Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.Cl.C[N:41](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]2[S:20][CH:21]([CH2:24][C:25]([NH2:41])=[O:26])[CH2:22][N:23]=2)=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 64 %

Procedure:
A mixture of (2-{7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (180 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (161 mg), 1-hydroxybenzotriazole ammonium salt (128 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15.5 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether. The obtained brown solid was recrystallized from ethanol to give the title compound (115 mg, yield 64%) as colorless crystals. melting point 147-148° C. MS 571 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:14]=2[CH:25]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:14]=2[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1

Procedure:
N-Bromosuccinimide (26 g.) was added to a cold solution of 5-methyl-3-(4-chlorophenyl)-1,2-benzisoxazole (35 g.) in carbon tetrachloride (250 ml.). Benzoyl peroxide (500 mg.) was added and the mixture was heated under reflux for 3 hours in the presence of U.V. light. The solid residue was filtered off, and the filtrate was evaporated to give 5-bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (m.p. 142°C.).
Reaction SMILES: [NH2:1][C@@H:2]([CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1.[OH-].[Na+]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)c1ccncc1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was then obtained in 76% yield using (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3,3-diphenyl-propionamide (product of example 72) and isonicotinic acid with general procedure A. However, 1.0N NaOH was used instead of 1.0N hydrochloric acid for the preparation of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33](OC)=O)=[CH:26][C:25]=2[O:24]1>>[O:31]1[C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33]3[NH:22][C:20](=[O:21])[C:3]4[N:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:26][C:25]=2[O:24][CH2:23]1
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Product: CC(O)C(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21

Procedure:
Analogously to the procedure of Example 29, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 20 mg (0.107 mmol) of methyl 3,4-methylenedioxyphenylacetate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[F:41][C:42]([F:71])([F:70])[CH2:43][O:44][C:45]1[CH:46]=[CH:47][C:48]([C@H:51]([NH:53][C:54]([C@H:56]2[CH2:58][C@@H:57]2[C:59]2[CH:69]=[CH:68][C:62]([O:63][CH2:64][C:65](O)=[O:66])=[CH:61][CH:60]=2)=[O:55])[CH3:52])=[N:49][CH:50]=1.Cl>>[F:33][C:34]1([F:40])[CH2:39][CH2:38][N:37]([C:65](=[O:66])[CH2:64][O:63][C:62]2[CH:61]=[CH:60][C:59]([C@H:57]3[CH2:58][C@@H:56]3[C:54]([NH:53][C@@H:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH2:43][C:42]([F:41])([F:70])[F:71])=[CH:50][N:49]=3)[CH3:52])=[O:55])=[CH:69][CH:68]=2)[CH2:36][CH2:35]1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCC(=O)N2CCC(F)(F)CC2)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A mixture of HBTU (28 mg, 0.075 mmol), triethylamine (0.03 mL, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) and 2-(4-((1S*,2S*)-2-(((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)carbamoyl)cycl opropyl)phenoxy)acetic acid (28 mg, 0.050 mmol) was stirring for 4 hours at room temperature. The mixture was poured into 2 mol/l hydrochloric acid, and the aqueous layer was extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 13.7 mg (50% yield) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH:13]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([CH2:2][O:1][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:12]2)=[CH:7][CH:8]=1)=[O:14]
Reactant: O=Cc1ccc2ccc(CO)cc2c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2ccc(C=O)cc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of the product of step 6 (430 mg, 2.31 mmol) in CH2Cl2 (5 mL) was added MsCl (318 mg, 2.7 mmol) and Et3N (559 mg, 5.5 mmol). The mixture was stirred at 0° C. for 2 h. Aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C.O1CCOCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH2:24][CH2:23]1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(Cc2ccc(CC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
In triethylamine (3 ml)-dioxane (80 ml) were dissolved 2.4 g of methyl 4-bromomethylphenylacetate and 1.9 g of 1-(2-methoxyphenyl)piperazine and the solution was stirred at room temperature for 4 hours. The solvent was then distilled off and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography [silica gel, hexane-ethyl acetate=2:1] and the resulting oil was refluxed in a mixture of 30 ml 2N-sodium hydroxide and 10 ml methanol for 3 hours. The solvent was then distilled off and the residue was dissolved in water and filtered. The filtrate was neutralized with acetic acid and extracted with chloroform. The solvent was then distilled off and the residue was recrystallized from methanol-ethylether to provide 2.0 g of the title compound melting at 87° C.-90° C. The IR absorption spectrum of this product is presented in FIG. 2.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[C:8]([CH:7]=1)[CH:9]=[O:10]
Reactant: O=Cc1cccc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
Fuming nitric acid (200 mL) was added to sulphuric acid (400 mL) at 0° C. and then 3-bromobenzaldehyde (100 g, 0.54 mol) was added dropwise in 15 minutes. After stirring for 10 minutes at the same temperature, the reaction mixture was poured into ice water and filtered to afford the mixture of products which was purified by flash column chromatography eluting with PE/EtOAc (100/1 to 20/1) to give 5-bromo-2-nitrobenzaldehyde as white solid (60 g, 48%). 1H-NMR (CDCl3, 400 MHz) δ 10.41 (s, 1H), 8.02˜8.06 (m, 2H), 7.88 (s, 1H). MS (M+H)+: 230/232.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])=[O:4].[OH-].[Na+].[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[NH:31][C:32](=O)[O:33]C1C=CC=CC=1.O>CS(C)=O>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH:23]1[NH:31][C:32]([N:11]1[CH2:10][CH2:9][C:8]2([C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:7]2)[CH2:13][CH2:12]1)=[O:33]
Reactant: O=C(NC1Cc2ccccc2C1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3Cc4ccccc4C3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
1-Methanesulfonylspiro[indoline-3,4′-piperidine]hydrochloride (60 mg) and 10M aqueous sodium hydroxide (33 μL) were added to a solution of phenyl N-(2-indanyl)carbamate (50 mg) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate to give the title compound (65 mg) as a colorless crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C([Li])CCC.CON(C)[C:17](=[O:33])[CH2:18][C:19]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:19]2([CH2:18][C:17]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=3)=[O:33])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C2(CC(=O)N(C)OC)CCCCC2)cc1
Reactant: Cc1cc(Br)ccn1
Agent: [Li]CCCC
Product: COc1ccc(C2(CC(=O)c3ccnc(C)c3)CCCCC2)cc1

