Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1[C:24]([O:26][CH3:27])=[O:25])=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Yield: 70.3 %

Procedure:
A solution of (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (20 g) in 90% aqueous trifluoroacetic acid was stirred at room temperature for 30 minutes and the solvent was evaporated in vacuo. The residue was dissolved in a mixture of chloroform and methanol (500 ml, 3:1) and the solution was washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was solidified with ether to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (10.7 g).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:15][CH:14]=[C:13]([C:16]#[N:17])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=1)[O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:19]>>[C:1]([C:3]([C:11]1[S:15][CH:14]=[C:13]([C:16]#[N:17])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][C:22]2[CH:32]=[CH:33][CH:34]=[C:20]([C:18]#[N:19])[CH:21]=2)[CH2:31][CH2:30]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCO)c1cc(C#N)cs1
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1cc(C#N)cs1

Procedure:
The title compound was obtained as a pale yellow oil (0.15 g, 58%) from 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanol and 1-[2-(3-cyanophenoxy)ethyl]piperazine in the same manner as in Example 68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(Cl)c(Cl)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3',4'-dichloroacetophenone (2.46 g, 12.8 mmol), trimethylsilyl triflate (3.0 mL, 15.4 mmol), triethylamine (3.6 mL, 26.0 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (4.0 g, 12.8 mmol) m.p. 204°-207° C.; 1H NMR (400 MHz, CDCl3) δ 1.33 (d, 6H), 3.55 (m, 1H), 6.71 (s, 1H), 7.00 (m, 1H), 7.08 (m, 1H), 7.20 (m, 1H), 7.30 (m, 1H), 7.56 (d, 1H), 7.69 (m, 1H), 7.74 (br, 1H), 7.98 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[NH:9][C:8]=1[C:19]([O:21][CH3:22])=[O:20].F[B-](F)(F)F.C[O+](C)C.C(=O)([O-])O.[Na+].[C:37](#N)[CH3:38]>ClCCl>[CH2:37]([O:18][C:10]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:19]([O:21][CH3:22])=[O:20])[N:9]=1)[CH3:38]
Reactant: COCCCCc1c(C(=O)OC)[nH]c(=O)n1-c1ccccc1
Reactant: CC#N
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOc1nc(C(=O)OC)c(CCCCOC)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (740 mg) was dissolved in acetonitrile (8 ml), a 1M solution (6.1 ml) of trimethyloxonium tetrafluoroborate in dichloromethane was added and the reaction mixture was stirred at room temperature for 3 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-80:20) was concentrated under reduced pressure to give the object product (79 mg).
Reaction SMILES: [CH:1]1([CH:4]([C:7](=O)[CH3:8])[C:5]#[N:6])[CH2:3][CH2:2]1.CC(O)=O.O.[NH2:15][NH2:16].C([O-])(O)=O.[Na+]>C(O)C.O>[CH:1]1([C:4]2[C:7]([CH3:8])=[N:15][NH:16][C:5]=2[NH2:6])[CH2:3][CH2:2]1
Reactant: CC(=O)C(C#N)C1CC1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(N)c1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 2-cyclopropyl-3-oxobutanenitrile (compound 266.1, 4.0 g, 32.5 mmol) in ethanol (18 mL). AcOH (3 mL) and hydrazine hydrate (3.15 mL, 65 mmol) were added and the reaction was stirred overnight at 80° C. The reaction was cooled, then the pH was carefully adjusted to 9 with NaHCO3 (aq. sat.). The mixture was diluted with water, then extracted with ethyl acetate (6×60 mL) and the combined organic extracts were washed with brine (80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a brown oil (4.17 g, crude), which was used in the next step without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[C:13](=O)([O:39]C1C=CC=CC=1)[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:26]=3[N:25]=[C:24]2[CH2:37][CH3:38])=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:10][C:13](=[O:39])[O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:27]4[CH:28]=[C:29]([Cl:36])[C:30]([C:32]([F:33])([F:35])[F:34])=[CH:31][C:26]=4[N:25]=[C:24]3[CH2:37][CH3:38])=[CH:21][CH:22]=2)(=[O:9])=[O:8])[CH:2]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
To a stirred solution of 3-pyridinesulfonamide (Rafik, Karaman; et al., J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, 0.76 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 27 mg, 0.68 mmol) at room temperature. After 10 min., phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 313 mg, 0.64 mmol) was added, and the mixture was stirred for 9 h at 80° C. The mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by TLC developing with dichloromethane/methanol (6:1) and TLC developing with dichloromethane/methanol (10:1) gave 67 mg (19%) of the title compound as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CCCCN1c1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Cl)cc1
Yield: 40.6 %

