Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]1[CH:26]=[C:27]([C:38]([F:41])([F:40])[F:39])[CH:28]=[C:29]([CH:37]=1)[C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[C:29]2[CH:37]=[C:25]([F:24])[CH:26]=[C:27]([C:38]([F:39])([F:41])[F:40])[CH:28]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1cc(F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from EDCI coupling between 3-amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech) and (5-fluoro-3-trifluoromethyl-benzoylamino)-acetic acid (prepared by the method similar to Ingersoll, A. W. et. al., Organic Syntheses 1932, XII, 40-2) using the procedure described in Step C of Example 1.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](F)[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[C:23]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Sc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 500 mg (3.1 mmol), DMF 10 ml, potassium carbonate 700 mg (5.1 mmol) and 4-chloro-2-fluoronitrobenzene 800 mg (5.0 mmol) was stirred at room temperature for 2 hours, and 5-(5-chloro-2-nitrophenylsulfanyl)isoquinoline 910 mg (92.7%) was obtained.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([S:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: c1ccc(Sc2ccc3[nH]ccc3c2)cc1
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Sc4ccccc4)cc23)CC1

Procedure:
5-Phenylthioindole (0.50 g, 2.22 mmol), 1-methylpiperid-4-one (0.292 g, 0.32 mL, 2.58 mmol) and sodium methoxide (0.139 g) were heated at reflux in MeOH (25 mL) for 20 hr. After cooling and work-up, 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole was obtained as a pale yellow solid, 0.399 g, (56%). This free base (0.20 g) was treated with fumaric acid (0.11 g, 0.94 mmol) in MeOH/Et2O to give: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole fumarate, 0.124 g (46%), m.p. 225°-28° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:35])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])[C:17]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:35])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCOC(=O)/C=C\C(=O)OCCCCCCCCCCCC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCCCCCCCCCCCC

Procedure:
The procedure of Example 1 is repeated using 7.15 grams of 2,6-di-tert-butyl-4-mercaptophenol, 13.58 grams of di-n-dodecyl maleate, and 0.3 gram of triethylamine. The product is purified by dry column chromatography to give a clear liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]2[CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)#[N:2].[NH:21]1[C:29]2[C:24](=[C:25]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:13][CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:14]2[CH2:19][CH2:18][CH:17]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]5[CH:23]=[CH:22][NH:21][C:29]=5[CH:28]=[CH:27][CH:26]=4)[CH2:31][CH2:32]3)[CH2:16][CH2:15]2)=[CH:7]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: CCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A solution of 4-(5-cyano-1-ethyl-indol-3-yl)-cyclohexanone (1.5 g, 5.6 mmol), 1-(indol-4-yl)piperazine (1.19 g, 5.9 mmol), sodium triacetoxyborohydride (1.73 g, 8.2 mmol) and acetic acid (0.9 ml, 15 mmol) in 1,2-dichloroethane (30 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×80 ml), and washed with brine (3×80 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) afforded 0.98 g (39%) of product as a white solid: mp 226° C. (dec.).
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])(=[O:24])=[O:25])=[CH:27][CH:28]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1NC(=O)C(F)(F)F)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)C(F)(F)F)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
To a solution of 1.0 g (2.54 mmol) of methyl 3-hydroxy-2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino}propionate in 10 ml of CH2Cl2 was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride. After 1 hour at room temperature, the solvent was removed. Dichloromethane was added several times and the solvent removed under vacuum after each addition. Methanol was then added 2 times and the solvent removed under vacuum to give methyl 2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]-amino}acrylate as a glass. The glass was dissolved in methanol and 0.213 g of anhydrous NaHCO3 was added. The mixture was stirred at room temperature overnight and concentrated under vacuum to dryness. To the residue was added ethyl acetate and water. The organic layer was separated, washed with H2O, brine and dried with Na2SO4. The solvent was removed and the residue (1.0 g) was chromatographed on silica gel thick layer plates with hexane-ethyl acetate (1:1) as solvent to give 0.365 g of product as a glass. Anal. for C20H19F3N2O6S: Calc'd: C,50.9; H,4.1; N,5.9; F,12.1; S,6.7; Found: C,50.8; H,4.4; N,5.5; F,11.7; S,6.7; Mass spectrum (ES) 473.1 (M+H).
