Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]([CH3:37])([CH3:36])[C:15]([NH:17][C:18]1[S:19][C:20]([C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)=[O:16].C([O-])([O-])=O.[K+].[K+].[CH2:44]1[CH2:50][O:49][CH2:48][CH2:47][NH:46][CH2:45]1.Cl>O.ClCCl.N1C=CC=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([C:20]2[S:19][C:18]([NH:17][C:15]([C:14]([NH:13][C:2]([N:46]3[CH2:45][CH2:44][CH2:50][O:49][CH2:48][CH2:47]3)=[O:4])([CH3:37])[CH3:36])=[O:16])=[N:22][C:21]=2[C:23]([F:25])([F:26])[F:24])=[O:35])=[CH:29][CH:30]=1
Reactant: C1CNCCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(NC(=O)N1CCCOCC1)C(=O)Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of triphosgene (79 mg, 0.27 mmol) and 2-Amino-N-[5-(4-fluoro-benzoyl)-4-trifluoromethyl-thiazol-2-yl]-2-methyl-propionamide (100 mg, 0.266 mmol), K2CO3 (147 mg, 1.07 mmol) in water (3 mL) and dichloromethane (3 mL) was stirred at RT for 1 h, and water layer was separated, and dichloromethane layer was dried over Na2SO4 and concentrated to give the crude intermediate, which was taken up in pyridine (10 mL). Homomorpholine HCl salt (269 mg, 2.66 mmol) was basified by partitioning between ethyl acetate and aqueous KOH, and after evaporation of the solvent, it was added to the intermediate above. The mixture was heated at 80° C. for 18 h, and most of pyridine was removed under vacuum, and the mixture was partitioned between ethyl acetate and 1 M HCl. The combined organic extract was dried over Na2SO4, concentrated and chromatographed to give the title compound. m/z 503.0 (MH+), 1H NMR (CDCl3) δ 11.4 (s, 1H), 7.92 (dd, J=8, 4 Hz, 2H), 7.16 (t, J=8 Hz, 2H), 4.64 (s, 1H), 3.80-3.75 (m, 4H), 3.60-3.50 (m, 4H), 2.02-1.93 (m, 2H), 1.63 (s, 6H). Retention time 1.31 min (method A).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH2:14]([CH:17]1[CH2:22][CH2:21]C(CO)[CH2:19][CH2:18]1)[C:15]#[CH:16].O>CCOCC>[C:5]([O:4][CH2:1][CH:2]1[CH2:21][CH2:22][CH:17]([CH2:14][C:15]#[CH:16])[CH2:18][CH2:19]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCC1CCC(CO)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: C#CCC1CCC(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Acetic anhydride (0.92 mL, 8.25 mmol) and pyridine (0.2 mL, 2.5 mmol) were added to a solution of 5.3 (250 mg, 1.65 mmol) in 25 mL ether. The reaction was allowed to stir at ambient temperature for 24 hours. Water was added to the reaction and the organic was further extracted with 10% NaHCO3. The organic layer was dried with MgSO4 and evaporated. The residue was chromatographed on silica gel with EtOAc-Hexanes (5:95) to yield 5.6 (47%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][C:4]1([NH:15][C:16](=[O:19])[O:17][CH3:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH2:2][CH:3]1[CH2:5][C:4]1([NH:15][C:16]([O:17][CH3:18])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (intermediate B7a) (3.5 g, 13.1 mmol, Eq: 1.00) in dichloromethane (20 ml) at 0° C. was added triethylamine (2.66 g, 3.66 ml, 26.3 mmol, Eq: 2.00) followed by dropwise addition of methanesulfonyl chloride (2.26 g, 1.54 ml, 19.7 mmol, Eq: 1.50) and the mixture was stirred at 0° C. for 2 h. Poured into ice cold 1 M HCl-sol., extracted with tert-butyl methyl ether, washed organic layer with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow oil. MS (ISP): m/z=362.1 [(M+NH4)+].
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[OH:20])[CH:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]O>>[CH3:25][O:23][C:22](=[O:24])[CH2:21][CH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:3](=[O:10])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:19]([OH:20])[CH:18]=2)[CH2:14][CH2:15]1
Reactant: CO
Reactant: O=C(O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Analogously to the description in Example 2, 7.5 g of 5-benzoyl-6-hydroxy-indane-1-acetic acid methyl ester and 50 ml of 2 N sodium hydroxide solution in 300 ml of methanol give 5-benzoyl-6-hydroxy-indane-1-acetic acid of melting point 148°-150° C. (from ether-petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.[CH2:18]=O.Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C(O)(C)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH:14]([CH2:15][CH3:16])[CH2:18][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: C=O
Reactant: CCCC(=O)c1ccc(OC)c2c1CCCC2
Reactant: C1CCNC1
Agent: Cl
Solvent: CC(C)O
Product: CCC(CN1CCCC1)C(=O)c1ccc(OC)c2c1CCCC2
Yield: 62.7 %