Procedure:
Proceeding as indicated in example 2, from 0.035 mole (10.4 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.07 mole (7 cm3) of 2-methylpiperidine and 0.035 mole (5 g) of calcium carbonate in ethanol, 5.1 g (Yield: 40%) of the expected product are obtained after recrystallization in ethanol. M.P. 142° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1[C:17]([CH3:22])=[N:18][O:19][C:20]=1[CH3:21].[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>CO>[CH3:22][C:17]1[C:16]([CH2:15][N:5]2[CH2:6][CH2:7][C:8](=[O:14])[N:9]([CH3:13])[C:10]3[C:4]2=[N:3][C:2]([NH:23][C:24]2[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[O:29])=[CH:26][C:25]=2[O:40][CH3:41])=[N:12][CH:11]=3)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1c(C)noc1C)CCC(=O)N2C
Temperature: 150 °C

Procedure:
9-chloro-6-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-methyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-3-one (Intermediate 156; 81 mg, 0.25 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 80 mg, 0.30 mmol) p-toluenesulphonic acid monohydrate acid (96 mg, 0.5 mmol) and isopropanol (4 mL) were combined in a 10 mL microwave reactor tube and heated in by microwave irradiation at 150° C. for 80 minutes. The sample was transferred to an SCX (20 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as an off white gum (61 mg, 45%).
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#[N:2].[BrH:11].[OH-].[Na+]>>[NH2:2][C:1]1[NH:6][C:5]([Br:11])=[C:4]([C:7]#[N:8])[C:3]=1[C:9]#[N:10]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)[nH]c(Br)c1C#N

Procedure:
Tetracyanoethylene (1) is reacted with HBr followed by treatment with a base such as NaOH produced 2-amino-5-bromo-3,4-dicyanopyrrole (3). Treatment of 3 with triethyl orthoformate followed by the addition of sodium hydride and 1 equivalent of the appropriate alkylating agent, with a catalytic amount of tetrabutylammonium iodide, gives the intermediate (5). The synthetic route is dependent upon correctly placing the alkyl substituents on the N7 position. Alkylation of 5 before cyclization controls the regiochemistry. Reaction of 5 with methanolic ammonia affords the 7-alkylated-4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidines (6). Thus, by selecting the appopriate alkyl substiuent, the desired 7-alkylated-4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidines can be prepared.
Reaction SMILES: [NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2I)=[C:4]([F:18])[CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)=[C:4]([F:18])[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1cc(F)c(Oc2ccnc(N)c2I)cc1F
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: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2c(Oc3cc(F)c(N)cc3F)ccnc2N)cn1
Yield: 65.1 %