Reaction SMILES: [C:1]1([S:11]([NH:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[CH:42]=2)[C:24]([S:27]CC2C=CC(OC)=CC=2)=[N:25][CH3:26])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]1([S:11]([NH:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([CH:43]=[CH:44][N:45]=3)[CH:42]=2)[C:24](=[S:27])[NH:25][CH3:26])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1OCCNS(=O)(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(=S)C1(c2ccc3nccn3c2)CCCCC1OCCNS(=O)(=O)c1cccc2ccccc12
Temperature: 0 °C
Yield: 64.6 %

Procedure:
A mixture comprising 0.4 g of the 2-(2-(1-naphthalenesulfonamido)ethoxy)-1-(imidazo[1,2-a]pyridin-6-yl)-1-((4-methoxybenzylthio)(methylimino)methyl)cyclohexane, 0.5 ml of anisole, 5 ml of trifluoroacetic acid and 5 ml of dichloromethane was stirred under cooling with ice for 1.5 hours, followed by the addition of ice-water. The resulting mixture was alkalinized with sodium carbonate and extracted with chloroform. The chloroform phase was dried over anhydrous magnesium sulfate and ditilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: a 80:1 dichloromethane/methanol mixture) and crystallized from ethyl acetate/n-hexane to give 0.21 g of the title compound as a white powder (yield: 65%).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[CH2:13]([O:15][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH3:36])[CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:14].C(N(CC)CC)C>ClCCl>[C:8]([O:7][C:1]([CH2:36][NH:35][CH2:34][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][CH:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH3:20])=[O:18])=[CH:23][CH:24]=2)[CH:33]=[CH:32][CH:31]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A solution of 0.4 g (1.9 mmol) of di-tert-butyl carbonate in 5 ml of dichloromethane is added dropwise to a solution of 0.6 g (1.9 mmol) of methyl 2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate and 0.25 ml (1.9 mmol) of triethylamine in 10 ml of dichloromethane. After stirring at room temperature for 48 hours, the medium is washed with water, extracted with dichloromethane, dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 0.78 g of methyl 3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxypropionate is obtained in a yield of 85%.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)nn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: c1ccc(-c2ccc(-c3ccc(-c4ccccn4)nn3)nn2)nc1

Procedure:
Specifically, it was envisioned, firstly, to use the 6,6′-dichloro-3,3′-bipyridazine dimer 17, which, when subjected to Stille heterocoupling in the presence of two equivalents of 2-tributylstannylpyridine 18, should produce the expected 6,6′-bis(pyridin-2-yl)-3,3′-bipyridazine 19.
Reaction SMILES: CC(C)(C)CC([N:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8](C=O)[CH2:7]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:35]CCCl>C(Cl)Cl>[ClH:35].[C:11]1([CH:9]2[CH2:10][NH:6][CH2:7][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)CC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cl
Product: c1ccc(C2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To 89 mg (0.35 mmol) of 1-isopropyl-3-methyl-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2,4-dione in DCE (5 mL) was added 97 mg (0.35 mmol) of (3R,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidine-3-carbaldehyde in DCE (5 mL) and stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (113 mg, 0.53 mmol) was then added and the reaction mixture stirred overnight at room temperature. The reaction mixture was diluted with DCM, the organic layer washed with sodium bicarbonate, and then dried over sodium sulfate. The reaction mixture was filtered, purified by semi-preparative HPLC (Method B) and lyophilized to give (3S,4S)-1-(3,3-dimethyl-butyryl)-3-[1-isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine hydrochloride (16 mg, 8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[O:6].C1COCC1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:6])[CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOc1c(Br)cc(C=O)cc1OC
