Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29]Br)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:29][CH2:28][CH2:27][O:26][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C@H:17]([CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:31])[CH2:18][CH2:19]3)=[C:3]([O:10][CH3:11])[CH:4]=1)#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cc3OC)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a mixture of 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17.6 mmol), ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45) (6 g, 17.6 mmol), and Cs2CO3 (6.9 g, 21.1 mmol) in DMF (30 mL) was added water (15 drops). The reaction mixture was stirred at 40° C. for 16 h and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. Recrystallization from MeOH (5 mL) gave 4.9 g (68%) of the title compound as an off-white solid. LC-MS: RT=3.59 min; (M+H)+ 410.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH:22][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(C(CCNC2CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 3,3-bis(4-fluorophenyl)propanal (1.00 g, 4.06 mmol, see Method H for preparation) in MeOH (15 ml) was added cyclopropanamine (0.285 ml, 4.06 mmol). The reaction mixture was stirred for overnight at 25° C. Sodium borohydride (0.307 g, 8.12 mmol) was carefully added to the reaction mixture over 15 min. After stirring an additional 15 min volatiles were removed by concentration under reduced pressure. The leftover residue was solubilized with 60 mL of a 1:2 mixture of 10% NaOH and ethyl acetate. The organic phase was separated and the aqueous phase was extracted further with ethyl acetate (2×40 mL). Purification by chromatography on silica (eluted with 0->10% MeOH/CH2Cl2+0->1% NH4OH) gave N-(3,3-bis(4-fluorophenyl)propyl)cyclopropanamine 181. The product was dissolved in CH2Cl2 and made into the HCl salt by precipitation with etheral HCl and then concentration of volatiles.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]([CH2:31]I)=[CH2:30])[C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:28][C:29](=[CH2:31])[CH2:30][C@H:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CI)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a cooled (−78° C.) solution of 1-benzyl 4-tert-butyl (2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate from step 1c (9.2 g) in THF (50 mL) was added dropwise LiHMDS (1.0 M in THF, 20.2 mL) at −78° C. during a period of 30 min. The mixture was stirred at −78° C. for 1 h, and then was allowed to warm to −30° C. during 3 h. The reaction mixture was quenched with 10% citric acid (10 mL) and diluted with brine (100 mL). The mixture was extracted with ethyl acetate (4×75 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified through Combiflash (hexane and ethyl acetate: gradient 0 to 5% during 12 min) to give the desired 2-benzyl 3-tert-butyl (2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate (3.45 g). MS (ESI): 422.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[N:28]([C:29]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])=[C:21]2[C:20](=[O:39])[N:19]([CH3:40])[C:18]1=[O:41])[CH2:27][CH2:26][CH2:25][C:24]3=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:24]1[C:23]2[N:28]([C:29]([C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=3)=[C:21]3[C:20](=[O:39])[N:19]([CH3:40])[C:18](=[O:41])[N:17]([CH3:16])[C:22]3=2)[CH2:27][CH2:26][CH:25]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (221 μL, 1.31 mmol) was added to an ice-cooled solution of 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (step 7) (350 mg, 1.01 mmol) and 2,6-lutidine (176 μL, 1.51 mmol) in DCM (5 mL). The solution was stirred at ice-bath temperature for 2 hours, further portions of 2,6-lutidine (88 μL, 0.78 mmol) and trifluoromethanesulfonic anhydride (85 μL, 0.50 mmol) were added. The reaction mixture was diluted with dichloromethane (40 mL) and was washed with water (2×20 mL) and sat. brine (1×20 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:28]2[CH2:29][C:30](=[O:31])[N:26]([CH3:25])[C:27]2=[O:32])[CH:7]=1