Procedure:
In analogy to example 151, step 1, 4-bromo-2-methylpyridine was reacted first with n-butyllithium and later with N-methoxy-2-[1-(4-methoxy-phenyl)-cyclohexyl]-N-methyl-acetamide to give the title compound as a light yellow oil, MS (ESI+): m/z=324.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][SH:11].[ClH:12].[C:13]([NH:15][C:16](=[N:19][CH3:20])SC)#[N:14]>N1C=CC=CC=1.O>[ClH:12].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][S:11][C:16](=[N:19][CH3:20])[NH:15][C:13]#[N:14]
Reactant: CN=C(NC#N)SC
Reactant: Cc1[nH]cnc1CSCCS
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN=C(NC#N)SCCSCc1nc[nH]c1C

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethanethiol (4.0 g) (prepared from the hydrochloride as in Example 1(b) and N-cyano-N', S-dimethylisothiourea (4.0 g) were heated together under nitrogen in pyridine (100 ml) at 100° for 20 hours. After this time the mixture was evaporated to dryness to give the crude title product. This residue taken up in water acidified to pH2 with concentrated hydrochloric acid. After extracting with ethyl acetate the volume of the aqueous fraction was reduced and on cooling gave S-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-N-cyano-N'-methylisothiourea hydrochloride, m.p. 225°.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24](C)(C)C[C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1>>[ClH:15].[CH3:24][O:25][C:26]1[CH:22]=[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([N:4]4[CH2:3][CH2:2][N:1]([CH2:7][C:8](=[O:9])[N:10]5[CH2:11][CH2:12][CH2:13][CH2:14]5)[CH2:6][CH2:5]4)=[O:47])=[CH:44][CH:45]=3)[N:30]=2)[CH:20]=[CH:19][C:18]=1[O:17][CH3:16]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CC(=O)N5CCCC5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone as described for compound 8. M.p. 160–161° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: c1ccoc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and furane
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=3)[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
The product of Example 125A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (s, 1H), 8.40-8.43 (m, 1H), 7.91-8.05 (m, 2H), 7.71-7.75 (m, 1H), 7.63-7.68 (m, 2H), 7.56-7.63 (m, 2H), 7.07-7.22 (m, 3H), 3.78 (s, 2H); MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.Cl.[CH3:37][O:38][C:39](=[O:87])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([C:72]4[CH:73]=[N:74][C:75]([N:78]5[CH2:83][C@H:82]([CH3:84])[NH:81][CH2:80][C@H:79]5[CH3:85])=[CH:76][CH:77]=4)=[O:71])=[C:65]([CH3:86])[N:64]=3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:37][O:38][C:39](=[O:87])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([C:72]4[CH:73]=[N:74][C:75]([N:78]5[CH2:83][C@H:82]([CH3:84])[N:81]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:8])[CH3:1])=[O:6])[CH2:80][C@H:79]5[CH3:85])=[CH:76][CH:77]=4)=[O:71])=[C:65]([CH3:86])[N:64]=3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)NC[C@H]5C)nc4)c(C)n3)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)c(C)n3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of (s)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.13 mg, 0.019 mmol), and HATU (8.52 mg, 0.022 mmol) was stirred in DMA (1 mL) for 10 min and then [(S)-1-((S)-2-{4-[4-(5-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-6-methyl-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 4 HCl (15 mg, 0.018 mmol; Preparation 59) and N,N-diisopropylethylamine (16.3 μL, 0.093 mmol) were added. The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the tri-TFA salt of the title compound (11 mg). m/z): [M+H]+ calcd for C44H55N9O5 790.43 found 790.4.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[C:13][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: O=C(CCC#Cc1ccc(C(F)(F)F)cc1)OCc1ccccc1

