Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CCOCC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CNc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a solution of 4-bromo-3-chloro-aniline (0.64 g, 3.10 mmol) in ethanol (7 ml) were added sodium carbonate (0.49 g, 4.65 mmol) and ethyl bromoacetate (0.38 ml, 3.41 mmol). The resulting suspension was stirred at room temperature for 10 min and was then heated at 100° C. for 30 min under microwave irradiation. The mixture was then cooled to room temperature, diluted with ether, and filtered. The filtrate was washed with 1 M aqueous hydrochloric acid, the phases separated, and the aqueous phase extracted with ether. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=gradient 100:0-70:30) to yield a brown oil (0.56 g, 62%); MS (ISP): 296.1, 294.1, 292.1 ([M+H]+.).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([F:31])[C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)#[CH:33]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N:1]3[CH:33]=[C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[N:3]=[N:2]3)[C:29]([CH3:30])=[C:28]([F:31])[CH:27]=2)[CH:15]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C#Cc1cccnc1
Reactant: COc1c(NC(=O)c2cc(F)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2cc(F)c(C)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 21 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-5-fluoro-4-methyl-benzamide and 3-ethynyl-pyridine in the same manner as Example 15. ESI MS m/z 553 [C27H29FN6O4S+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CC(N=C=N[CH:12]([CH3:14])[CH3:13])C.[CH3:15]N(C=O)C>CN(C1C=CN=CC=1)C>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:14]([CH2:12][CH3:13])[CH3:15]
Reactant: NCC(=O)O
Reactant: CN(C)C=O
Reactant: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
The incorporation of the first amino acid, in this case glycine, implies the formation of an ester-type link between the handle and the Fmoc Gly derivative. For this kind of incorporation the resin is reacted with 4.1 g (5 equivalents) of Fmoc Gly in the presence of 168 mg (0.5 equivalents) of DMAP and 2.094 ml (5 equivalents) of DIPCDI in DMF for 90". Once the reaction is complete the resin is washed five times with DMF. An amino acid analysis or an acid hydrolysis of the resin gives the ratio of the Ile amino acid (internal standard) and the first amino acid Gly. In this way the real functionalization of the resin is known, normally varying between 0.35-0.69 mmol/g.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:23]=[C:24]([OH:26])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:37])[CH:15]([C:20]1[CH:21]=[C:22]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:36])[F:35])=[CH:31][CH:32]=2)[CH:23]=[C:24]([O:26][CH2:39][C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyl-3-[2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (18.77 g, 36.73 mmol) in acetonitrile (184 mL) at 0° C. was added 1-bromomethyl-3,5-difluoro-benzene (7.13 mL, 55.10 mmol) and Cs2CO3 (23.94 g, 73.46 mmol) in portions over 5 minutes. The resulting white suspension was stirred at room temperature for 2 h. The white solid was filtered off and the solvent was removed in vacuo to obtain relatively pure 4-benzyl-3-{2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[BrH:18]>CCOC(C)=O.[OH-].[Na+]>[Br:18][C:2]1[N:17]=[N:16][C:5]2[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Br
Reactant: O=C1Nc2ccccc2Nc2nnc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2Nc2nnc(Br)cc21
Temperature: 100 °C
Yield: 36 %

Procedure:
2-Chloro-5,10-dihydro-3,4,5,10-tetraaza-dibenzo[a,d]cyclohepten-11-one from Example 2 (400 mg, 1.62 mmol) was added to HBr (10 ml, 47% in water) and heated at 100° C. for 63 hours. The solution was cooled and diluted with EtOAc and NaOH (1M). The resultant precipitate was collected by filtration, washed with EtOAc and water and then dried under vacuum to give the title compound as a white solid (170 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[CH2:15]([O:17][P:18]([C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1)([O:20][CH2:21][CH3:22])=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CC#N>[OH:14][C:3]1[C:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:24]=[C:23]([P:18](=[O:19])([O:17][CH2:15][CH3:16])[O:20][CH2:21][CH3:22])[CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[C:5]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:4]=1
Reactant: Nc1cnc(-c2cccnn2)nc1O
Reactant: CCOP(=O)(OCC)c1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(OCC)c1cccc(CC(=O)Nc2cnc(-c3cccnn3)nc2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 5-amino-2-(pyridazin-3-yl)pyrimidin-4-ol, 35i-h, (0.5 g, 2.6 mmol), 2-(3-(diethoxyphosphoryl)phenyl)acetic acid, 35i-d, (0.7 g, 2.6 mmol), HATU (1.5 g, 3.9 mmol) and Et3N (1.2 g, 11.8 mmol) in MeCN (25 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum. The residue was extracted with EA (100 mL), and then washed with sat. NH4Cl (50 mL), water (50 mL), and brine (50 mL). The organic layer was concentrated and the residue was purified by column chromatography to afford the product, 35i, (280 mg, 25%). LC-MS (M+H)+ 444.1.
Reaction SMILES: [CH2:1](I)I.[Cl:4][C:5]1[C:17]([Cl:18])=[C:16]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[C:14]2[C:6]=1[C:7]1[C:12]([CH:26]=[CH2:27])([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:28])[CH:8]=1>O1CCCC1.C1(C)C=CC=CC=1.[Cu].[Zn]>[Cl:4][C:5]1[C:17]([Cl:18])=[C:16]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[C:14]2[C:6]=1[C:7]1[C:12]([CH:26]3[CH2:1][CH2:27]3)([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:28])[CH:8]=1
Reactant: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2
Reactant: ICI
Agent: [Cu]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(C1CC1)C2
Reaction time: 24 h