Reactant: CN1C(=O)CNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Yield: 35.1 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (817 mg) described in Preparation Example 167 and 3-methylimidazolidine-2,4-dione (339 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Preparation Example 241, the title compound (310 mg) was obtained.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[NH:20][CH2:21][CH3:22])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[NH:20][CH2:21][CH3:22])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCNC(=O)Nc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)OCC)cc3)C3CCCCC3)c(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a mixture of ethyl 3-[({4-[(cyclohexyl{5-[(ethylcarbamoyl)amino]-3-methyl-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (304 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (258 mg, 89%) as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O.[NH2:57][C:58]1[NH:62][N:61]=[N:60][N:59]=1>CN(C=O)C.O>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:57][C:58]4[NH:62][N:61]=[N:60][N:59]=4)=[O:19])=[CH:15][CH:14]=3)[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cn2nc(-c3ccc(OC(F)(F)F)cc3)cc2C2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 128 mg product from Step D above, 66.3 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 46.8 mg 1-hydroxybenzotriazole hydrate (HOBt) in 1 mL DMF was stirred at room temperature for 30 minutes. 5-Aminotetrazole monohydrate (35.7 mg) was added and the mixture stirred for additional 16 hours. Precipitate the product by adding 1 mL water to the reaction mixture. Collect the product by filtration, wash it with 1:1 DMF and water, water, and MeCN, and dry to give the title compound as a white solid. 1H NMR (CD3OD, 500 MHz) δ 7.995 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.6 Hz, 2H), 7.27˜7.29 (m, 4H), 6.58 (s, 1H), 5.52 (s, 2H), 2.59˜2.65 (m, 1H), 1.75˜1.81 (m, 4H), 1.69˜1.73 (m, 1H), 1.39˜1.46 (m, 2H), 1.24˜1.37 (m, 3H). LC-MS: 2.32 min. (M+H=512.3).
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[F:16][C:13]1([F:15])[CH2:14][C@H:10]([OH:9])[C@@H:11]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=2)[CH2:12]1
Reactant: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1O
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of the (1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl benzoate (90 mg, 0.294 mmol) prepared in Example 107d in methanol (3.0 mL), potassium carbonate (60 mg, 0.434 mmol) was added, and the reaction solution was stirred for 30 minutes. To the reaction solution, water (10 mL) was added, and an organic layer was extracted with ethyl acetate (20 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=96:4) to yield the title compound (48 mg, 81%) as a colorless oil.
Reaction SMILES: [N:1]#[C:2][NH2:3].C[O-].[Na+].CO[C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12]>CO>[C:2]([NH:3][C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12])#[N:1]
Reactant: COC(=NC#N)C1CC1
Reactant: N#CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CN=C(NC#N)C1CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 0° C. 8,4 g of cyanamide in 50 ml methanole are added to 36 g of a 30% solution of sodium methylate in methanol and stirred for 30 min. at 10° C. The resulting solution is then cooled to -20° C. and mixed with a solution of 22 g N-cyano-cyclopropanecarboximidic acid methylester in 60 ml methanole. The reaction mixture is then stirred for 30 min. at 20° C. and then evaporated. 100 ml of dioxane is added to the resulting residue which is then concentrated by evaporation. Then again 100 ml of toluene is added and the solution is concentrated at an ambient temperature of 60° C. up to a residual weight of 33 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[C:37]([CH3:39])[N:36]([CH2:40][CH2:41][C:42]([NH2:45])([CH3:44])[CH3:43])[N:35]=2)=[CH:30][CH:29]=1.[BH4-].[Na+].CC(C)=O>C(O)C.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:25])[CH2:20][NH:45][C:42]([CH3:44])([CH3:43])[CH2:41][CH2:40][N:36]2[C:37]([CH3:39])=[N:38][C:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)=[N:35]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: COc1ccc(-c2nc(C)n(CCC(C)(C)N)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(O)CNC(C)(C)CCn2nc(-c3ccc(OC)cc3)nc2C)ccc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
8.5 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 4.9 g of 3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine in 100 mL ethanol are stirred for three hours at 60° C., cooled to 10° C., combined batchwise with 0.8 g of sodium borohydride and stirred for a further three hours at ambient temperature. Then 10 mL acetone are added and the mixture is stirred for one hour. It is then poured onto ice and acidified with glacial acetic acid. The ethanol is distilled off, the aqueous phase remaining is made alkaline with sodium hydroxide and extracted with ethyl acetate. The organic phases are dried with sodium sulphate and evaporated down. The residue is combined with 80 mL ethanol, acidified with 3.2 g of oxalic acid, dissolved in ethanol, and seeded. The product that crystallises out is suction filtered and washed. Yield: 8 g (69%, oxalate); m.p.=210-213° C.
