Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].[C:37](=[O:40])([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:8]1([C:5]2[C:4]([NH:14][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=4[F:28])[N:21]=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:19]=3[CH3:36])=[CH:3][C:2]([N:6]3[CH2:7][CH2:37][O:40][CH2:4][CH2:5]3)=[CH:7][N:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(Br)cnc1C1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-cyclohexenylpyridin-3-amine (0.19 g, 0.76 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.061 g, 1.53 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.26 g, 0.91 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 18 h, the incomplete reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as N-(2-(1-cyclohexen-1-yl)-5-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.72 (1H, d, J=3.9 Hz), 8.15 (3H, m), 7.89 (1H, d, J=7.8 Hz), 7.68 (1H, d, J=9.0 Hz), 7.53 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.46 (1H, m.), 7.01 (1H, s), 5.92 (1H, m.), 2.37 (1H, dd, J=3.5, 1.8 Hz), 2.16 (3H, s), 1.99 (2H, m), 1.63 (2H, m), 1.46 (2H, m.).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C@@H:11]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O1CCCC1>[CH:5]1([C@@H:11]2[C:12](=[O:14])[O:13][C:1](=[O:2])[N:15]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)CN[C@@H](C(=O)O)C1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)OC(=O)[C@H]1C1CCCCC1
Reaction time: 0.75 h
Yield: 95 %

Procedure:
Phosgene (28.9 kg, 291.9 mol) was added to (2R)-2-cyclohexyl-2-[(2-ethoxy-2-oxoethyl) amino]ethanoic acid (44.2 kg, 182 mol, obtained analogously to the method described in step (c) (Alternative A) above) in tetrahydrofuran (340 kg) at 40° C. over one hour. The reaction was deemed to be complete after a further hour. The mixture was concentrated at reduced pressure. The residue was diluted with tetrahydrofuran (272.6 kg) and the pH was adjusted at 0° C. to 6.5 with N-methylmorpholine (15.3 kg). The reaction was continued for a further 45 minutes. HCI/dioxane (0.34 kg) was then added and the residue was filtered through Celite®. The filter cake was washed twice with tetrahydrofuran. The combined filtrates were concentrated at reduced pressure at 20° C. To the residue was added heptane (250 kg), and the mixture was concentrated again. To the resultant residue further heptane (81 kg) was added. The temperature was adjusted to 0° C. and the mixture was allowed to crystallise for five hours. The crystals were filtered, washed (3×30 kg heptane) and dried (low pressure, 20° C.), to yield 46 kg (95%) of the sub-title compound.
Reaction SMILES: C([NH:3][C:4]1[CH2:5][CH2:6][C:7](NCC)=[C:8]2[C:17]=1C(=O)C1C(=CC=CC=1)C2=O)C.N[C:24]1([CH:46]=[CH:45][C:44](OC)=[CH:43][CH2:42]1)[NH:25][C:26]1[CH2:27][CH2:28][CH:29]=[C:30]2[C:39]=1[C:38](=[O:40])[C:37]1[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:31]2=[O:41]>>[NH:3]([C:29]1[CH2:28][CH2:27][C:26]([NH:25][C:24]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:39]2[C:30]=1[C:31](=[O:41])[C:32]1[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]2=[O:40])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:17]=1
Reactant: COC1=CCC(N)(NC2=C3C(=O)c4ccccc4C(=O)C3=CCC2)C=C1
Reactant: CCNC1=C2C(=O)c3ccccc3C(=O)C2=C(NCC)CC1
Product: O=C1C2=C(Nc3ccccc3)CCC(Nc3ccccc3)=C2C(=O)c2ccccc21