Procedure:
A mixture of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-1-butanone (2.50 g), paraformaldehyde (0.42 g), pyrrolidine hydrochloride (1.51 g), and hydrochloric acid (0.2 ml) in isopropyl alcohol (7 ml) was refluxed for 15 hours. The reaction mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl ether. The aqueous layer, was extracted, neutralized with ammonia water, and then extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-2-ethyl-3-pyrrolidino-1-propanone (2.13 g, Yield: 62.8%) as an oil. ##STR186##
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:22]1([S:32](Cl)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.C(OCC)(=O)C>[C:22]1([S:32]([N:9]2[C:8](=[O:13])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]2=[O:12])(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1S(=O)(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthalenesulfonyl chloride (471 mg) was added at 0° C., and the mixture was stirred at room temperature overnight. After water was added carefully, ethyl acetate (100 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The material was dissolved in ethyl acetate, and purified by silica gel chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain 100 mg of white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][C@H:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[C:51](O)=[O:52])=[O:44])=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])([O:14][C:51](=[O:52])[CH:50]([NH:54][C:55]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])[CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:43]([O:42][CH2:41][C:38]2[CH:37]=[CH:36][CH:35]=[CH:40][CH:39]=2)=[O:44])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1

Procedure:
A suspension of 96 mg of 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (MW: 481.52, 0.2 mmol), 195 mg of Z-Lys (Z)—OH (MW: 414.46, 0.4 mmol) and 49 mg of 4-dimethylaminopyridine (MW: 122.17, 0.4 mmol) in 2 ml dichloromethane was treated under stirring at room temperature with 115 mg N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid hydrochloride (MW: 191.70, 0.6 mmol). The reaction mixture was stirred over night. The mixture was diluted with 20 ml ethyl acetate and the organic layer washed successively with 10 ml N aqueous hydrochloric acid, 20 ml water and 20 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was purified by chromatography on silica, using a 9/1 dichloromethane/methanol mixture as eluent to leave a colorless sticky oil. Yield: 150 mg, 88%. MS: 878.8 (M+H)+, Method ESI+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH3:13].[H][H]>[Co]>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: N
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Reactant: [H][H]
Agent: [Co]
Product: CC1(C)CC(N)CC(C)(CN)C1

Procedure:
Isophoronenitrile (130 ml/h), ammonia (600 g/h) and 300 l/h of hydrogen are passed at about 80–100° C. in the upflow mode through the first reactor (imination reactor, 200 ml) charged with γ-Al2O3 as catalyst. The imination occurs here. The reaction mixture is fed into the first reactor (trickle-bed reactor) containing the cobalt catalyst. The temperature there is 90° C. In the third (last) reactor, the after-hydrogenation is carried out at 130° C. in the upflow mode in the presence of the cobalt catalyst. The product mixture is depressurized and cooled and analyzed by gas chromatography.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:20][CH2:19][C:18]4[C:14](=[CH:15][NH:16][N:17]=4)[CH2:13]3)[C:8]2=[O:21])=[C:4]([Cl:24])[CH:3]=1.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O>[Cl:24][C:4]1[CH:3]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([C:33]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:34])=[CH:40][CH:39]=2)[CH:23]=[CH:22][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:20][CH2:19][C:18]3[C:14](=[CH:15][NH:16][N:17]=3)[CH2:13]2)[C:8]1=[O:21]
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CN1CCN(C(=O)c2ccc(-c3ccc(CC4CCN(C5CCc6n[nH]cc6C5)C4=O)c(Cl)c3)cc2)CC1
Yield: 13 %