Reaction SMILES: [CH3:1]OC1C=C(NC2N=C(NC3C=CC(C(OC)=O)=C(OC)C=3)C(F)=CN=2)C=CC=1C(OC)=O.[CH3:34][C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[C:37]([CH3:44])[C:36]=1[OH:45].C(=O)([O-])[O-].[K+].[K+].IC>>[CH3:34][C:35]1[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[C:37]([CH3:44])[C:36]=1[O:45][CH3:1]
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(OC)c3)n2)cc1OC
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c(C)cc([N+](=O)[O-])cc1C

Procedure:
In a manner analogous to the preparation of N2,N4-bis[3-methoxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,6-dimethyl-4-nitrophenol (1.67 g, 10 mmol), potassium carbonate (13 g, 0.1 mol) and iodomethane (2.5 mL, 50 mmol) gave 2,6-dimethyl-1-methoxy-4-nitrobenzene. Hydrogenation of 2,6-dimethyl-1-methoxy-4-nitrobenzene gave 3,5-dimethyl-4-methoxyaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Cl)CC1

Procedure:
By general method 1 from 20.66 g (75 mmol) of 2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one with 25.14 g (135 mmol) of Boc-piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=1.Cl.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:8]2[N:29]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])[N:30]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:7]=1
Reactant: O=C(C=Cc1cc(Br)ccc1F)C(F)(F)C(F)(F)F
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: CC(=O)O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
1-(5-Bromo-2-fluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (620.0 mg, 1.8 mmol) prepared in Step 4 and 2,4-difluorophenylhydrazine hydrochloride (390.0 mg, 2.1 mmol) were added to acetic acid (30.0 mL). The reaction mixture was stirred at 125° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 250.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C([O:5][C@@H:6]([C@@H:8]1[CH2:12][O:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[C:27]([Cl:38])[CH:26]=2)=[N:9]1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:38][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:10]4[O:11][CH2:12][C@@H:8]([C@H:6]([OH:5])[CH3:7])[N:9]=4)[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: C[C@@H](OC(C)(C)C)[C@@H]1COC(Nc2ccc3ncnc(Nc4ccc(OCc5nccs5)c(Cl)c4)c3c2)=N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@@H]1COC(Nc2ccc3ncnc(Nc4ccc(OCc5nccs5)c(Cl)c4)c3c2)=N1

Procedure:
(R)-1-((S)-2-(4-(3-chloro-4-(thiazol-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-4-yl)ethanol is prepared from (1R,4S)—N6-[4-(1-tert-butoxyethyl)-4,5-dihydrooxazol-2-yl]-N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-quinazoline-4,6-diamine by standard deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 497, 499 (M+1, Cl pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.08 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.76 (dd, 1H), 7.66 (m, 2H), 7.33 (d, 1H), 5.55 (s, 2H), 4.81 (m, 1H), 4.37 (m, 1H), 4.20 (m, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 1.06 (d, 3H).