Procedure:
In analogy to the procedure described for example 8 a], pent-4-ynoic acid benzyl ester (Rosowsky, Andre; Forsch, Ronald A.; Queener, Sherry F., Journal of Medicinal Chemistry (2003), 46(9), 1726-1736) was reacted with 4-iodobenzotrifluoride in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH3:11][C@H:12]1[CH2:17][N:16]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Yield: 63 %

Procedure:
Following the procedures as described for compound 108a, reaction of 5-bromo-2-nitropyridine (1.5 g) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate (2.3 g), gave 107a as a yellow solid (1.5 g, 40%). MS: [M+H]+ 323. See FIG. 7.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1=Cc2cc(OCC3CCCCC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCC3CCCCC3)ccc2CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To methyl 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (425 mg, 1.35 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4 ml), and the resulting mixture was stirred at 50° C. for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-cyclohexylmethyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (389 mg, 1.29 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:15]([C:17]1[O:21][C:20]([C:22](Cl)=[O:23])=[CH:19][CH:18]=1)#[N:16].CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([NH:8][C:22]([C:20]2[O:21][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1N1CCCCC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2cccc(Cl)c2N2CCCCC2)o1
Yield: 10 %

Procedure:
Using a procedure similar to Example 3, step (d), 3-chloro-2-piperidin-1-yl-phenylamine (54 mg, 0.25 mmol, as prepared in the previous step) was allowed to react with 5-cyano-furan-2-carbonyl chloride (55.8 mg, 0.360 mmol) in the presence of DIEA (95 μL, 0.55 mmol) to afford 8.4 mg (10%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 10.70 (br s, 1H), 8.42 (dd, 1H, J=1.4, 8.1 Hz), 7.30 (dd, J=1.5, 3.7 Hz), 7.24 (d, 1H, J=3.7 Hz), 7.17 (t, 1H, J=8.1 Hz), 7.07 (dd, 1H, J=1.4, 8.1 Hz), 3.58-3.52 (m, 2H), 2.85-2.82 (m, 2H), 2.02-1.99 (m, 1H), 1.89-1.72 (m, 4H), 1.52-1.38 (m, 1H), Mass spectrum (ESI, m/z): Calcd. for C17H16ClN3O2, 330.0 (M+H), found 330.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].C(OC(=O)C)(=O)C.[N+:17]([O-])([OH:19])=[O:18]>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(N)cc1
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Ethylaniline (15.0 g, 124 mmol) was carefully added to acetic anhydride (100 mL, 1.06 mol) that was pre-cooled to 0° C., and the mixture was warmed to rt over 30 min, then recooled to 0° C., and nitric acid (7.90 mL of a 70% v/v aq. solution, 124 mL) was added dropwise. After 30 min, the reaction mixture was quenched into an ice-water bath, the resulting slurry was filtered, and the filter cake was dried in vacuo. The crude solid product was dissolved in 6M HCl (100 mL) and dioxane (60 mL), and the resulting mixture was heated at 0° C. After 3 h, the reaction mixture was cooled to rt and concentrated in vacuo. The crude residue was suspended in EtOAc and neutralized via addition of 6N NaOH. The layers were separated, and the aq. layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound, i-6a, m/z (ES) 167 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Br)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Nc1ccccc1)c1ccccc1F
Yield: 99.8 %

Procedure:
A solution of bromo-(2-fluoro-phenyl)-acetic acid methyl ester (I259) (1.47 g, 5.95 mmol), aniline (814 ul, 8.93 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.53 mL, 8.93 mmol) in acetonitrile (10 mL) is heated under microwave irradiation at 100° C. for 1 hour. The solvent is evaporated, the residue is taken up with DCM and washed with water and brine, dried over Na2SO4 and evaporated to afford intermediate I262 as a dark brown oil (1.54 g, quantitative yield).