Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl.O>[CH3:4][C:2]([Si:5]([CH3:18])([CH3:19])[O:6][CH2:7][CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=2)=[CH:13][CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC=CSc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCC=CSc1ccc(NC(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A 0° C. solution of Example 126B (0.92 g, 3.0 mmol) in dichloromethane (10 mL) was sequentially treated with pyridine (0.3 mL, 3.7 mmol) and 4-trifluoromethoxybenzoyl chloride (0.53 mL, 3.4 mmol), stirred at 0° C. for 0.5 hours and then at room temperature for 1 hour. The reaction was diluted with water and extracted with dichloromethane (3×15 mL). The combined extracts were washed with saturated NaHCO3, dried, filtered, concentrated and purified on silica gel by flash column chromatography eluting with 6:1 hexanes/ethyl acetate to give 1.37 g of the desired product. MS (ESI): 501 (M+NH4+), 506 (M+Na+).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][C:6]1=[O:19])C.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[Na+].[Na+].NC1N=CC2C(=O)CC(C3C=CC(Cl)=CC=3)CC=2N=1>>[NH2:23][C:22]1[N:24]=[CH:4][C:5]2[C:6](=[O:19])[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:9][C:10]=2[N:21]=1
Reactant: CN(C)C=C1C(=O)CC(c2ccc(F)cc2)CC1=O
Reactant: N=C(N)N
Agent: Cl
Agent: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Agent: O=C([O-])[O-]
Product: Nc1ncc2c(n1)CC(c1ccc(F)cc1)CC2=O

Procedure:
The title compound was prepared from 2-dimethylaminomethylene-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (600 mg, 2.29 mmol) prepared in stage 1, guanidine hydrochloride (438 mg, 4.59 mmol) and sodium carbonate (728 mg, 6.87 mmol), following the procedure described for 2-amino-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/a stage 2).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:12](O)[C:6]=2[CH:5]=1)([O-:3])=[O:2].S([O-])(O)(=O)=O.[K+].O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCCC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)C=CCCC2
Temperature: 160 °C
Yield: 74.5 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (70.67 g) and potassium hydrogensulfate (53.00 g) was heated at 160° C. for 1 hour. After cooling, to the mixture was added a mixture of water (400 ml) and ethyl acetate (400 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and chloroform (1:1) as an eluent to give 2-nitro-6,7-dihydro-5H-benzocycloheptene (48.1 g).
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][CH:7]([C:9](=[O:11])[CH3:10])[CH:6]([CH3:12])[CH2:5]1)([CH3:3])[CH3:2].O1CCC(=O)[CH2:15][CH2:14]1>>[CH:1]([CH:4]1[CH2:8][CH:7]([C:9]([OH:11])([C:14]#[CH:15])[CH3:10])[CH:6]([CH3:12])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1CCOCC1
Reactant: CC(=O)C1CC(C(C)C)CC1C
Product: C#CC(C)(O)C1CC(C(C)C)CC1C

