Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[N:14]=[CH:13]1>>[Cl:9][C:5]1[C:4]([CH3:10])=[CH:3][C:2]([C:15]2[N:14]=[CH:13][N:12]([CH3:11])[CH:16]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cn1cnc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(Br)cc(C)c1Cl
Product: Cc1cc(-c2cn(C)cn2)cc(C)c1Cl

Procedure:
The title compound is prepared from 5-bromo-2-chloro-1,3-dimethyl-benzene and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-imidazole following a procedure analogous to that described in Step 1 of Intermediate 56.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1OCCCCCCC1C=CC=C(OCC2C=CC=CC=2)C=1OCC1C=CC=CC=1)[C:5]([OH:7])=[O:6].[H][H]>[Pd].O1CCCC1>[C:5]([OH:7])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1

Procedure:
A mixture of 0.6 g of 3-chloro-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid and 60 mg of 10% palladium on carbon in 20 ml of tetrahydrofuran was stirred in a hydrogen atmosphere for 6 hours. Workup as in Example 36 and recrystallization from ethyl acetate-hexane gave 0.24 g, mp benzoic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:31][CH2:30]2)[N:3]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-methoxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield the 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methoxy-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=414.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28]([C:32](=[N:34]O)[NH2:33])[CH:29]=[CH:30][CH:31]=1>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:34]=[C:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)[N:33]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 34 mg (0.22 mmol, 1.1 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 47 mg (53% of theory)
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:31]=[CH:30][C:13]3/[C:14](=[CH:23]/[C:24]4[NH:28][C:27](=[O:29])[O:26][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH2:2][CH3:3].CO.[C:38]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:31]=[CH:30][C:13]3/[C:14](=[CH:23]/[C:24]4[N:28]([CH3:38])[C:27](=[O:29])[O:26][N:25]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:32]=[CH:33][CH:34]=[CH:35][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(E)-2-(2-Propylbenzimidazol-1-yl)methyl-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (69 mg, 0.15 mmol) obtained in Example 5 and methanol (30 μL, 0.75 mmol) were dissolved in THF (1 mL), polymer-supported triphenylphosphine (150 mg, 0.45 mmol) and di-tert-butyl azodicarboxylate (104 mg, 0.45 mmol) were added at 0° C., and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3 to 0/10) to give the title compound (compound 6) (65 mg, 92%).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH3:19])[O:9][C:8]=1[CH2:20][O:21][CH3:22])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:9][C:8]([CH2:20][O:21][CH3:22])=[C:7]([CH:2]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:11]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1oc(-c2ccc(F)cc2C)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1oc(-c2ccc(F)cc2C)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-5-(4-fluoro-2-methylphenyl)-2-(methoxymethyl)furan (487 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 60% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (45 mg, 6%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)=O.[OH-].[Na+]>CCO.O>[NH2:5][C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:22][C:35]([C:36]6[N:37]=[CH:38][CH:39]=[CH:40][N:41]=6)=[N:34][N:33]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1
Reactant: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1(c2ccc(-c3nc4ccn5nc(-c6ncccn6)nc5c4cc3-c3ccccc3)cc2)CC(O)C1
Temperature: 100 °C

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-hydroxy-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-3) (10 mg, 0.016 mmol) in EtOH (1.0 mL) was added NaOH (2M in water, 1.0 mL, 2.00 mmol), and the mixture was heated under microwave irradiation at 100° C. for 1 hour. The mixture was diluted with water, extracted with CHCl3, washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by preparative TLC, eluting with 10% MeOH in CHCl3 to give 3-amino-3-{-4-[9-phenyl-2-(2-pyrimidinyl)[1,2,4]triazolo[5,1-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanol (6-1) as a colorless solid. MS (M+H)+: observed=486, calculated=486.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:30][CH2:31][N:32]4[CH2:35][CH2:34][CH2:33]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23](OC)[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.N1(CCN2C=C(C3C=CC(F)=C(C)C=3)N=C2C2CCNCC2)CC[CH2:37]1.Cl.N1(CCN2C=C(C3C=CC(F)=C(OC)C=3)N=C2C2CCNCC2)CCC1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:30][CH2:31][N:32]4[CH2:35][CH2:34][CH2:33]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:37])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Agent: COc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: Cl
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile of using 4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidine instead 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methoxy-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28]>>[F:31][C:26]([F:32])([C:27]([F:28])([F:29])[F:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)CCCCCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Product: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9 and the 1-iodo-7,7,8,8,8-pentafluoro-octane prepared in Example 4, the same procedure as shown in Example 5 was repeated to give ethyl 2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([O:3][CH3:4])=[O:2].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:26]Cl)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])[CH3:14]>>[CH3:25][C:22]([C:20]1[CH:19]=[C:18]([CH2:26][C:5]2([C:1]([O:3][CH3:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2=[O:11])[CH:17]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[CH:21]=1)([CH3:23])[CH3:24]
Reactant: COC(=O)C1CCCCC1=O
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1
Product: COC(=O)C1(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CCCCC1=O

Procedure:
The title compound is prepared by the method of Example 12, except that 2-carbomethoxycyclohexanone is used in place of 2-carbomethoxycyclopentanone, and that the title product of Example 3 is used in place of the title product of Example 11.
Reaction SMILES: CS[C:3]([N:7]([CH3:16])[N:8]=CC1C=CC=CC=1)=[N:4][C:5]#[N:6].[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1.CC(C)=O.Cl>O>[CH3:16][N:7]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)=[N:4][C:5]([NH2:6])=[N:8]1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Yield: 57.2 %

