Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH3:3].[K].ClC1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)C=O>C(OCC)C>[CH3:1][S:2][C:3]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CSC
Reactant: CCOC(=O)c1ccc(Cl)cc1C(=O)OCC
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC)cc1C(=O)OCC

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH2:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:14][C:13]1[C:8]([CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[CH2:3][C:2]([NH2:1])=[O:39])=[N:9][C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:11][CH:12]=1
Reactant: Cc1cnc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cnc(Nc2ccc(N3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.1 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (A10) (28 mg, 0.053 mmol) in DCM (8 mL) was added TFA (2 mL) and the resulting solution was stirred at 25° C. for 24 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and 2 M NaOH (20 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic layers washed with brine (10 mL) and dried (MgSO4). The solvent was removed in vacuo to give a brown solid which was taken up in MeOH and purified by SCX cartridge (5 g, MeOH followed by 0.5 M NH3 in MeOH). The volatiles from the ammoniacal filtrate were removed in vacuo and the resulting solid residue suspended in cyclohexane and sonicated. The resulting suspension was filtered and the filter cake dried to give the title compound 2 as a light brown solid (8 mg, 35%); 1H NMR (400 MHz, d6-DMSO) δ 9.08 (s, 1H), 8.11 (s, 1H), 7.60 (dd, J=9.2, 2.2 Hz, 2H), 7.41 (s, 1H), 7.26-7.20 (m, 1H), 7.19-7.13 (m, 3H), 6.92 (s, 1H), 6.85 (d, J=9.1 Hz, 2H), 4.02 (s, 1H), 3.50 (s, 2H), 3.03 (dd, J=10.1, 5.7 Hz, 2H), 2.97 (m, 2H), 2.85 (m, 4H), 2.69-2.64 (m, 2H), 2.36-2.30 (m, 2H), 2.05 (s, 3H). LCMS-A: rt 4.364 min; m/z 431.1 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]1=O)[CH3:4].[CH3:26][NH:27][NH2:28]>CO>[ClH:1].[CH3:2][N:3]([CH3:4])[CH2:5][C:6]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:8]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:27]([CH3:26])[N:28]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CNN
Reactant: CN(C)CC1(c2ccccc2)CCCC(=Cc2ccccc2)C1=O
Agent: Cl
Solvent: CO
Product: CN(C)CC1(c2ccccc2)CCCC2C1=NN(C)C2c1ccccc1
Yield: 36.4 %

Procedure:
A solution of 10.7 g of 2-[(dimethylamino)methyl]-2-phenyl-6-(phenylmethylene)cyclohexanone, monohydrochloride in 70 ml of methanol is treated with 1.5 g of methylhydrazine and the resulting solution is refluxed for 4 hours. The solution is cooled and the solvent is removed on a rotary evaporator to give 13.7 g of a semi-crystalline solid residue, which is crystallized from 30 ml of isopropanol to give 4.2 g of the title compound, melting point 225°-227° C (dec.). An additional 0.77 g of product is recovered from the filtrate giving a total yield of 4.97 g of the title compound, melting point 225°-227° C. Recrystallization of 5.6 g of this material from 100 ml of isopropanol gives 4.8 g of product, melting point 225°-227° C (dec.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone and 2-bromo-5-cyanopyridine. MS (ESI) 415 (M+H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:29])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@H:9]([CH3:29])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OC[C@@H](C)N)cc2)cc1

Procedure:
Ethyl 4′-[(R)-2-(tert-butoxycarbonylamino)propyloxy]biphenyl-4-carboxylate was dissolved in ethanol (30 mL), and a 48% solution of hydrogen chloride in ethanol (5 mL) was added dropwise to the solution at room temperature with stirring. After being stirred at that temperature for 5 hrs, the reaction mixture was concentrated in vacuo. The residue was purified by aminopropyl silica gel flash column chromatography (eluent: methylene chloride/ethyl acetate=1/1 and methylene chloride/methanol=10/1) to afford the title compound (0.484 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14][CH2:13]1>C(#N)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: C1CCN(CCC2CCNCC2)CC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCC(CCN2CCCCC2)CC1
Temperature: 175 °C
Yield: 90 %