Procedure:
The title compound was prepared according to the procedures described in Example 6A, substituting 1-(4-isopropyl-2-methylcyclopentyl)ethanone (prepared as described in Roger, A. et al. Bull. Soc. Chim. Fr. 1967, 3030-3037) for tetrahydro-4H-pyran-4-one used in Example 6A.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCCCCCC(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Lithium hydroxide monohydrate (43.7 mg) was added to a solution of methyl Z-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (200 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (169 mg, yield 87%) as colorless crystals. m.p. 54-57° C.
Reaction SMILES: [F:1][C:2]([CH3:16])([CH3:15])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(OI(O)C2C=CC=CC=2)(=O)=O)=CC=1.[NH2:36][C:37]([NH2:39])=[S:38]>CC#N>[NH2:39][C:37]1[S:38][C:4]([C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[O:6])=[C:3]([C:2]([F:1])([CH3:16])[CH3:15])[N:36]=1
Reactant: CC(C)(F)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NC(N)=S
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(F)c1nc(N)sc1C(=O)c1ccc(F)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-Fluoro-1-(4-fluoro-phenyl)-4-methyl-pentane-1,3-dione (900 mg) and Koser's reagent (4.2 g) in MeCN (20 mL) was heated at 80° C. for 50 min. The mixture was cooled to RT, and thiourea (820 mg) was added. The mixture was heated at 80° C. for 3 h., cooled to RT and partitioned between ethyl acetate and aq. KOH. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 283.2 (MH+). 1H NMR (DMSO-d6) 7.81 (dd, J=8, 4 Hz, 2H), 7.73 (s, 2H), 7.32 (t, J=8 Hz, 2H), 1.61 (d, J=20 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)(=[O:14])=[O:13])[CH2:10]Cl)=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[N+:21]([C:17]1[CH:16]=[C:15]([S:12]([C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH2:10])(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)C(CCl)Sc2ccc(Br)cc2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(Sc1ccc(Br)cc1)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 48.3 %

Procedure:
2-Chloro-1-(m-nitrophenylsulfonyl)ethyl p-bromophenyl sulfide (27.1 g, 62.1 mmoles) was dissolved in 125 ml of tetrahydrofuran. The solution was diluted with 125 ml of diethyl ether and treated with 8.65 ml (6.3 g, 62.3 mmoles) of triethylamine. After one hour the mixture was filtered to remove 7.52 g (88%) of triethylamine hydrochloride, m.p. 255°-258°. Removal of solvent from the filtrate gave a yellow oil which crystallized upon scraping. Recrystallization from 25 ml of ethyl acetate and 10 ml of pentane gave 12 g (48%) of product m.p. 109°-111°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][C:16]#[N:17])[N:14]=2)=[CH:6][CH:5]=1.[CH3:18]I>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH:15]([CH3:18])[C:16]#[N:17])[N:14]=2)=[CH:8][CH:9]=1
Reactant: CI
Reactant: N#CCc1coc(-c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
NaH (360 mg, 60% dispersion in oil) was added portionwise over 5 min to a solution of 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (1.5 g, 7.42 mmol) in dry THF (60 mL) at 0° C. The resulting reaction mixture was slowly allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was again cooled to 0° C. and a solution of methyl iodide (0.5 mL, 7.4 mmol) in dry THF (10 mL) was added dropwise at 0° C. over 30 min. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for another 1 h. The reaction mixture was quenched with saturated NH4Cl solution, diluted with EtOAc and further extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get 2-(2-(4-fluorophenyl)oxazol-4-yl)propanenitrile (360 mg, yield 23%). 1H NMR (400 MHz, CDCl3) δ 8.05-8.02 (m, 2H), 7.71-7.70 (d, J=1.1 Hz, 1H), 7.19-7.14 (t, J=8.7 Hz, 2H), 3.97-3.92 (m, 1H), 1.73-1.72 (d, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C12H19FN2O: 216.07. found: 216.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1cncc(-c2ccc(OC(F)(F)F)cc2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 11.8 g (41.4 mmol) of N-(5-bromopyridin-3-yl)benzamide, 12.8 g (62.1 mmol) of [4-(trifluoromethoxy)phenyl]boronic acid and 11.4 g (82.7 mmol) of potassium carbonate were dissolved in 70 ml of 1,2-dimethoxyethane, 21 ml of water and 156 ml of DMF. The mixture was flushed with argon, 0.24 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was triturated with methyl tert-butyl ether. The solid was filtered off and the filtrate was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1=>1:5). The separated solid and the appropriate fraction from the chromatography were combined. Yield: 6.7 g (45% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH:39]1[N:43]=C[N:41]([C:44](N2C=NC=C2)=[O:45])[CH:40]=1.NCC#N>C(Cl)Cl>[C:39]([CH2:40][NH:41][C:44](=[O:45])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)#[N:43]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(N)c3)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N#CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(NC(=O)NCC#N)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4-(3-aminophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (103 mg, 0.250 mmol), DIPEA (0.131 mL, 0.749 mmol) in DCM (1 mL) was added CDI (81 mg, 0.50 mmol). The reaction mixture was stirred at room temperature overnight. At that point aminoacetonitrile (70.0 mg, 1.25 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated and purified by chromatography on silica eluting with 0-100% ethyl acetate/hexanes to give ethyl 4-(3-(3-(cyanomethyl)ureido)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a pale yellow solid. LRMS (ESI) calc'd for C24H31N6O4Si [M+H]+: 495, found 495.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[CH:17]=CC(C#C)=CN=1>>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1)#[CH:17]
Reactant: CN(C)c1ccc(I)cn1
Reactant: C#Cc1ccc(Cl)nc1
Product: C#Cc1ccc(N(C)C)nc1