Procedure:
1,4-bis(ethylamino)-2,3-dihydroanthraquinone and leuco dyes bearing CI numbers 61100, 61105, 61107, 61116, 61120, 61140, 61500, 61505, 61510, 61515, 61520, 61525, 61530, 61535, 61540, 61545, 61565 and 61650 [for instance, 1-amino-4-methoxyanilino-2,3-dihydroanthraquinone and 1-p-(2-hydroxyethylamino)anilino-4-methylamino-2,3-dihydroanthraquinone].
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:7]2[N:8]([CH3:21])[C:9]([C@@H:12]([NH2:20])[CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:10][N:11]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C([O-])=[O:25].[CH3:29][C:30]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[CH:1]1([CH2:4][S:5]([C:7]2[N:8]([CH3:21])[C:9]([C@@H:12]([NH:20][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[N:38][C:30]=3[CH3:29])[CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:10][N:11]=2)(=[O:25])=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: O=C([O-])C(F)(F)F
Reactant: Cn1c([C@@H](N)CN2CCOCC2)nnc1S(=O)CC1CC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)N[C@@H](CN1CCOCC1)c1nnc(S(=O)(=O)CC2CC2)n1C

Procedure:
The title compound was prepared from (1S)-1-{5-[(cyclopropylmethyl)sulphinyl]-4-methyl-4H-1,2,4-triazol-3-yl}-2-morpholin-4-ylethanamine bis(trifluoroacetate and 2-methyl-6-(trifluoromethyl)nicotinoyl chloride using the conditions described in Example 65 steps f and g. 1H NMR (500 MHz, d6-DMSO) δ (ppm) 9.23 (1H, d, J=8.1 Hz), 7.99 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=7.9 Hz), 5.57-5.53 (1H, m), 3.94 (3H, s), 3.65-3.51 (6H, m), 3.07 (1H, dd, J=9.4, 12.7 Hz), 2.90 (1H, dd, J=5.7, 12.8 Hz), 2.62 (3H, s), 2.61-2.58 (2H, m), 2.51-2.46 (2H, m), 1.06-0.98 (1H, m), 0.56-0.48 (2H, m), 0.22-0.14 (2H, m); m/z (ES+) 517 (M+H).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[C@H:19]1([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:39])[CH:35]=3)[N:30]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[C@H:19]1([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:39][C:1]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[O:12])[CH:35]=3)[N:30]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1COCCN1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCOCC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, morpholine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=389.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH2:15]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:7])[CH2:3][C:4](=[O:5])[NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8]1
Reactant: CC(C)=CC(=O)O
Reactant: NC1CCCCC1N
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N[C@@H]2CCCC[C@H]2N1
Yield: 10.2 %

Procedure:
10.8 g β,β-dimethylacrylic acid was placed in a 250 ml flask, and 10 ml toluene was added followed by 11.4 g 1,2-diaminocyclohexane. The mixture is heated under an inert gas atmosphere, preferably argon, at 175°-180° C. with a Dean-Stark trap. 1.6 ml water was collected. The mixture is cooled down after 7 hr. Toluene was removed under vacuum. The reaction product obtained is recrystallized from acetone to give 2 g of a white crystalline product having a m.pt. of 188°-189° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 43.1 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (40 mg, 0.039 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (37 mg, 0.078 mmol) and cesium carbonate (952 mg, 2.92 mmol). 6-Bromo-4-(4-chloro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 16) (800 mg, 1.95 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.204 g, 2.33 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (350 mg, 43%). MS: m/z=417 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[N:15]([CH3:17])[CH3:16].[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[N:15]([CH3:17])[CH3:16])=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N(C)C)nc1Cl
Yield: 69.4 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl cis(±)-4-amino-3-(dimethylamino)piperidine-1-carboxylate obtained in Example (200c) (93 mg, 0.382 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (80.1 mg, 0.459 mmol), 1-hydroxybenzotriazole hydrate (77.5 mg, 0.573 mmol), WSC hydrochloride (110 mg, 0.573 mmol) and triethylamine (79.9 μL, 0.573 mmol), to obtain 106 mg of the title compound (69%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:27])=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1.[CH2:28]([N:30](CC)[CH2:31][CH3:32])[CH3:29].N1CCCC1>CN(C=O)C>[N:30]1([C:11]2[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:14])[C:2]=2[NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:27])=[CH:21][C:22](=[O:26])[O:23]3)=[CH:18][CH:17]=2)[CH2:31][CH2:32][CH2:29][CH2:28]1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Cc1cc(=O)oc2cc(NC3=C(N4CCCC4)C(=O)c4ccccc4C3=O)ccc12
Temperature: 100 °C
Yield: 13.1 %