Procedure:
A mixture of the zinc-copper couple, prepared as described above, (48 gm.) and methylene iodide (37.5 gm.) in tetrahydrofuran (300 ml.) is heated under reflux in a nitrogen atmosphere for an hour. Ethyl [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetate (8.2 gm., 0.02 mole) is added to the cooled mixture and stirring continued at 25° C. for 24 hours. The mixture is diluted with toluene (200 ml.), filtered and the filtrate is washed successively with saturated aqueous solutions of ammonium chloride and sodium bicarbonate and then with water. The organic lager is dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator at reduced pressure. The residue is purified by column chromatography using a silica-gel column to give ethyl [(5,6-dichloro-9a-cyclopropyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]-acetate.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.N1(C(=O)C2N(C)C=NC=2N(C)C1=O)C.[C@@H:24]1([O:55]P(O)(O)=O)[C@@H:29]([O:30]P(O)(O)=O)[C@H:28]([O:35]P(O)(O)=O)[C@@H:27]([O:40]P(O)(O)=O)[C@@H:26]([O:45]P(O)(O)=O)[C@H:25]1[O:50]P(O)(O)=O.[C@H](O)([C@H](O)C(O)=O)[C@H](O)[C@@H](O)C(O)=O>>[O:55]=[C:24]1[O:40][C@H:27]([C@H:28]([CH2:29][OH:30])[OH:35])[C:26]([OH:45])=[C:25]1[OH:50]
Reactant: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Agent: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C(O)c1ccccc1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
0.5 to 10%, caffeine benzoate: 0.1 to 5%, phytic acid: 0.1 to 5%, mucic acid: 0.1 to 5%, hydrolysates of vegetable proteins: 0.1 to 10%, polyglucan: 0.1 to 5%
Reaction SMILES: [F:1][C:2]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CCO>[F:1][C:2]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:33][CH:34]([O:36][CH3:37])[CH2:35]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: COC1CN(c2ncc(N3CCN(c4cccc(CN5C(=O)c6ccccc6C5=O)c4F)CC3)cn2)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC1CN(c2ncc(N3CCN(c4cccc(CN)c4F)CC3)cn2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-(2-Fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl)-1H-isoindole-1,3(2H)-dione (135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (28% aqueous ammonia/MeOH/CHCl3) to obtain 1-(2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}phenyl)methan amine (100 mg).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11](F)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1NCC1CCCCC1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCN(c2cc(NCC3CCCCC3)c([N+](=O)[O-])cc2Nc2ccccc2)CC1
Yield: 78.7 %

Procedure:
A solution of N4-cyclohexylmethyl-2-fluoro-5-nitro-N1-phenyl-benzene-1,4-diamine (0.23 g, 0.66 mmol), N-methylpiperazine (0.22 mL, 1.97 mmol) and N,N′-diisopropylethylamine (0.34, 1.97 mmol) in DMF (3.0 mL) was stirred at 100° C. under an inert atmosphere for 16 h. The reaction mixture was transferred to a separatory funnel containing water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (5% MeOH/CH2Cl2) to give N4-cyclohexylmethyl-2-(4-methyl-piperazin-1-yl)-5-nitro-N1-phenyl-benzene-1,4-diamine as a red foam (0.22 g, 80.7% yield). M+, 424
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH2:10][C:11](=O)[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].O.[C:24]([OH:28])(=O)[CH:25]=O.O.[NH2:30][NH2:31]>C1COCC1.C(O)C>[CH3:22][C:2]([CH3:21])([CH3:1])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([C:10]3[CH:25]=[C:24]([OH:28])[N:30]=[N:31][C:11]=3[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: O=CC(=O)O
Reactant: NN
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC(=O)C2
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1nnc(O)cc1-2
Yield: 36.3 %

Procedure:
A solution of methyl 7-(2,2-dimethylpropionylamino)-3-oxochroman-8-carboxylate (Intermediate 10, 2.66 g) and glyoxylic acid monohydrate (0.802 g) in THF (6 mL) was heated in an open flask for 17 hours to give a viscous syrup which was diluted with ethanol (25 ml) and treated with hydrazine hydrate (0.471 g). The solution was stirred and heated at reflux for 45 minutes then cooled. The solid was collected by filtration to give methyl 7-(2,2-dimethylpropionylamino)-3-hydroxy-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (1.13 g) as a sandy coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:34])=[C:21]([O:32][CH3:33])[CH:22]=[C:23]([O:24][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4].[F-].[NH4+]>CO>[CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:34])=[C:21]([O:32][CH3:33])[CH:22]=[C:23]([OH:24])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OCCCC(=O)N1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCC(=O)N1