Procedure:
A mixture of 0.576 g (3.00 mmol) of 2,5-dichloronitrobezene and 0.589 g (3.00 mmol) of 1-(2-piperidin-4-yl-ethyl)-piperidine in acetonitrile (5 mL) are heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and concentrated under reduced pressure to provide 0.95 g (90% yield) of 1-(4-chloro-2-nitro-phenyl)-4-(2-piperidin-1-yl-ethyl)-piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1)=[O:37])([O-:33])=[O:32]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647 μmol) in dichloromethane (15 mL) was added triethylamine (200 μL, 1.43 μmol) and 2-nitrobenzoyl chloride (190 μL, 1.43 mmol). The solution was stirred at room temperature for 96 hours, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.12 min, MH+ 459].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ccc2Cl)c(F)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (3.2 g, 0.02 mol), 2,5-dichlorophenol (3.59 g, 0.022 mol), and potassium carbonate (3.0 g, 0.022 mol) in 25 ml of anhydrous DMF was heated to 150° C. with stirring overnight. After cooling to room temperature, the reaction mixture was poured into 500 ml of ice water and stirred for 30 min. The precipitates were collected by filtration, washed with water, and dried in vacuo to give 5.72 g (94.7%) of crude product.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=1.Cl[C:24]1[N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH:27]=[C:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[N:25]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[C:26]1[N:25]=[C:24]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:18]=[C:17]([NH2:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[N:29]2[CH:30]=[CH:31][N:32]=[C:28]2[CH:27]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: NCCCNc1ccc([N+](=O)[O-])c(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
104 mg (0.32 mmol) of the amine (Example 57A) are introduced into 3 ml of isopropanol, 73.6 mg (0.25 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine and 95.6 mg (0.74 mmol) of DIPEA are added, and the mixture is heated in a microwave at 150° C. for 2 h. Purification by preparative HPLC results in 96 mg (82% of theory) of the product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)[CH:11]=3)=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:38]([O-])=[O:39])C=1.[CH:41]1([CH:44]([OH:46])[CH3:45])[CH2:43][CH2:42]1>N1C=CC=CC=1.O.C(Cl)Cl>[CH:41]1([CH:44]([O:46][C:38](=[O:39])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:25]4[CH2:27][CH2:26]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)[CH:11]=4)=[CH:4][CH:3]=2)[CH3:45])[CH2:43][CH2:42]1
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CC2)c2cc(OC3CCCO3)ccc12
Reactant: CC(O)C1CC1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC4CCCO4)cc3n2C2CC2)cc1)C1CC1
Temperature: 35 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(4-aminophenyl)-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indole-3-carbonitrile (36 mg, 0.1 mmol), 4-nitrophenylchloroformate (50 mg, 0.25 mmol) in pyridine (2.0 mL) is stirred at 35° C. for 2 h, followed by the addition of 1-cyclopropylethanol (98 μL, 1.0 mmol). The mixture is then stirred at 60° C. overnight and diluted with water (10 mL) and DCM (5 mL). The organic is washed with water (3×5 mL), HCl (2N, 3×5 mL), saturated NaHCO3 (3×5 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the title compound, {4-[3-cyano-1-cyclopropyl-6-(tetrahydrofuran-2-yloxy)indol-2-yl]phenyl}carbamic acid 1-cyclopropylethyl ester (32 mg, 68%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[N:24]=[C:23]([NH:25][CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:28].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]=O)=[C:32]([O:40][C:41]([F:44])([F:43])[F:42])[CH:31]=1.CC(O)=O.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O>[ClH:28].[ClH:28].[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:7][C@@H:8]2[CH2:9][CH2:10][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([NH:25][CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12][CH2:13]2)=[C:32]([O:40][C:41]([F:42])([F:43])[F:44])[CH:31]=1
Reactant: O=CCCc1ccc(Br)cc1OC(F)(F)F
Reactant: CNc1nc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CNc1nc(N[C@H]2CC[C@@H](NCCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of cis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester obtained in step B of example 50 (8.68 g, 23.4 mmol) in CHCl3 (87 mL) was added 4 M hydrogen chloride in EtOAc (100 mL). The reaction mixture was stirred at ambient temperature for 2 hr, and concentrated. The residue was alkalized with saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated (10.57 g). To a suspension of the above residue (594 mg) in MeOH (6 mL) were added 3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehyde obtained in step C of example 62 (650 mg, 2.19 mmol), AcOH (132 mg, 2.19 mmol), and NaBH3CN (207 mg, 3.29 mmol). The reaction mixture was stirred at ambient temperature for 16 hr, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane and silica gel, 16% MeOH in CHCl3) to give a yellow oil. To a solution of the residue in EtOAc (6 mL) was added 4 M hydrogen chloride in EtOAc (0.14 mL). The reaction mixture was stirred at ambient temperature for 30 min, and concentrated. A solution of the residue in Et2O (10 mL) was stirred at ambient temperature for 1 hr and the precipitate was collected by filtration to give cis-N2-{4-[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N4-methyl-quinazoline-2,4-diamine dihydrochloride (59 mg, 7%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:13].O>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O-:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3].[Na+:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc([O-])cc1