Procedure:
2,3-dichloro-1,4-naphthoquinone (0.5 mmol, 114 mg) was dissolved in anhydrous DMF (1.5 mL) in a 5 mL vial. 7-Amino-4-methylcoumarin (0.5 mmol 88 mg) and triethylamine (0.5 mmol, 70 μL) were added. The solution was heated at 100°C. for 16 hr. Pyrrolidine (2 mmol, 0.17 mL) was added. The solution was heated at 100° C. for 16 hr. The excess volatile amines were removed under vacuum. The residue was dissolved in 3 mL acetonitrile containing 1% TFA. The crude product (1.0 mL) was purified with HPLC to give a dark purple solid (26.3 mg). 1H NMR (CDCl3): 8.09-7.98 (m, 2H), 7.64-7.55 (m, 2H), 7.45 (d, 1H, J=8.6 Hz), 6.74 (d, 1H, J=8.6 Hz), 6.31 (s, 1H), 6.09 (s, 1H), 3.63-3.54 (m, 4H), 2.36 (s, 3H), 1.78-1.69 (m, 4H) ppm.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].C(O)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26]Cl.[C:32](=[S:34])=[S:33]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][S:34][C:32]([N:2]1[C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:33]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)c(Cl)c1
Yield: 54 %

Procedure:
In the same manner as described in Example 16, (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (1.75 g), 70% ethanol (45 ml), carbon disulfide (0.88 ml) and 3,4-dichlorobenzyl chloride (3.52 g) are reacted and treated. The product is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=97:2:1) to give the title compound (3.63 g, 54%), as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:18]([NH2:19])=[N:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[CH2:25](N(CC)CC)C>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:18]([NH:19][S:21]([CH3:20])(=[O:23])=[O:22])=[N:17][C:12]2[N:13]=[C:14]([CH3:25])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN(CC)CC
Reactant: Nc1nc2ncncc2cc1-c1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCCl
Product: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(NS(C)(=O)=O)nc2n1
Temperature: 0 °C

Procedure:
A stirred suspension of 3.0 g of 6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-amine in 100 ml of dry 1,2-dichloroethane is cooled to 0° C. and treated with 1.2 g of methanesulfonyl chloride followed by dropwise addition of 1.0 g of triethylamine. Stirring is continued while the mixture is allowed to warm to room temperature during 4 hours. If the reaction is not complete as judged by thin layer chromatography on silica gel, the reaction mixture is cooled to 0° C. and treated with an additional 1.2 g of methanesulfonyl chloride followed by 1.0 g of triethylamine. The mixture is stirred overnight at room temperature, filtered from insoluble material and chromatographed on 150 g of silica gel to separate the crude product. Recrystallization from toluene gives pure N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-yl]methanesulfonamide, mp 212°-213° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[C:21](Br)[CH:20]=[C:19]([Cl:24])[C:18]=1[O:25][CH3:26].[F-].[Cs+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:20]=[C:19]([Cl:24])[C:18]=1[O:25][CH3:26])=[O:27]
Reactant: COC(=O)c1cc(Br)cc(Cl)c1OC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(Cl)c1OC
Temperature: 85 °C
Yield: 76.4 %

Procedure:
4-Trifluoromethylphenylboronic acid (0.815 g, 4.29 mmol) was added to a solution of 5-Bromo-3-chloro-2-methoxy-benzoic acid methyl ester (1.0 g, 3.57 mmol), Pd(PPh3)4 (0.2 g, 0.178 mmol) and CsF (1.08 g, 7.15 mmol) in DME (10 mL ) and heated at 85° C. for 10 h. The reaction was diluted with EtOAc (20 mL) and filtered, filtrate was washed water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the silicagel column chromatography gave pure 5-Chloro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.94 g).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:37])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:39][C:40]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:41][NH2:42]>>[CH3:28][O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:42][CH2:41][C:40]([F:47])([F:39])[C:43]([F:46])([F:45])[F:44])[CH3:14])=[O:37])[C:18]2[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=2[C:20]2[CH:32]=[CH:31][CH:30]=[CH:29][C:21]1=2
Reactant: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)OC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)OC(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using carbonic acid (S)-1-[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 5c. White solid (49%). MS: m/e=530(M+H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH3:24])[CH3:23].O>CN(C)C=O>[Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:22]([CH3:24])[CH3:23])=[CH:12][CH:13]=2)=[N:4][N:3]=1
Reactant: Oc1ccc(Oc2nnc(Br)s2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2nnc(Br)s2)cc1
Temperature: 85 °C
Yield: 99.3 %

