Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.ClCCl.[NH3:36]>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1(=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH2:36])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (2E)-3-{4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoic acid (11) (0.23 g, 0.66 mmol) in toluene (6 mL) was slowly added oxalyl chloride (0.12 mL, 0.175 g, 1.38 mmol, 2.1 eq) followed by DMF (2-3 drops) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 0.25 h. Dichloromethane (6 mL) was added to the reaction mixture (to aid the dissolution of solids) and the reaction mixture was stirred at room temperature for 2 h. Oxalyl chloride (0.12 mL, 0.175 g, 1.38 mmol, 2.1 eq) and DMF (2 drops) were added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was concentrated in vacuo. Toluene was added to the crude acid chloride and the solvent was removed in vacuo. To the crude acid chloride were added ammonia (0.5 M in 1,4-dioxane) (6 mL, 3 mmol, 4.5 eq) followed by CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was transferred to a separatory funnel with the aid of CH2Cl2 and the solution was washed with water. The layers were separated and the organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to give the crude amide as a gold-yellow oil. The crude product was purified by flash chromatography on silica gel with CH2Cl2:MeOH (100:0 to 95:5) to give a solid which was dried at 70° C. under vacuum to give 0.058 g (25%) of compound 13 as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 8H), 2.22 (m, 4H), 6.53 (d, J=15.9 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 7.06 (br s, 1H), 7.12 (d, J=8.1 Hz, 2H), 7.35 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.50 (br s, 1H), 9.29 (s, 1H). HRMS (ESI) Calcd for C23H26NO2: 348.1964 (M+H)+. Found: 348.1951.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:15][C:16]([CH3:22])([C:19](=[O:21])[CH3:20])[C:17]#[N:18].C(NCC)C>C(OCC)(=O)C.O>[CH3:15][C:16]([CH3:22])([C:19](=[O:21])[CH:20]=[CH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:17]#[N:18]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)C(C)(C)C#N
Solvent: CCNCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)C(=O)C=Cc1ccncc1
Temperature: 25 °C
Yield: 59 %

Procedure:
Pyridine-4-carboxaldehyde (6.9 ml, 72 mmol) was added to dry pyridine (16 ml) under argon. 2,2-Dimethyl-3-oxo-butyronitrile {J. K. Rasmussen et al., Synthesis, 1973, 682} (8.0 g, 72 mmol) and diethylamine (7.3 ml, 71 mmol) were subsequently added and the solution heated under reflux for 18 hours. After cooling to room temperature, the mixture was poured into water and ethyl acetate. The mixture was separated and the aqueous phase re-extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to yield a solid which was triturated with diethyl ether to give the title compound (8.5 g, 59%); MS (ES+) m/e 201 [M+H]+.
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=2)=[C:11]1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH:41]2[CH2:43][CH2:42]2)[CH:31]=1)C1C=CC=CC=1.C(OCN1C2C=NNC(=O)C=2C(CC2C=CC=CC=2F)=C1C1C=CC(OC(F)F)=C(OC2CC2)C=1)C1C=CC=CC=1>>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:12]1[C:13]2[C:18](=[O:19])[NH:17][N:16]=[CH:15][C:14]=2[NH:10][C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH:41]2[CH2:43][CH2:42]2)[CH:31]=1)([OH:29])=[O:28]
Reactant: O=C(O)c1cccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)n(COCc3ccccc3)c3cn[nH]c(=O)c23)c1
Agent: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Product: O=C(O)c1cccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)[nH]c3cn[nH]c(=O)c23)c1
Yield: 81.3 %