Procedure:
In 2500 cc of methanol was dissolved 2000 g of p-t-butylphenol. Separately, 520 g of sodium hydroxide was added to a mixed solvent comprising 2100 cc of methanol and 400 cc of water. Both the liquids were mixed together with stirring in a 10-liter separable flask, and sodium p-t-butylphenolate was formed with generation of heat. Methanol and water were removed by distillation, and the residue was dried in vacuum at 120° C. to isolate sodium p-t-butylphenolate in the form of a yellow powder having a melting point higher than 400° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH:53]([CH2:57][CH2:58][CH2:59][CH2:60][N:61]([CH2:88][C:89]3[N:90]([CH2:94][C:95]([N:97]([CH2:106][C:107]([O:109][C:110]([CH3:113])([CH3:112])[CH3:111])=[O:108])[CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])=[O:96])[CH:91]=[CH:92][N:93]=3)[CH2:62][C:63]3[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:85])([CH3:84])[CH3:83])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH:65]=[CH:66][N:67]=3)[C:54](O)=[O:55])=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:110]([O:109][C:107](=[O:108])[CH2:106][N:97]([CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])[C:95](=[O:96])[CH2:94][N:90]1[CH:91]=[CH:92][N:93]=[C:89]1[CH2:88][N:61]([CH2:62][C:63]1[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:83])([CH3:84])[CH3:85])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:75])([CH3:76])[CH3:77])[CH:65]=[CH:66][N:67]=1)[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:53]([C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:52][C:50](=[O:51])[O:49][CH2:48][CH:46]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:47]1=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:111])([CH3:112])[CH3:113]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of (5)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (97 mg, 0.20 mmol), 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (132 mg, 0.12 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 2 days. The reaction mixture was purified by biotage eluting with 1% MeOH in DCM to afford (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxo ethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (impure) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20]([OH:22])=O)[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:6][CH:5]=2.C[O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([OH:33])=[O:24])=[CH:27][CH:28]=2)=[O:22])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([C:15]([F:17])([F:16])[F:18])(=[O:13])=[O:14])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Product: Cc1cc2cc(NS(=O)(=O)C(F)(F)F)ccc2n1CC(=O)Nc1ccc(C(=O)O)cc1

Procedure:
Same procedure as Example 82 except (2-Methyl-5-trifluoromethanesulfonylamino-indol-1-yl)-acetic acid and 4-aminobenzoic methyl ester was used. 1H-NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H, COOH), 11.45 (s, 1H, SNH), 10,73 (s, 1H, NHCO), 7.90 (d, J=7 Hz, 2H, ArH), 7.70 (d, 2H, ArH), 7.38 (d, J=9 Hz, 1H, H-7), 7.32 (d, J=2 Hz, 1H, H-4), 6.94 (dd, J=2, 8 Hz, 1H, H-6), 6.28 (s, 1H, H-3), 5.04 (s, 2H, CH2), 2.38 (s, 3H, CH3), MS m/z 454 (M−H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH:16]=2)O1.Br[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[Cl:34].C(OCC)(=O)C>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:34][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:27]=1[C:15]1[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH:16]=1)[NH2:31]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=CCC3(CC2)OCCO3)c(Cl)c1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
A 2N aqueous solution of potassium carbonate (26.5 mL) and tetrakis(triphenylphosphine) palladium(0) (1.23 g, 1.06 mmol) were added sequentially, each in one portion, to a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (Intermediate 78ii, 5.65 g, 21.2 mmol) and 4-bromo-3-chloro aniline (4.39 g, 21.2 mmol) in dimethoxyethane (80 mL) at room temperature under an argon atmosphere. The reaction mixture was then heated at 80° C. for 24 h under an argon atmosphere. The reaction mixture was cooled to room temperature and ethyl acetate was added and then the mixture was washed twice with H2O and then brine. The organic layer was dried (MgSO4) and concentrated in vacuo to leave an oil, which was purified by column chromatography, using a gradient of 20-50% ethyl acetate:isohexane as eluent, to give the title compound (3.5 g, 62%) as a solid; 1H NMR δ 1.7-1.8 (2H, m), 2.26-2.43 (4H, m), 3.91 (4H, s), 5.28 (2H, s), 5.4-5.47 (1H, m), 6.45 (1H, dd), 6.59 (1H, d), 6.86 (1H, d).