Procedure:
Dissolve 3-(4-Bromo-2-chloro-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Example 6) (0.471, 1.16 mmol) in DME (5.0 mL) and de-gas with a stream of nitrogen for 5.0 minutes. Add (4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone hydrochloride (0.1.14 g, 1.58 mmol), followed by 2.0 M sodium carbonate (2.03 mL, 4.06 mmol) and continue de-gas. Add Pd(Ph3)4 (0.134 g, 0.116 mmol) and heat to 80° C. for 17 hours. Dilute with ethyl acetate and water, separate and save both layers. The pH of the aqueous layer adjusted to ph 9 with 1.0 N HCl, and back extract with three portions of ethyl acetate. The organic layers are combined, dry over sodium sulfate and evaporate. Chromatography (silica 95:5 CH2Cl2/MeOH/1% NH3) yields 0.08 g (0.6%) of the title compound as an amorphorous foam. MS (m/z): 533 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].[NH:8]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-:27].[K+]>C(O)C>[NH:8]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH2:24][S:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][CH2:24][CH:23]([CH3:25])[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:16][CH:17]=2)=[O:27])=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: SCCSCCS
Reactant: C=C(C)C(=O)Nc1ccc(Nc2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Product: CC(CSCCSCCSCC(C)C(=O)Nc1ccc(Nc2ccccc2)cc1)C(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 50 °C

Procedure:
Sixty-one grams of 2-mercaptoethyl sulfide was added to a solution of 200 grams of N-(4-anilinophenyl) methacrylamide in 2450 milliliters of ethanol. A solution of 5 grams of potassium hydroxide in 50 milliliters of ethanol was then added, and the mixture was heated at 50°C. for 5 hours. Product began to precipitate after about 2 hours. The mixture was then allowed to cool to room temperature and the solid product was filtered off. The product, after drying, weighed 231.5 grams (89 percent of theory) and melted at 131° to 133.5°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C@H:10]([CH2:12][C@@H:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=[CH2:15])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C(C=C)CBr)(C)C.[Mg]>>[CH2:19]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@@H:10]([OH:11])[CH2:12][C@@H:13]([CH:16]([CH3:17])[CH3:18])[CH:14]=[CH2:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Agent: C=CC(CBr)C(C)C
Agent: [Mg]
Product: C=C[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Yield: 49 %

Procedure:
In a manner analogous to that described in Example 1 for the preparation of (αS,βS)-β-t-butoxycarbonylamino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol, from 56.6 g (320 mmol) of (RS)-2-isopropyl-3-butenyl bromide 7.7 g of magnesium and 24.2 g of N-t-butoxycarbonyl-L-phenylalanal26 there were obtained 15.6 g (49%) of t-butyl [(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamate as an epimer mixture. The desired (1S,2S,4S)-epimer was isolated as the less polar isomer. MS: 256 (M-benzyl)+, by flash chromatography on silica 5 gel using a 9:1 mixture of methylene chloride and ether as the eluting agent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]CC)=O)=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:31])=[O:28])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(F)c(Cl)c3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3ccc(F)c(Cl)c3)nc3c2CCC3)cc1
Yield: 37 %

