([CH3:33])[CH3:34]
Reactant: CC1CCCC(C)N1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4C(C)CCCC4C)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2,6-dimethyl-piperidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 100 mg (0.20 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 50.0 μl (0.40 mmol) 2,6-dimethyl-piperidine. The title compound was obtained as its formiate in form of a white amorphous solid. Yield: 72 mg MS (ES+): m/e=594, chloro pattern.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(=CC#N)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:31]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]3)=[O:20])=[CH:14][CH:13]=2)[CH:18]=[C:10]1[C:8]([N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]1)=[O:9])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCc1ccccc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3Cc2ccccc2)CC1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
The suspension of 0.15 g (0.36 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 72 μL (76 mg, 0.72 mmol) benzylalcohol and 173 mg (0.72 mmol) (triphenylphosphoranylidene)acetonitrile in 2 mL toluene was stirred for 3 hours under reflux. The volatile components were evaporated at a rotary evaporator and the residue was purified using flash chromatography on silica gel with dichloromethane:methanol (19:1 v/v) as eluant to give 0.11 g (63%) of the desired compound as a light brown foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].Br[CH2:33][CH2:34][Cl:35].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:33][CH2:34][Cl:35])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])=[CH:19][CH:20]=1)#[N:2]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OCCCl
Temperature: 55 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (400 mg, 0.9166 mmol) was dissolved in dimethylformamide (5.0 ml), and then 1-bromo-2-chloroethane (0.12 ml, 1.4479 mmol) and potassium carbonate (200 mg, 1.4479 mmol) were added and the mixture was heated and stirred at 55° C. for 4 hours. After cooling, tetrahydrofuran and ethyl acetate were added, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in diethyl ether, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (331 mg, 0.6941 mmol, 75.72%) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][NH:36][CH3:37]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:36]([CH3:37])[CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CNC
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, Dimethyl-amine (98 mg, 1.2 mmol) DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 339 (61.4 mg, yield: 12%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.71 (m, 2H), 7.42-7.40 (m, 2H), 7.19 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.16-3.11 (m, 8H). ESI-MS: m/z=503 [M+H+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>CC(C)=O.O>[CH2:39]([O:38][C:36](=[O:37])[O:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][CH:8]([O:24][C:25](=[O:27])[NH2:26])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:13]2)=[CH:18][CH:19]=1)[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (0.93 mmol) prepared in Example 88 was dissolved in acetone (15 mL), and triethylamine (1.86 mmol) was added and ethyl chloroformate (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)(Cl)Cl>[NH2:9][C:10]1[S:11][C:12]([Br:1])=[C:13]([CH3:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N)sc(Br)c1C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
N-Bromosuccinimide (1.78 g) was added portion-wise to a solution of ethyl 2-amino-4-methylthiophene-3-carboxylate (1.71 g) in chloroform (25 ml) at 0° C. After 1 hour, the mixture was diluted with chloroform (20 ml) and washed with a mixture of brine and saturated aqueous sodium hydrogen carbonate (100 ml, 1:1). The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (1.32 g) as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([CH3:10])=[C:4]([Cl:11])[N:3]=1.C(O)C>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]([CH3:10])=[C:4]([Cl:11])[N:3]=1
Reactant: Cc1c(Cl)nc(Cl)nc1C=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(Cl)nc(Cl)nc1CO
Reaction time: 0.17 h

Procedure:
To a solution of 2,6-dichloro-5-methylpyrimidine-4-carbaldehyde (0.325 g, 1.70 mmol) in ethanol (10 mL) sodium borohydride (0.032 g, 0.85 mmol) was added at 0° C. The mixture was stirred for 10 minutes. Acetic acid (4 drops) was added and the volatiles were removed in vacuum. The residue was treated with 10% solution of methanol in chloroform (10 mL). The slurry was filtered through a pad of silica gel. The filtrate was concentrated and purified by column chromatography on silica using a gradient 0-4% of methanol in dichloromethane as eluent to yield the title product, 0.23 g (71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14]C)[CH:11]=[C:10]([I:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([I:16])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(I)cc(-c2cccc(F)c2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Product: Oc1cc(I)cc(-c2cccc(F)c2)c1
Yield: 97.9 %