Procedure:
To a degassed solution of 4-(4-amino-2,5-difluorophenoxy)-3-iodopyridin-2-amine (0.33 g, 0.91 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.28 g, 1.36 mmol) in dioxane (5 ml) was added a degassed solution of K2CO3 (0.37 g, 2.73 mmol) in water (2 mL) and tetrakis(triphenylphosphine)palladium(0) (0.105 g, 0.09 mmol). The resultant mixture was stirred for 16 h at 90° C. Sat. NaHCO3 solution (35 mL) was added. The resultant mixture was extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/CH2Cl2) to afford 4-(4-amino-2,5-difluorophenoxy)-3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (188 mg, 65.2%) as white solid (188 mg, 65.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.57 (s, 1H), 7.06 (dd, J=11.2 Hz, 7.2 Hz, 1H), 6.66 (dd, J=12.0 Hz, 8.0 Hz, 1H), 5.86 (d, J=5.6 Hz, 1H), 5.60 (s, 2H), 5.39 (s, 2H), 3.85 (s, 3H); MS (ESI) m/z: 318.1 (M+H+).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:41]([NH:43][C@H:44]([C:48]([NH:50][C@H:51]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH2:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:42])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:40])[NH:21][S:22]([C:25]1[C:38]([CH3:39])=[C:36]([CH3:37])[C:35]2[O:34][C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28]=2[C:26]=1[CH3:27])(=[O:24])=[O:23])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1CCCCC1>ClCCl.CCCCCCC>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:41]([NH:43][C@H:44]([C:48]([NH:50][C@H:51]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[CH2:52][C:53](=[O:58])[O:54][CH2:55][CH:56]=[CH2:57])=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:42])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:40])[NH:21][S:22]([C:25]1[C:38]([CH3:39])=[C:36]([CH3:37])[C:35]2[O:34][C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][C:28]=2[C:26]=1[CH3:27])(=[O:23])=[O:24])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCCCCCC
Product: C=CCOC(=O)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CCC(C)(C)O2)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of Fmoc-Glu(OBut)-Arg(Pmc)-Val-Asp(OAllyl)-OBzl (SEQ ID NO: 37) (12.3 g, 10.3 mmol) in 105 mL of dichloromethane is added piperidine (3.5 g, 41.3 mmol) at ambient temperature. The mixture is stirred 2 hours, then diluted with heptane, concentrated to half volume, and left standing in the freezer overnight. The liquor is decanted from the oily residue, which is then taken up in dichloromethane. The solution is washed with 0.5M aqueous citric acid, water, and brine, dried (magnesium sulfate), filtered, and concentrated. The crude solid is triturated twice with heptane and filtered to give 9.0 g of Glu(OtBu)-(L)Arg(Pmc)-Val-Asp(OAllyl)-OBzl as a white powder. (Mcalc 970.2; M+1obsvd 971).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:36])[N:25]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:33]([CH2:32][CH2:31][N:25]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24](=[O:36])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)(=[O:35])[NH2:34]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC(N)=O)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of (2-{3-[(2-carbamoyl-ethyl)-cyclopentyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.074 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure to give the title compound (0.060 g) as a colourless gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19]C(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12]([CH:18]=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3ccsc23)cc1
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)c2sccc12

Procedure:
In analogy to the procedure described in example 91 b], 7-benzyloxy-benzo[b]thiophene (prepared from benzo[b]thiophen-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-7], benzylchloride, potassium carbonate in N,N-dimethylformamide at room temperature) was reacted with dichloromethyl methyl ether in dichloromethane at 0° C. to give 7-benzyloxy-benzo[b]thiophene-4-carbaldehyde. Treatment of 7-benzyloxy-benzo[b]thiophene-4-carbaldehyde with (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride and potassium carbonate in 2-propanol in analogy to the procedure described in example 93 a] gave 3-(7-benzyloxy-benzo[b]thiophen-4-yl)-2(Z,E)-ethoxy-acrylic acid ethyl ester. Reduction of 3-(7-benzyloxy-benzo[b]thiophen-4-yl)-2(Z,E)-ethoxy-acrylic acid ethyl ester with magnesium in THF/MeOH (1:1) at 50° C. in analogy to the procedure described in example 93 b] yielded [rac]-3-(7-benzyloxy-benzo[b]thiophen-4-yl)-2-ethoxy-propionic acid methyl ester, subsequent removal of the benzyl protective function with dimethyl sulfide and boron trifluoride diethyl etherate in dichlormethane at room temperature in analogy the procedure described in example 93 c] gave [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester as light yellow oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:25]([NH:26][C@@H:27]3[CH2:34][C@@H:30]4[CH2:31][NH:32][CH2:33][C@@H:29]4[C@H:28]3[CH3:35])=[C:24]([C:36]([NH2:38])=[O:37])[CH:23]=[N:22][N:21]2[CH:39]=1.[OH:40][CH2:41][C:42](O)=[O:43]>CN(C)C=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:25]([NH:26][C@@H:27]3[CH2:34][C@@H:30]4[CH2:31][N:32]([C:41](=[O:40])[CH2:42][OH:43])[CH2:33][C@@H:29]4[C@H:28]3[CH3:35])=[C:24]([C:36]([NH2:38])=[O:37])[CH:23]=[N:22][N:21]2[CH:39]=1
Reactant: C[C@@H]1[C@H]2CNC[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2CN(C(=O)CO)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 1 h
Yield: 94.7 %