Procedure:
(5-Ethynyl-pyridin-2-yl)-dimethyl-amine was prepared from (5-iodo-pyridin-2-yl)-dimethyl-amine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([C:35]([OH:37])=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1>>[C:35]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]2[C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:24]=1)([OH:37])=[O:36]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccc(Nc2ncccc2C(=O)O)cc1)C(=O)O
Product: O=C(O)c1cccnc1Nc1ccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1

Procedure:
In close analogy to the procedure described in Example 104b, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-{[4-(2-amino-2-carboxyethyl)phenyl]amino}pyridine-3-carboxylic acid (prepared by reaction of 2-amino-3-(4-aminophenyl)-propionic acid with 2-chloronicotinic acid as in Example 104a) to provide the title compound in good yield.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=[C:12]([CH3:24])[CH:11]=2)[CH:5]=1.[C:26]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH3:27]>>[C:30]([O:29][C:26](=[O:28])[CH2:27][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=[C:12]([CH3:24])[CH:11]=2)[CH:5]=1)=[O:2])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2cc(C)nc(COC3CCCCO3)c2)c1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
Reaction of (RS)-3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-benzoic acid methyl ester with tert.-butyl acetate according to general procedure K (method d; example K8) yielded the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([O:15]C)=O)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC1C=C(C2C=C(C(O)=O)ON=2)C=CC=1.S(Cl)(Cl)=O.[NH2:36][NH2:37]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([NH:36][NH2:37])=[O:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cccc(F)c2)no1
Reactant: NN
Agent: O=C(O)c1cc(-c2cccc(F)c2)no1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NNC(=O)c1cc(-c2cccc(F)c2)no1

Procedure:
A mixture of methyl 3-(3-fluorophenyl)isoxazole-5-carboxylate (prepared according to the literature method: T. T. Dang, U. Albrecht and P. Langer, Preparation 2006, No. 15, 2515-252; or treatment of 3-(3-fluorophenyl)isoxazole-5-carboxylic acid with thionyl chloride and methanol) (5.55 g, 25 mmol, 1.0 equiv.), hydrazine (960 mg, 30 mmol) and MeOH (100 mL) was refluxed for 1 h and concentrated. The residue was washed with dichloromethane and dried in vacuum to give 3-(3-fluorophenyl)isoxazole-5-carbohydrazide (5.6 g, quant.). LRMS (M+H+) m/z 222.0
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH3:15].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24]O)=[CH:19][N:18]=1.C(O)(=O)C.[ClH:30]>CC(C)=O>[ClH:30].[ClH:30].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH2:1])=[C:3]([O:14][CH3:15])[CH:4]=2)=[CH:19][N:18]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COc1ccc2ccc(OC)c(N)c2c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2c(Cc3cnc(N)nc3N)cc(OC)c(N)c2c1
Yield: 78 %