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOc1c(Br)cc(C(O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 1l round bottomed flask with a stirring bar and an argon inlet was added 3-bromo-4-(2-methoxyethoxy)-5-methoxybenzaldehyde (12.00 g, 41.50 mmol) and dry THF (150 mL). This solution was cooled in an ice bath and phenylmagnesiumbromide in diethyl ether (16.6 mL of a 3.0 M solution, 49.81 mmol) was added with a syringe. The resulting solution was stirred for 1 h at 0° C. The reaction was quenched with aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This material was chromatographed on 400g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol as an oil. 1H NMR (CDCl3): δ2.29 (d, j=4Hz, 1H); 3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.82 (s, 3H); 4.13 (t, j=4 Hz, 2H); 5.75 (d, j=4Hz, 1H); 6.88 (s, 1H); 7.12 (s, 1H); 7.35 (m, 5H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](C=O)=[CH:4]1.[Br:14][CH2:15][CH2:16][CH2:17]Br.Cl.CN([CH:23]=[O:24])C>O>[Br:14][CH2:15][CH2:16][CH2:17][N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:23]=[O:24])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: BrCCCBr
Reactant: CN(C)C=O
Reactant: O=Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc2c(ccn2CCCBr)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
0.70 g (30.31 mmol) of 60% sodium hydride suspension are added to 14 ml of anhydrous DMF and a solution of 2.40 g (16.53 mmol) of 1H-indole-3-carbaldehyde in 10 ml of DMF added dropwise. After 45 min of stirring at room temperature the solution is cooled externally with an ice/water bath and a solution of 2.52 ml (5.01 g; 24.80 mmol) of 1,3-dibromopropane in 6 ml of DMF added dropwise. The solution is stirred at room temperature for 2 hr before adding 10 ml of water and 10 ml of 2N HCl. The suspension is extracted thrice with ethyl ether, washed with water, dried and concentrated in vacuo. The residue is chromatographically purified (hexane to hexane/EtAcO 4:1) to give 1.4 g of the pure title compound (33% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([N:19]([CH3:26])[CH:20]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21]2)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46]([N:48]2[C:52]([CH3:53])=[N:51][N:50]=[N:49]2)[CH:47]=1)[NH2:44].CO>O>[C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:44][C:43]3[CH:45]=[C:46]([N:48]4[C:52]([CH3:53])=[N:51][N:50]=[N:49]4)[CH:47]=[C:41]([O:40][CH3:39])[CH:42]=3)[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=3)[C:17]([N:19]([CH3:26])[CH:20]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21]3)=[O:18])[C:5]2=[N:10][CH:9]=1)#[N:12]
Reactant: COc1ccc(CN(c2cccc(C(=O)N(C)C3CCN(C)C3)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: COc1cc(N)cc(-n2nnnc2C)c1
Solvent: CO
Solvent: O
Product: COc1cc(Nc2cc(Nc3cccc(C(=O)N(C)C4CCN(C)C4)c3)c3ncc(C#N)n3n2)cc(-n2nnnc2C)c1

Procedure:
Example 254 was prepared from 254A and 3-methoxy-5-(5-methyl-1H-tetrazol-1-yl)aniline by utilizing the procedure as described in Example 6. HPLC: Rt=1.53 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min. with 1 min. hold time, flow rate=5 mL/min., detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). MS (ES): m/z=579.13 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.[CH3:12][NH2:13].[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:5]1[N:4]=[CH:3][C:2]2[N:1]=[C:30]([C:29]3[CH:32]=[CH:33][C:26]([O:25][CH:22]4[CH2:23][CH2:24][N:19]([CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:20][CH2:21]4)=[CH:27][CH:28]=3)[N:13]([CH3:12])[C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: Nc1cnc(Cl)cc1C(=O)O
Reactant: CN
Reactant: O=Cc1ccc(OC2CCN(C3CCCC3)CC2)cc1
Product: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-chloroisonicotinic acid, methylamine and 4-[(1-cyclopentyl-4-piperidinyl)oxy]benzaldehyde.