Procedure:
N,N-diisopropylethylamine (0.532 mL, 3.05 mmol) was added to a solution of 6-bromo-4-(((3 aS,4R,5R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt from Step 2 of Example 59 (250 mg, 0.508 mmol), 2-hydroxyacetic acid (77 mg, 1.016 mmol) and (benzotriazol-1-yloxy)tris(dimethylamine)phosphonium hexafluorophosphate (449 mg, 1.016 mmol) in N,N-dimethylformamide (5 mL). After 1 h at room temperature, the mixture was diluted with saturated sodium bicarbonate (5 mL) and ethyl acetate (100 mL), washed with water, brine, dried (MgSO4) and concentrated to give the expected product (210 mg). This material was used in the next reaction without purification. 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1 H, s), 7.63 (1 H, s), 7.03 (1 H, d, J=1.32 Hz), 4.83-4.96 (2 H, m), 4.06-4.36 (2 H, m), 3.43-3.75 (3 H, m), 3.04-3.10 (1 H, m), 2.80-2.85 (1 H, m), 2.41-2.58 (1 H, m), 1.60-1.94 (1 H, m), 1.39-1.56 (1 H, m), 1.08-1.20 (3 H, m), MS (ES+) m/z: 436.1, 438.2 (M+H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:32][C:33]([F:36])([F:35])[F:34].CC(=O)OCC>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:32][C:33]([F:34])([F:36])[F:35]
Reactant: C=C(c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(OCC(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (253 mg, 1.06 mmol) and 1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (360 mg, 1.06 mmol) in DMF (10 mL) at rt was added TEA (107 mg, 1.06 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound (105 mg; yield 18.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.76-7.69 (m, 5H), 4.80 (q, J=8.8 Hz, 2H), 4.37 (q, J=18.4 Hz, 2H), 1.48 (s, 6H) ppm; HPLC purity: 96.2% at 220 nm and 98.3% at 254 nm; MS: m/z=542.2 (M+, ESI+).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:12]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1>CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:12][C:13]=1[O:20][CH2:21][C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)C(CC1CC1)c1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Solvent: CO
Product: CCOC(=O)C(CC1CC1)c1ccc(N)c(OCC(F)(F)F)c1
Reaction time: 6 h
Yield: 98.1 %

Procedure:
To a stirred solution of ethyl 3-cyclopropyl-2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)propanoate (1.0 g), in dry MeOH (100 mL) Pd(OH)2 (500 mg) was added and the mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered off through a pad of Celite™, washing with MeOH. The combined filtrates were concentrated under reduced pressure to give ethyl 2-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (0.9 g) as a thick liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:28]3[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]3)[CH:15]=[CH:14][C:13]=2[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 48.6 %

Procedure:
1-(2-(1-(3,5-Dichlorophenyl)ethylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (110 mg, 0.29 mmol), N,N-diisopropylethylamine (74.6 mg, 0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (77.0 mg, 49% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C25H28Cl2F3N3O3: 545.15; Observed: 568.4 (M++Na).