Procedure:
Following General Procedure C, ethyl 2-(4-((2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate (0.075 g, 0.18 mmol) was reacted with ammonia in methanol (7 M, 4 mL), followed by the formation of the hydrochloride salt to afford the title compound (0.028 g, 37%) as a brown solid. MW=432.32. 1H NMR (DMSO-d6, 300 MHz) δ 14.06 (s, 1H), 9.80 (s, 1H), 8.14-8.07 (m, 1H), 7.82-7.74 (m, 1H), 7.65 (t, J=8.9 Hz, 1H), 7.54 (s, 1H), 7.41-7.32 (m, 4H), 7.01 (s, 1H), 6.94 (s, 1H), 3.42 (s, 2H), 3.15 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.33-2.17 (m, 2H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:10][C:11]([NH2:13])=[S:12])#[N:9].CN1CCOCC1>C(O)C>[C:8]([C:10](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:11]([NH2:13])=[S:12])#[N:9]
Reactant: N#CCC(N)=S
Reactant: O=Cc1cccs1
Solvent: CN1CCOCC1
Solvent: CCO
Product: N#CC(=Cc1cccs1)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a mixture of 2-thiophencarbaldehyde (22.4 g, 0.2 mol) and 2-cyanothioacetamide (22 g, 0.22 mol) in 250 ml of ethanol was added N-methylmorpholine (30.3 g, 0.3 mol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solid was filtered and washed with ethanol to give 28.2 g (72%) of product as a yellow solid after drying in vacuo. 1H-NMR (300 MHz, DMSO-d6): δ 10.0 (brs, 1H), 9.45 (brs, 1H), 8.37 (s, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.32 (dd, J=3.3, 4.8 Hz, 1H). ES MS m/z 195 (M+H)+, 193(M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]([OH:41])[C:30]3[O:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][N:34]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]([OH:41])[C:30]3[O:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][N:34]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1C(O)c1ncc(-c2ccccc2)o1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2C(O)c2ncc(-c3ccccc3)o2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step (B) (200 mg, 0.305 mmol) in 10.2 ml of CH3CN, Me3SiCl (199 mg, 1.83 mmol) was added and followed by NaI (274 mg, 1.83 mmol). The mixture was stirred at room temperature for 1 hr. Additional Me3SiCl (199 mg, 1.83 mmol) and NaI (274 mg, 1.83 mmol) were added in three portions and the reaction was stirred for additional 5.5 hr. The mixture was added to 5 ml H2O and 50 ml EtOAc. The organic layer was washed with sat. Na2S2 O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 27% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 73% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (65 mg, 37%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:4]=2[N:3]=1.[H][H]>C(Cl)Cl.CCO.[Pd]>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCOP(=O)(/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCOP(=O)(CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonate (3-1) (Example 10—Step 1) (1.0 equiv.) in DCM (0.05 M) and EtOH (0.08 M) was added 10% palladium on carbon (0.09 equiv.). A reaction vessel was charged with a hydrogen balloon and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, solvents were removed, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonate (3-3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[N+](CC)([O-])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([F:19])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC[N+](=O)[O-]
Product: COC(=O)c1cc(Br)cc2c1c(F)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 20.7 %

Procedure:
To a 20 ml vial was added methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (50.0 mg, 0.169 mmol), (selectfluor) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (78 mg, 0.219 mmol) followed with a magnetic stir bar and nitroethane (2 ml). The vial was capped and the reaction stirred at room temperature. Reaction progress was monitored by LCMS. After reaction completion the reaction solvent was removed in-vacuo. The residue was dissolved with DCM(1.4 ml). The DCM solution was charged onto an analogix Si35 SF10−8 gram column. The compound was eluted with EtOAc/Hexanes, 5-15%, 20 min. The desired product and side MW629 co-eluted. The mixture was dissolved with DMSO (1 ml) and purified by reverse phase HPLC using a Gemini 5 g 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient. The desired product eluted at 6.8 minutes and the side product MW 629 at 9.5 minutes. The desired fractions were concentrated to a residue. LCMS and NMR support the desired structure and analytical HPLC showed 100% purity. The product, methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (11 mg, 0.035 mmol, 20.53% yield), was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (t, J=1.77 Hz, 1H), 7.78 (d, J=1.77 Hz, 1H), 7.47 (d, J=2.53 Hz, 1H), 4.76-4.84 (m, J=1.64, 6.65, 6.65, 13.36 Hz, 1H), 3.96 (s, 3H), 1.50 (d, 6H). MS(ES)[M+H]+315.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH2:28])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27][NH:28][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCc1ccc(Br)cc1
Product: O=C(NCCc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 4-bromophenethylamine (65 mg, 0.32 mmol). The title compound was obtained as a solid (30 mg, 21% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.88 (1H, m), 8.38 (1H, m), 7.47(2H, dd), 7.18 (2H, dd), 3.43 (2H, m), 2.78 (2H, m). MS m/z: 529.92, 531.95, 533.95 [M+H]+.