Procedure:
Reaction was carried out in the same manner as in Example 22-(b) except for using 1.05 g (1.79 mmol) of 1-benzyloxymethyl-3-(3-carboxybenzyl)-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 27-(a) in place of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction mixture was extracted with an alkaline aqueous solution with a pH 10, washed with diethyl ether, and after adjusting a pH of the aqueous layer to 2, the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 0.68 g of the title compound as a beige solid. (Yield: 82%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH3:31])[C:27]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:26]=2[C:25]2[CH:37]=[CH:38][CH:39]=[CH:40][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH3:31])[C:27]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:26]=2[C:25]2[CH:37]=[CH:38][CH:39]=[CH:40][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2cc(F)ccc21
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@@H](NC(=O)[C@@H](O)c2cc(F)cc(F)c2)C(C)C)c2ccccc2-c2cc(F)ccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-W), the title compound was prepared. The product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the product of Step A was added ethanol (8 mL) followed by a solution of NaOH (0.378 g, 9.45 mmol) in water (8 mL). The reaction was stirred at ambient temperature for 45 minutes. To the mixture was added 1 N HCl (23 mL), and the mixture was stirred overnight. The solids were collected by filtration, washed with water (1×5 mL), and dried by vacuum filtration to give 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.50 (bs, 1H), 10.30 (bs, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.28-7.11 (m, 4H); MS (ESI) m/z 362.3 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](O)=[O:13])=[CH:8][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>C1COCC1.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][N:7]=1
Reactant: O=C(O)c1ccc(-c2cccs2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccs2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(thien-2-yl)-5-pyridinecarboxylic acid (0.333 g, 1.60 mmol) in THF (5 mL) at 0° C. is added 1.0M lithium aluminum hydride in diethyl ether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction is allowed to stir at ambient temperature for 3 hours, cooled to 0° C., and water (0.10 mL), 4N aq. NaOH (0.10 mL), and water (0.30 mL) are added sequentially. The reaction is filtered through a pad of Celite and the filtrate is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: Nc1cc(Cl)n2nccc2n1
Reactant: OB(O)c1cccs1
Product: Nc1cc(-c2cccs2)n2nccc2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and thiophen-2-ylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.82 (s, 2H), 6.24 (d, J=1.7 Hz, 1H), 6.52 (s, 1H), 7.21-7.25 (m, 1H), 7.66 (d, J=5.1 Hz, 1H), 8.02 (d, J=1.7 Hz, 1H), 8.22 (d, J=3.8 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH2:15])[CH:5]=1)(=[O:3])[CH3:2].[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>N1C=CC=CC=1>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH:15][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:17]=2[F:16])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(N)c1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(NC(=O)c2ccc(F)cc2F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 4'-acetyl-2'-aminomethanesulfonanilide (1.6 g) and 2,4-difluorobenzoyl chloride (1.5 g) in pyridine (15 ml) was stirred at 0° C. for 3 hours. The mixture was evaporated and the residue was stirred with 5% sodium hydroxide (40 ml) for 1 hour at room temperature. The mixture was washed with toluene, and the aqueous layer was acidified with hydrochloric acid. The precipitates obtained were recrystallized from a mixture of acetone and ethyl acetate (1:1) to give pale brown needles of N-(5-acetyl-2-methanesulfonamidophenyl)-2,4-difluorobenzamide (1.3 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]2[O:15][CH2:16][O:17][C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+].O>CS(C)=O>[C:18]([CH2:2][C:3]1[C:8]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]2[O:15][CH2:16][O:17][C:5]=2[CH:4]=1)#[N:19]
Reactant: [C-]#N
Reactant: CC(=O)NCCc1cc2c(cc1CCl)OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)NCCc1cc2c(cc1CC#N)OCO2

Procedure:
4.7 g of N-(6-chloromethyl-3,4-methylenedioxyphenethyl) acetamide was dissolved in 10 ml of DMSO and 1.32 g (0.028 mole) of sodium cyanide added to the stirred solution. Within a few minutes, the temperature rose from 25° to 32° C. After 1.5 hrs at ambient temperature the mixture was poured into ice and water. The suspension was extracted with three 50-ml portions of benzene. The benzene layers were washed with saturated brine six times, then with water, the solution dried, and the solvent distilled in the rotary evaporator leaving the above-named product as a crystalline solid, m.p. 153.3-155.5.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH2:5][C:4](=[O:7])[CH:3]=1.[Cl-].[Ca+2].[Cl-].[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.B(OC(CC)C)(OC(CC)C)OC(CC)C>ClCCl.CN(C)C=O.C(N)CCC.C(O)(=O)C>[OH:11][C:12]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[C:5]1[C:4](=[O:7])[CH:3]=[C:2]([CH3:1])[O:6]1
Reactant: CC1=CC(=O)CO1
Reactant: O=Cc1ccc(O)cc1O
Agent: CCC(C)OB(OC(C)CC)OC(C)CC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCCCN
Solvent: CC(=O)O
Product: CC1=CC(=O)C(=Cc2ccc(O)cc2O)O1
Temperature: 2.5 °C
Yield: 56.2 %