Procedure:
A solution of Example 24B (1.4 g, 5.11 mmol) in N,N-dimethyl formamide (20 mL) was treated with K2CO3 (1.06 g, 7.66 mmol) and 2-iodopropane (5.1 mL, 51.1 mmol) and the reaction mixture was sealed in a screw-top pressure vessel and heated at 85° C. for 2 hours. The reaction was cooled to 25° C., poured into water (200 mL), and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (3×80 mL) and brine (80 mL), dried (Na2SO4), filtered and evaporated to provide 1.6 g of a light brown solid. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 14% ethyl acetate in hexanes to provide 0.8 g (50%) of the title compound as a clear colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.37 (d, J=9.19 Hz, 2H) 7.01 (d, J=9.19 Hz, 2H) 4.63 (heptet, J=5.88 Hz, 1H) 1.27 (d, J=5.88 Hz, 6H); MS (ESI) m/z 316.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Na].[CH3:23][OH:24]>>[C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]1[CH:21]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][N:11]=1)([O:24][CH3:23])=[O:20]
Reactant: CO
Reactant: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Agent: [Na]
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 2-(4-methoxyphenyl)pyrazolo[5,1-a]isoindol-8-one (100 mg), methanol (10 ml), and sodium (0.1 g). was stirred overnight at 25°. Evaporation of the methanol left 120 mg (96%) of colorless gum which was the ester 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole. The crude ester was dissolved in benzene and stirred overnight with 2 g of Florisil. Filtration and evaporation of the benzene solution, followed by recrystallization from hexane-ethyl acetate (1:1), gave 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, mp 92-93°.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:37]([NH:36][CH2:34][CH3:35])=[O:38])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, ethyl isocyanate (0.16 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCL (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3CN 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(ethylamino)carboxamide (0.2 g, 30%) as a white solid: mp 173–175° C.; 1H NMR (DMSO-d6) δ d 11.13 (s, 1H), 7.86–7.69 (m, 3H), 6.44 (t, J=6.1 Hz, 1H), 6.11 (t, J=5.55 Hz, 1H), 5.18–5.11 (dd, J=5.4 and 12.6 Hz, 1H), 4.63 (d, J=6.1 Hz, 2H), 3.07–2.83 (m, 3H), 2.64–2.49 (m, 2H), 2.08–2.04 (m, 1H), 0.99 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.73, 169.80, 167.58, 167.03, 157.93, 141.15, 134.61, 133.37, 131.49, 126.96, 121.61, 48.83, 38.71, 34.17, 30.92, 21.98, 15.58; Anal. Calcd. For C17H18N4O5+0.14 H2O: C, 56.58; H, 5.11; N, 15.53. Found: C, 56.56; H, 5.05; N, 15.28.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[F:24][C:25]([F:35])([F:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[CH3:16][CH:17]([CH3:23])[CH2:18][S:19]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH2:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)CC1

Procedure:
White crystalline solid. MS (ESI): 433.19 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and 4-(2,2,2-trifluoro-ethyl)-phenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Yield: 91.4 %

Procedure:
26.3 g (0.1 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 6.4 g (0.06 M) of sodium carbonate, 8 ml (0.123 M) of methyliodide and 200 ml of ethanol are mixed and heated for 4 hours in a water bath at 70°-75°. The ethanol is distilled off. The residue is washed with water and filtered. The sediment, after drying, is boiled with 180 ml of iso-propanol and then is filtered. From the filtrate 15.3 g (55.2% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-methylisothiourea with a melting point of 137°-141° are isolated.