Procedure:
A similar procedure as described in Example 12, step 6 was used, starting from 3′-fluoro-3-iodo-5-methoxy-biphenyl (1.1 g, 3.35 mmol), sodium iodide (5.024 g, 33.52 mmol), and trimethylsilyl chloride (2.12 mL, 16.76 mmol) to give 3′-fluoro-5-iodo-biphenyl-3-ol (1.03 g, 98%) as an amorphous light brown oil: ES(+)-HRMS m/e calculated for C12H8FIO (M+H)+ 314.9677, found 314.9676.
Reaction SMILES: [CH:1]1[C:22]2[CH2:21][C:20]3[C:7](=[CH:8][C:9]4[CH2:10][C:11]5[C:16]([C:17](=O)[C:18]=4[CH:19]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C2CC3C(=CC4C(=O)C5C(CC=4C=3)=CC=CC=5)C(=O)C=2C=CC=1>COCCOCCOC>[CH:4]1[C:5]2[C:22](=[CH:21][C:20]3[C:7]([CH:6]=2)=[CH:8][C:9]2[C:18](=[CH:17][C:16]4[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:19]=3)[CH:1]=[CH:2][CH:3]=1
Reactant: O=C1c2ccccc2Cc2cc3c(cc21)Cc1ccccc1C3=O
Agent: O=C1c2ccccc2Cc2cc3c(cc21)C(=O)c1ccccc1C3
Solvent: COCCOCCOC
Product: c1ccc2cc3cc4cc5ccccc5cc4cc3cc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 gram of 7,14-dihydropentacene-5,12-dione and pentacene-5,7(12H,14H)-dione, and 10 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 1.03 grams of sodium borohydride and stirring was continued at room temperature overnight. To the mixture was added 10 mL of 2-methoxyethyl ether and 6.3 mL of methanol and stirring was continued for 1.5 hours at room temperature. To the mixture was added 15 mL of acetic acid and 10 mL of concentrated hydrochloric acid. The mixture was stirred for one hour at room temperature and heated to 60° C. for one hour. To the mixture was added 50 mL of water, and the resulting solid was isolated by filtration and washed with water. The solid was washed with tetrahydrofuran until a pale filtrate resulted. The solid was washed with heptane and dried to give pentacene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[CH:13][C:14]=1[NH2:15])=[O:4].[Br:16]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[CH:12]=[C:13]([Br:16])[C:14]=1[NH2:15])=[O:4]
Reactant: COC(=O)c1c(N)ccc2ncccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c(Br)cc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.8 %

Procedure:
To a mixture of 6.6 g (32.6 mmol) of 6-amino-quinoline-5-carboxylic acid methyl ester, prepared as in step b in example 45, in 50 mL of N,N-dimethylformamide is added 5.80 g (17.78 mmol) of N-bromosuccinimide. The reaction is stirred at ambient temperature for 4 hours. The solvent is then evaporated and the residue is submitted to column chromatography purification on silica gel with ethyl acetate as eluent to afford 1.59 g (17%) of the product as a yellow solid; LC/MS:281/283 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([N:10]1[C:18]2[N:17]=[CH:16][NH:15][C:14]=2[C:13](=[O:19])[NH:12]/[C:11]/1=[N:20]\[NH2:21])[CH2:6][CH2:7][CH2:8][CH3:9].C([O-])(O)=O.[Na+]>Cl>[CH2:5]([N:10]1[C:18]2[N:17]=[CH:16][NH:15][C:14]=2[C:13](=[O:19])[N:12]2[N:1]=[N:21][N:20]=[C:11]12)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCn1c2nc[nH]c2c(=O)n2nnnc12
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A saturated aqueous NaNO2 (130 mg, 1.89 mmol) solution was added dropwise to a solution of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (150 mg, 0.63 mmol) in 5% aqueous HCl solution (3 ml) under stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was neutralized by saturated NaHCO3 solution and extracted by ethyl acetate (3×). The combined organic phases were washed by brine and dried over MgSO4. The filtration and evaporation of solvent gave the desired product (94.6 mg, 60.7%) as white solid. LCMS calculated for C10H14N7O (M+H): 248.1. found: 248.0.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Mg]Cl)(C)C.[CH2:15]([O:17][C:18](=[O:32])[C:19](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([CH:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH3:24]
Reactant: c1cc2cc[nH]c2cn1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.9 %

Procedure:
To a RT solution of 1H-pyrrolo[2,3-c]pyridine (595 mg, 5.04 mmol) in THF (20 mL) was added i-PrMgCl (1.5 M in THF, 5.0 mL, 7.6 mmol) followed by ZnCl2 (1M in Et2O, 7.6 mL). The resulting mixture was stirred at RT for 5 min then a solution of 2-benzylidene-malonic acid diethyl ester (2.2 mL, 10 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at RT for 1 hour, quenched by addition of a saturated solution of NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH), affording 2-[Phenyl-(1H-pyrrolo[2,3-c]pyridin-3-yl)-methyl]-malonic acid diethyl ester (0.33 g, 18% yield).