Procedure:
A mixture of N-cyano-1-methyl-2-(phenylmethylene)hydrazine-carboximidothioic acid methyl ester (166 mg) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (104 mg) was heated at 45° under a reduced pressure of 20 mm of mercury for 3 hr. Acetone was added, and the resulting solution treated with dilute hydrochloric acid for 1 hour at room temperature. The mixture was diluted with water, washed with ether, basified with excess sodium carbonate and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave an oil which crystallised from ethyl acetate/light petroleum b.p. 60°-80° to give the title compound as colourless crystals m.p. 95°-96.5° (87 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:16]1[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccccc1Cl
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1Cl
Yield: 59.7 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.043 g (60%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([CH:13]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccc(F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of rac-1-(4-Fluoro-phenyl)-3-oxo-2,6-diaza-spiro[3.5]nonane-6-carboxylic acid tert-butyl ester (850 mg, 2.54 mmol) in THF (15 ml) was treated with 1M LHMDS in THF (3.30 ml, 3.30 mmol) followed by the addition of iodomethane (0.238 ml, 3.81 mmol). The solution was stirred at RT. After 4 hours, the reaction was quenched with water (30 mL) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield the title compound as a yellow oil;
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(CC)CC.[C:27](Cl)([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CO>[C:14]([O:13][C:12]([NH:11][C@@H:3]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C@@H:2]([NH:1][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:19])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: C[C@H](N)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a mixture of tert-butyl (2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate (0.153 g, 0.57 mmol) and Et3N (0.19 mL, 1.42 mmol) in methanol (5 mL) at 0° C. was added dropwise a solution of CBZCl (0.116 g, 0.68 mmol) in methanol (3 mL). The mixture was warmed to rt, stirred 2 h, evaporated to remove methanol, diluted with water (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried and evaporated to give benzyl (2S,3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexylbutan-2-ylcarbamate (0.117 g, 51%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.32 (m, 5H), 5.37 (brs, 1H), 5.09 (s, 2H), 4.36 (brs (1H), 3.76 (m, 2H), 1.82 (m, 1H), 1.66 (m, 4H), 1.44 (s, 9H), 1.35-1.10 (m, 6H), 1.07 (d, J=6.4 Hz, 3H), 1.00-0.78 (m, 2H); MS (E/Z): 405 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35]C)=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:9])[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([OH:35])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:20])=[O:21])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCC[C@@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 110 °C
Yield: 36.8 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-2-yl)carbonylamino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 146, 0.120 g) and lithium hydroxide monohydrate (0.095 g) was suspended in dioxane (5 mL) and water (1 mL) and the mixture was stirred and heated at 110° C. for 22.5 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-2-yl)carbonylamino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.043 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=NC=C(F)C=3)=CC([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21]([N:46]3[CH2:44][CH2:47][NH:48][C:49](=[O:51])[CH2:50]3)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cncc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cncc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CCN1

Procedure:
100 mg (0.28 mmol) of the compound of Example 61A is reacted analogously to the synthesis of the compound of Example 98 with 31 mg (0.31 mmol) of 2-oxopiperazine. 71 mg (58% of theory) of the title compound is obtained.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:2]3[N:6]4[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:5]4=[N:4][C:3]=3[CH:13]([CH3:15])[CH3:14])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: COc1ccn2c(I)c(C(C)C)nc2n1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COc1ccn2c(C(O)c3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C(C)C)nc2n1
Yield: 62.7 %

Procedure:
[step 4] Using 3-iodo-2-isopropyl-7-methoxyimidazo[1,2-a]pyrimidine (649 mg, 2.05 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (300 mg, 1.02 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[(hydroxy) (2-isopropyl-7-methoxyimidazo[1,2-a]pyrimidin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (310 mg, 63%) was obtained.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.CCN(CC)CC.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CC#N>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)=[N:4]1
Reactant: Oc1cccc(-c2nn[nH]n2)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Cn1nnc(-c2cccc(O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)phenol (250.8 mg, 1.547 mmol) in MeCN (10 mL) at rt was added Et3N (0.237 mL, 1.701 mmol) followed by methyl bromoacetate (260 mg, 1.701 mmol). The reaction was stirred at rt for 16 h. Volatiles were removed. Chromatography over silica eluting with 30-60% EtOAc/hexanes afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, 1H, J=7.5 Hz), 7.69 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.01 (dd, 1H, J=8.0, 2.3 Hz), 5.53 (bs, 1H), 5.50 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: COc1ccc(CS)cc1
Product: COc1ccc(CSCC(O)CC(NS(=O)(=O)c2ccc(-c3ccc(OC)cc3)cc2)C(=O)O)cc1

Procedure:
Example 50 is prepared from 4-methoxy-α-toluenethiol and 1d using the procedure described for compound 20.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Li])CCC>>[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]([OH:22])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(Br)cc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: [Li]CCCC
Product: COc1cc(C(O)c2ccc(C)cc2)ccc1OCc1ccccc1

Procedure:
The synthesis is based essentially on the reaction of 4-bromotoluene with 4-(benzyloxy)-3-methoxybenzaldehyde in the presence of butyllithium to give 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol. By oxidation to 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone and subsequent debenzylation there is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone. After regioselective nitration to 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone and subsequent hydrolysis of the methoxy group there is obtained the aforementioned inhibitor 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.