Procedure:
(R)-15-(tert-Butyl-dimethylsilanyloxy)-13-methoxy-12-methyl-6,11-dioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-15-hydroxy-13-methoxy-12-methyl-6,11-dioxo-3,4,5,6,7,8,9,11 -octahydro-1 H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][N:15]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=3[CH:4]=2)[C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[CH2:29][CH2:28]1
Reactant: O=CC1CC1
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC2CC2)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 43.4 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.085 g, 0.24 mmol) was reacted with cyclopropane carboxaldehyde (180 μL, 2.4 mmol) to give 0.042 g (43%) of the title compound as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:25])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.53) (0.21 g, 0.52 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.21 g, 0.62 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.15 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17]C4CCCNC4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H:42]4[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]4)C(F)=CN=3)=CNC2=NC=1.[CH2:49]([N:52]=[C:53]=[O:54])[CH2:50][CH3:51]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:43]4[CH2:42][CH2:47][CH2:46][CH2:45][N:44]4[C:53]([NH:52][CH2:49][CH2:50][CH3:51])=[O:54])[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC1CCCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCNC(=O)N1CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine, 5b, (0.020 g, 0.058 mmol) in 1:1 mixture of CH2Cl2/pyridine (2 mL) was added propylisocyanate (0.005 mL, 0.058 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 196.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.P(OCC)(OCC)(O[CH2:20][CH3:21])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:14]([CH2:20][CH3:21])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Br)cc1
Reactant: CCOP(=O)(OCC)OCC
Product: Brc1ccc2c(c1)[nH]c1ccccc12
Product: CCn1c2ccccc2c2ccc(Br)cc21
Reaction time: 5 h

Procedure:
17.93 g (64.47 mmol) of 4′-bromo-2-nitrobiphenyl and 56.09 mL (322.37 mmol) of triethyl phosphate were put into a round bottom flask under nitrogen, and then refluxed and agitated for 5 hours. After the reaction was finished, the solvent was removed by distillation, and the column was used at a ratio of hexane:MC=3:2 (v/v) to obtain 7.2 g of 2-bromo-9H-carbazole and 4.26 g of 2-bromo-9-ethyl-9H-carbazole.
Reaction SMILES: [NH2:1][C:2]1[C:9](Br)=[CH:8][C:5](C#N)=[CH:4][N:3]=1.[I-:11].[Na+].CN[C@@H]1CCCC[C@H]1[NH:21][CH3:22]>O1CCOCC1.[Cu]I>[I:11][C:9]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([N+:21]#[C-:22])[CH:8]=1
Reactant: N#Cc1cnc(N)c(Br)c1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: [C-]#[N+]c1cnc(N)c(I)c1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
The mixture of 6-amino-5-bromonicotinonitrile (3.315 g, 15.9 mmol, 1 eq), sodium iodide (4.77 g, 2 eq), copper(I) iodide (303 mg, 0.1 eq), and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.52 mL, 0.2 eq) in anhydrous dioxane (40 mL under nitrogen atmosphere was stirred at 120° C. for 20 hours. The mixture was cooled to room temperature then partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, further washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the crude solid residue was subject to a column chromatography started first with EtOAc-Hex (1:5 to 1:1) followed by MeOH—CHCl3 (1:100 to 1:20). Product containing fractions were all collected and concentrated. The solid residue was triturated with EtOAc-Hex (1:4) yielding 3-iodo-5-isocyanopyridin-2-amine as an off-white solid in the amount of 2.75 g upon filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:20][O:21][C:22](=[O:45])[C@@H:23]([NH2:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:21][C:22](=[O:45])[CH:23]([NH:44][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:29][CH:30]=1
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N1CC(C)CC(C)C1
Yield: 78.1 %

Procedure:
A solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g, 0.933 mmol) in DMF (4.0 mL) was reacted with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol), and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM (+20% hexane) to give 0.435 g (62%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050 g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 584 (M+1)+. 1H NMR (CDCl3) 11.20 [d, 1H], 8.21 [d, 1H], 7.45 [m, 2H], 7.39 [m, 2H], 7.23 [m, 8H], 7.02 [m, 2H], 6.86 [m, 2H], 4.90 [m, 1H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1H], 2.80 [m, 2H], 2.16 [t, 1H], 2.04 [t, 1H], 1.70 [m, 2H], 1.43 [m, 1H], 0.76 [m, 6H], 0.58 [m, 1H].
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][CH:33]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Oc3cccnc3)cc2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-2-oxo-5-[4-(pyridin-3-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (1.70 g, 3.02 mmol) in methanol (10 ml) was added a solution (7.26 ml, 3.63 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (1.39 g, 86%).