Reaction SMILES: I.[C:2]1([NH:8][C:9](=[NH:12])[NH:10][NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@:20]3([OH:35])[CH2:21][CH2:22][C@@H:23]2[CH:33]=O)[CH2:15]1>O.O1CCOCC1>[C:2]1([NH:8][C:9](=[NH:12])[NH:10]/[N:11]=[CH:33]/[C@H:23]2[CH2:22][CH2:21][C@:20]3([OH:35])[C@H:19]4[C@H:28]([CH2:27][CH2:26][C@:24]23[CH3:25])[C@:29]2([CH3:32])[C@@H:16]([CH2:15][C@@H:14]([OH:13])[CH2:31][CH2:30]2)[CH2:17][CH2:18]4)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: N=C(NN)Nc1ccccc1
Agent: I
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/NC(=N)Nc3ccccc3)CC[C@]12O
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To a solution of 0.83 g of 3-phenyl-1-aminoguanidine hydroiodide (prepared following the procedure described in Houben-Weil, Metoden der Organischen Chemie, Band VIII, page 183) in 10 ml of water and 5 ml of dioxane a solution of 0.64 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 5 ml of dioxane was added dropwise at room temperature. After 2 hrs, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 89/10/1 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethanol to give 0.20 g of the title compound (I-ah) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([O:17]CC)=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([OH:17])=[O:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product of Step A was added ethanol (6.4 mL) followed by a solution of NaOH (0.483 g, 12.1 mmol) in water (6.4 mL). The reaction was stirred at ambient temperature for 1 hour. To the mixture was added 1 N HCl (22.8 mL), and the mixture stirred at ambient temperature overnight. The solids were collected by filtration, washed with water (2×4 mL) and dried in a vacuum oven at 45° C. overnights to give 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.51 (bs, 1H), 10.68 (bs, 1H), 8.30 (t, J=1.8, 1H), 8.14 (dt, J=7.7, 1.4, 1H), 7.99 (ddd, J=7.8, 2.0, 1.1, 1H), 7.70 (t, J=7.8, 1H), 7.27 (m, 1H), 6.94-6.82 (m, 3H); MS (ESI) m/z 294 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]([N:16]=[CH:17]OCC)#[N:15]>C(O)C>[C:14]([NH:16][CH:17]=[N:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=2)=[CH:8][CH:9]=1)#[N:15]
Reactant: CCOC=NC#N
Reactant: Cc1nc(-c2ccc(N)cc2)c[nH]1
Solvent: CCO
Product: Cc1nc(-c2ccc(N=CNC#N)cc2)c[nH]1
Yield: 77.9 %

Procedure:
A solution of 2-methyl-4-(4-amino-phenyl)-1H-imidazole (15 g) and ethyl N-cyanoformimidate (9.35 g) in ethanol (150 ml) was stirred at room temperature overnight. The product which crystallized out was collected by filtration, washed with cold ethanol and dried to give 15.2 g of the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[Br:14][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N1CCC(CCBr)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethanone (0.500 g, 2.92 mmol) in dichloromethane (15 mL) was added carbon tetrabromide 1.45 g, 4.38 mmol), triphenyl phosphine (0.728 g, 2.77 mmol) and imidazole (0.398 g, 5.84 mmol) at 0° C. The temperature of the reaction mixture was slowly raised to room temperature and stirring continued at rt for 18 h. The reaction was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The product was chromatographed over silica gel using gradient of 0-10% methanol in dichloromethane. GC-MS m/z 235
Reaction SMILES: [CH:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:30][CH:29]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+:45]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:32][CH:33]=3)=[O:27])=[CH:18][CH:17]=2)[C:10]([O-:12])=[O:11])=[CH:42][CH:43]=1)([CH3:3])[CH3:2].[Na+:45]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3OC)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1-c1ccc(C(=O)NCCOc2ccc(CC(Oc3ccc(C(C)C)cc3)C(=O)[O-])cc2)cc1

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-(2′-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (700 mg), which is the product of Example 94, was reacted with aqueous sodium hydroxide solution (1N, 3.60 ml) and the reaction mixture was treated to give the title compound (528 mg) as a white powder.