Procedure:
5-methyl-furan-3-one (2, 5.9 g g, 0.060 mol) was dissolved in dichloromethane (80 mL) and taken in a 3-necked 500 mL round bottomed flask fitted with a mechanical agitator and calcium chloride guard tube. 2,4-Dihydroxybenzaldehyde (3d, 7.4 g, 0.053 mol) dissolved in dimethylformamide (8 mL) was added. The mixture was cooled to 0-5° C. with stirring. Tri-sec-butyl borate (13.4 g, 0.058 mol) was added and stirred for 2 h. n-Butyl amine (9 drops) was added over a period of 3 h and the reaction mixture allowed to warm to room temp. on its own and stirred at room temp. overnight. The dark red color solution was poured into 5% aq. acetic acid solution (120 mL) preheated to 60° C. with stirring. This was stirred for 30 min., and then allowed to settle down. The dichloromethane layer was isolated and concentrated under reduced pressure to get red color gummy material. This gummy material was washed with water (3×20 mL). Acetonitrile (20 mL) was added to the gummy material and stirred vigorously. The product precipitated out. This was filtered, washed with acetonitrile (20 mL), and the filtered solid dried in vacuo at 110° C., get pure 2-(2,4-Dihydroxy-benzylidene)-5-methyl-furan-3-one (4d) as a red powder (6.5 g, 50% yield), m.p. 239.4-242.5° C. (decomposes).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CN(C=O)C.O.CCOC(C)=O>[C:16]1([CH2:15][N:4]2[C:5](=[O:6])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:1]2(=[O:2])=[O:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2S(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a stirred solution of saccharin 82 (0.154 g, 0.75 mmol) in anhydrous THF (10 mL) at 0° C., under nitrogen atmosphere was added NaH (0.019 g, 0.8 mmol, using a 60% dispersion in mineral oil) and the resulting slurry was gradually warmed to room temperature over 1 hour period. Solvent was removed under reduced pressure, and the saccharin sodium salt was dissolved in anhydrous DMF (5 mL). To this solution, was added a solution of benzyl bromide (0.051 g, 0.3 mmol) in DMF (5 mL), under nitrogen, at room temperature and the mixture warmed to 80° C. and stirred for 4 hours. The reaction mixture was cooled to room temperature and diluted with dropwise addition of water (5 mL) and AcOEt (20 mL). The organic layer was separated and the aqueous layer extracted with AcOEt. The combined organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel (50% diethyl ether-hexane) to give 83.1 (0.054 g, 66% yield), as a white solid (in p 106-108° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C=C(CCCCc1ccccc1)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=CC(=O)O)CCCCc2ccccc2)cc1OC
Yield: 85.7 %

Procedure:
A mixture containing ethyl 3-(3,4-dimethoxyphenyl)-7-phenyl-2-heptenoate (0.9 g, 2.4 mmol) and 10% sodium hydroxide (10 mL) in ethanol (20 mL) is heated under reflux for 1 hour. The mixture is cooled and is added to aqueous HCl and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo to provide 3-(3,4-Dimethoxyphenyl)-7-phenyl-2-heptenoic acid as an oil (0.7 g, 87% ) 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.48-1.60 (m, 2H), 1.60-1.80 (m, 2H), 2.58-2.69 (t, 2H), 3.10-3.20 (t, 2H), 3.90 (s, 6H), 6.08 (s, 1H), 6.80-6.90 (d, 1H), 6.90-6.98 (s, 1H), 6.98-7.09 (d, 1H), 7.09-7.32 (m, 5H); MS (EI) m/e 340 (M+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]1[OH:65]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][C@@H:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@H:60]5[OH:65])=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCC[C@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and trans-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.93 (m, 18H) 3.32 (s, 1H) 3.45 (m, 1H) 3.64 (m, 1H) 3.95 (s, 3H) 4.07 (t, J=13.39 Hz, 2H) 4.48 (m, 1H) 4.64 (br. s., 1H) 7.49 (d, J=8.0 Hz, 1H) 7.55 (s, 1H) 7.90 (s, 1H) 8.03 (d, J=8.08 Hz, 1H) 8.22 (s, 1H) 8.28 (d, J=8.34 Hz, 1H). [M+H] calculated for C28H36F2N6O4, 559. found 559.
Reaction SMILES: [C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2].Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COC(C)n1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(C)n1c(C(=O)C2CCN(CCCCC#N)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix 1-[(1-carbomethoxy methoxy ethyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.45 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a suspension of (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (2.01 g, 3.78 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (TFA) (3 mL) dropwise. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with CH2Cl2 (30 mL) and aqueous saturated sodium bicarbonate. Phases were separated and the aqueous layer was extracted with CH2Cl2 (30 mL). Organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (1.648 g, 101%)as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC1(C)[O:28][C:27](=O)[C:24]2([CH2:26][CH2:25]2)[C:23](=[O:30])[O:22]1>>[O:28]=[C:27]1[CH:24]([C:23]([OH:30])=[O:22])[CH2:25][CH2:26][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:18])([F:19])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: O=C(O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3c) from 4-(4-trifluoromethyl-benzyloxy)-phenylamine and 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione. Yield: 37% of a colorless solid. MS: m/e=380.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=[C:4]1[CH2:12][OH:13])[CH3:2].O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=[C:4]1[CH2:12][O:13][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCn1c(CO)nc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-ethyl-2-hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 28), 1.313 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.77 ml of tributylphosphine, 0.712 g of 1,1'-(azodicarbonyl)dipiperidine and 80 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 300 mg of the title compound having Rf=0.55 (on silica gel thin layer chromatography using a 1:3 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Br:20]Br.N([O-])=O.[Na+]>Br>[Br:20][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Nc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: -20 °C
Yield: 80.3 %

Procedure:
48% HBr 50 mL was added to 11 g (44 mmol) of 2-amino-4,6-diphenylpyrimidine and stirred. The solution was cooled down to −20° C., and 8.5 g (53 mmol) of bromine was dropwise added thereto. Further, 3.1 g (44 mmol) of sodium nitrite was dropwise added thereto. The solution was stirred for 3 hours while elevating the temperature up to room temperature. After finishing the reaction, the solution was extracted with ethyl acetate, and the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 11 g (yield: 82%) of 2-bromo-4,6-diphenylpyrimidine.