Reaction SMILES: C1(NC=CP(=O)(OCC)[O:11][CH2:12][CH3:13])CCCCC1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:36]([CH:37]=O)=[C:35]([CH:39]([CH3:41])[CH3:40])[N:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31](=[O:42])[NH:32]3)=[CH:23][CH:22]=1.O.O.C(O)(=O)C(O)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:36](/[CH:37]=[CH:13]/[CH:12]=[O:11])=[C:35]([CH:39]([CH3:40])[CH3:41])[N:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31](=[O:42])[NH:32]3)=[CH:25][CH:26]=1
Reactant: CC(C)c1nc2[nH]c(=O)ccc2c(-c2ccc(F)cc2)c1C=O
Reactant: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc2[nH]c(=O)ccc2c(-c2ccc(F)cc2)c1/C=C/C=O
Reaction time: 0.5 h

Procedure:
A solution of 13.1 g (50 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphonate in 80 ml of tetrahydrofuran is added dropwise at 0° C. under argon to a suspension of 3.0 g (100 mmol) of 80% strength sodium hydride in 80 ml of anhydrous tetrahydrofuran and the mixture is stirred at this temperature for 30 min. A solution of 13.0 g (42 mmol) of the compound from Example 4 in 80 ml of tetrahydrofuran is then added dropwise at 0° C.-5° C. and the mixture is then heated under reflux for 1 h. 200 ml of water are added cautiously and the mixture is extracted three times with ethyl acetate. After concentrating the organic phases, the residue is heated under reflux for 2 h with a mixture of 500 ml of toluene, 500 ml of water and 27.5 g (218 mmol) of oxalic acid dihydrate. The toluene phase is concentrated and the residue is treated with ethyl acetate. 11.35 g (80% of theory) of colorless crystals of m.p. 261° C. are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23]Br)=[CH:20][CH:19]=1.[OH-].[Na+]>CO>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: COc1ccc(CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCn2cnc(-c3cc(C(=O)O)ccn3)c2)cc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 4-methoxyphenethyl bromide according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 3.02 (2H, t, J=7.2 Hz), 3.71 (3H, s), 4.24 (2H, t, J=7.2 Hz), 6.83 (2H, t, J=8.6 Hz), 7.12 (2H, t, J=8.6 Hz), 7.58 (1H, d, J=3.7 Hz), 7.62 (1H, s), 7.82 (1H, s), 8.26 (1H, s), 8.63 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H17N3O3, 324. Found, 324.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(C2C=C(C3CCNCC3)C=CC=2NC(C2NC=C(C#N)N=2)=O)CCCCC=1.BrCC(OC(C)(C)C)=O.CCN(CC)CC.C([O:56][C:57](=[O:87])[CH2:58][N:59]1[CH2:64][CH2:63][CH:62]([C:65]2[CH:70]=[CH:69][C:68]([NH:71][C:72]([C:74]3[NH:75][CH:76]=[C:77]([C:79]#[N:80])[N:78]=3)=[O:73])=[C:67]([C:81]3[CH2:86][CH2:85][CH2:84][CH2:83][CH:82]=3)[CH:66]=2)[CH2:61][CH2:60]1)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:79]([C:77]1[N:78]=[C:74]([C:72]([NH:71][C:68]2[CH:69]=[CH:70][C:65]([CH:62]3[CH2:61][CH2:60][N:59]([CH2:58][C:57]([OH:87])=[O:56])[CH2:64][CH2:63]3)=[CH:66][C:67]=2[C:81]2[CH2:86][CH2:85][CH2:84][CH2:83][CH:82]=2)=[O:73])[NH:75][CH:76]=1)#[N:80]
Reactant: CC(C)(C)OC(=O)CN1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Agent: CC(C)(C)OC(=O)CBr
Agent: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CC(=O)O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 38.9 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (33 mg, 0.067 mmol) (as prepared in Example 14, step (b)), t-butyl bromoacetate (10 μL, 0.067 mmol), NEt3 (20 μL, 0.135 mmol) and 0.25 mL of DCM and stirred for 10 h at 25° C. The reaction mixture was loaded on a 5 g SPE cartridge (silica) and 23 mg (70%) of (4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-acetic acid tert-butyl ester was eluted with 25% EtOAc/DCM. This compound was dissolved in 1 mL of DCM and 20 μL of EtOH and 1 mL of TFA were added and the reaction stirred for 3 h at 25° C. The title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 10 mg (40%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.16 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.10 (d, 1H), 5.72 (m, 1H), 4.04 (s, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 2.90 (m, 1H), 2.29 (m, 4H), 2.10 (m, 4H), 1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H27N5O3, 434.2 (M+H). found 434.2.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]([F:56])([F:55])[F:54])[N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]([F:54])([F:56])[F:55])[N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C(F)(F)F)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7S,10aS)-5-oxo-7-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (19 mg, 0.035 mmol) and Intermediate 77 (9.0 mg, 0.034 mmol) to give a white solid (25 mg, 90% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-6.82 (m, 16H), 5.21 (t, J=6.7 Hz, 2H), 4.97-4.84 (m, 2H), 4.76 (t, 1H), 3.98-3.82 (m, 1H), 3.79 (s, 3H), 3.46-3.30 (m, 1H), 3.25-3.08 (m, 1H), 2.93-2.75 (m, 2H), 2.75-2.53 (m, 3H), 2.44-2.29 (m, 3H), 2.21-1.28 (m, 16H).