Procedure:
A mixture of 1-amino-2,7-dimethoxynaphthalene (2.03 g, 10.00 mmol) [O. Fischer and W. Kern, J. Prakt. Chem., 94, 34(1916)], 2,4-diamino-5-hydroxymethylpyrimidine (1.40 g, 10.0 mmol), glacial acetic acid (20 mL) and concentrated hydrochloric acid (1.4 mL) was refluxed for 2 hr. The cooled reaction mixture was diluted with acetone and the resulting precipitate was collected and dried giving the title compound as a grey solid (3.40 g, 78%). Recrystallization from aqueous ethanol with concentrated HCl gave an analytical sample, mp >210° dec. Anal. Calcd for C17H19N5O2.2HCl.2H2O: C, 47.01; H, 5.80; N, 16.12; Cl, 16.32. Found: C, 47.19; H, 5.90; N, 16.05; Cl, 16.37.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([O:36]C)=[O:35])#[N:2].[OH-].[Na+].Cl>O1CCCC1CO>[C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([OH:36])=[O:35])#[N:2]
Reactant: CCCc1nc(-n2cccc2C(=O)OC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: CCCc1nc(-n2cccc2C(=O)O)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of methyl 1-[5-cyano-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazol-4-yl]1H-pyrrole-2-carboxylate (Example 35) in tetrahydrofuran-methanol (2:1) was treated with two equivalents of 1N NaOH at 0° C. The reaction mixture was stirred at reflux for 20 hours then treated with two equivalents of 1N HCl. The reaction mixture was then partitioned between ethyl acetate and brine and the organic layer is dried over MgSO4 and evaporated to afford the title compound. MS (FAB, thioglycerol) 479 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][CH2:13][CH:14]([NH2:17])[CH2:15][CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH:14]([CH2:15][CH3:16])[CH2:13][CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CCC(N)CC
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CCC(CC)NC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and 3-pentanamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([S:12][CH2:13][CH2:14]3)=[C:10]([CH2:16]O)[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(#N)C.[I-].[Na+].C[Si](Cl)(C)C>C1COCC1.[Zn].O.C(O)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:15]3[C:11]([S:12][CH2:13][CH2:14]3)=[C:10]([CH3:16])[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: OCc1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1SCC2
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1SCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
The compound of example 12 (2.05 g, 6.3 mmol) is brought into solution in a mixture of abs. acetonitrile (16 ml), glacial acetic acid (1.6 ml) and a little abs. DMF at 50° C., sodium iodide (2.35 g, 15.7 mmol) is added and then trimethylsilyl chloride (TMSCl, 1.6 ml, 1.37 g, 12.7 mmol) is added dropwise. The temperature of the batch is kept at 50° C. for 2 h. Glacial acetic acid (1.6 ml) and zinc powder (2.87 g, 44 mmol) is added in three portions and the mixture is stirred at 80° C. for 16 h. The mixture is cooled, treated with a little water and extracted with CH2Cl2. The CH2Cl2 extracts are dried over Na2SO4 sicc. and concentrated. The residue obtained is taken up in THF and eluted through Al2O3 (50 g) using THF. From the residue (1.4 g) obtained after evaporation of the THF, using acetone 0.6 g of pale yellow substance (94%; HPLC: RP 18; acetonitrile/NaH2PO4 buffer 70:30) is obtained, which is recrystallized from MeOH in the presence of heat: 0.43 g of pale yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH2:18])([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:19]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1.Cl.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.O.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH:18][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=3)([C:13]([F:15])([F:16])[F:14])[C:7]=2[CH:19]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
While stirring a solution of DMF (20 mL) containing [6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methylamine hydrochloride (2.0 g, 6.3 mmol), 4-fluorobenzoic acid (972 mg, 6.94 mmol), hydroxybenzotriazole hydrochloride (852 mg, 6.3 mmol) and triethylamine (2.1 mL, 15.8 mmol) at 0° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.45 g, 7.57 mmol) was added little by little thereto. After the reaction solution was stirred at room temperature for 5 hours, water was added thereto. Then, the resulting solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (2.1 g, 82%) was obtained as a white solid.