Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>CS(C)=O>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:21])[NH:1][C:2]2[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1nccnc1C(=O)O
Solvent: CS(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1nccnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminopyrazine-2-carboxylic acid (0.7 g) in DMSO (10 ml) was treated with 3-trifluoromethylphenylisocyanate (0.9 ml), stirred at room temperature overnight and then quenched with water. A gummy residue separated. After decantation the residue was washed thoroughly with water, stirred with NaOH to basic pH, filtered and chromatographied on silica with CH2Cl2:MeOH:acetone (4:1:1) followed by CH2Cl2:MeOH:NH4OH (40:9:1) when the product started coming off the column. This gave 3-[3-(3-trifluoromethyl-phenyl)-ureido]-pyrazine-2-carboxylic acid. Mp.>300° C.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[C:19]([NH:1][C:2](=[S:12])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:20])[C:18]1[CH:17]=[CH:21][CH:13]=[CH:3][CH:4]=1
Reactant: COC(=O)c1c(N)sc2c1CC(C)(C)OC2
Reactant: C1CCOC1
Product: COC(=O)c1c(NC(=S)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a combined mixture of methyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (ChemBridge, CAS 713111-73-0, 31 mg, 0.13 mmol, 1 equiv.) and PhCONCS (0.02 mL, 0.15 mmol, 1.2 equiv.) was added THF (0.7 mL). The resulting solution was stirred at 50° C. for 3 days. The solvent was then removed under reduced pressure and the crude product was triturated with hexanes, filtered, and rinsed with hexanes (4×5 mL). The product was further purified by preparatory HPLC (0-50% EtOAC:hexanes) and isolated as a white solid (38 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ 14.83 (s, 1H), 9.14 (s, 1H), 7.98 (dd, J=8.4, 1.2 Hz, 2H), 7.72-7.63 (m, 1H), 7.56 (dd, J=10.5, 4.8 Hz, 2H), 4.77 (t, J=1.5 Hz, 2H), 4.04 (s, 3H), 2.85 (s, 2H), 1.35 (s, 6H). LCMS retention time: 3.508 min; LCMS purity at 215 nm=96%. HRMS m/z calculated for C19H21N2O4S2 [M++1]: 405.0937. found 405.0942.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1>O>[N+:6]([C:14]1[CH:13]=[C:12]([C:11]([F:19])([F:20])[F:10])[CH:17]=[CH:16][C:15]=1[I:18])([O-:9])=[O:7]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1I
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 87.6 ml of concentrated sulphuric acid and 46.8 ml of concentrated nitric acid (d=1.52) is prepared at 0° C. This mixture is added dropwise to 272 g of p-trifluoromethyliodobenzene maintained at 50° C., which takes about 1 hour, after which time the application of heat is ceased and stirring is continued for a further 30 minutes. The mixture is then hydrolysed by pouring onto 750 ml of water. The product is subsequently extracted three times with 600 ml of dichloromethane each time, and the organic phase is washed in succession with water and a 20% solution of sodium bicarbonate. The solvent is then evaporated and distillation yields 273 g of 2-nitro-4-trifluoromethyliodobenzene, b.p./8 mm =120°-125° C. (yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.C([NH2:13])=O.C(O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: O=CO
Product: CC(N)c1ccc(Cl)cc1
Temperature: 180 °C

Procedure:
A mixture of 4'-chloroacetophenone (103.3 g), formamide (98%; 123 g) and formic acid (97%; 8.3 ml) was stirred and heated at 180° C. The water produced in the reaction was removed by distillation together with some of the starting acetophenone which was separated and returned to the reaction vessel. Formic acid (70 ml total) was added in small aliquots over 8 hours. The reaction mixture was cooled and exhaustively extracted with toluene. The combined toluene extracts were washed with water, dried, filtered and the filtrate evaporated. Concentrated hydrochloric acid (70 ml) was added to the residue and the mixture boiled under reflux for 1 hour. The mixture was cooled, extracted with toluene and the aqueous layer basified with aqueous sodium hydroxide (5M). The solution was steam distilled until 1.4 1 of distillate had been collected and the distillate was extracted with ethyl acetate. The combined ethyl acetate extracts were dried, filtered and the filtrate evaporated to give an oil which was distilled to give (±)-1-(4-chlorophenyl)ethylamine, b.p. 120°-122° C. (19 mmHg). A small portion of the distillate was dissolved in dry ether and an equal volume of saturated ethereal hydrogen chloride was added. The solid formed was collected by filtration and dried to give (±)-1-(4-chlorophenyl)ethylamine hydrochloride, m.p. 186°-189° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][C:3]=1[I:13].[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17].NCC1CCN(C(OC(C)(C)C)=O)CC1>>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:25][CH2:24][CH:21]2[CH2:22][CH2:23][N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)=[O:12])=[CH:4][C:3]=1[I:13]
Reactant: COc1nc(N)c(I)cc1C(=O)O
Reactant: CCCCN1CCC(CN)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CCCCN1CCC(CNC(=O)c2cc(I)c(N)nc2OC)CC1

Procedure:
The title compound was prepared according to the procedure of step 1 in example 1 using 6-amino-5-iodo-2-(methyloxy)-3-pyridinecarboxylic acid (step 3) and (1-butyl-4-piperidinyl)methylamine instead of 6-amino-5-chloro-2-(methyloxy)-3-pyridinecarboxylic acid and 1,1-dimethylethyl 4-(aminomethyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([NH2:16])[CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]=1[NH:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 113.1 %

Procedure:
Methansulfonyl chloride (1.26 g, 18.43 mmol) was added to a 0° C. solution of 4-nitro-2-aminobromobenzene (1.6 g, 7.37 mmol) and triethlyamine (1.86 g, 18.43 mmol) in 20 ml of CH2Cl2. The reaction mixture was allowed to warm to room temperature and stirred 72 hr. The mixture was poured onto 50 ml of 1M HCl and extracted with 2×100 ml ethyl acetate. The extracts were washed with brine then dried (anhydrous MgSO4) and concentrated. The material was dissolved in 10 ml of methanol and treated with 10 ml of 3M NaOH solution. The mixture was stirred overnight. The methanol was removed at reduced pressure, then 10 ml of water were added and the solution was washed with 50 ml of CH2Cl2. The aqueous was acidified to pH 1 by the dropwise addition of concentrated HCl. The product was extracted with ethyl acetate (2×75 ml). The extracts were dried (anhydrous MgSO4) and concentrated to give 2.46 g of N-(2-bromo-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: [CH3:1][C:2]([CH3:32])=[CH:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:21][CH:20]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH:19]2[CH2:18]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([N:17]3[CH2:18][CH:19]4[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:22][CH:20]4[CH2:21]3)[N:5]([CH2:4][CH:3]=[C:2]([CH3:32])[CH3:1])[C:9]=2[CH:10]=1
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(N)cc21
Yield: 85 %

Procedure:
A solution of 44 mg (0.10 mmol of tert-butyl 5-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 7.5 ml of ethanol was added dropwise to a suspension of 56 mg (1.00 mmol) of iron and 10 mg (0.18 mmol) of ammonium chloride in 0.75 ml of water, and the mixture was boiled at reflux for 3 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. The 35 mg of the desired product thus obtained were used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc2c(Cl)ccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (0.85 g) in N,N-dimethylformamide (8.5 ml) was added 60% oil-suspended NaH (245 mg) under nitrogen atmosphere while being cooled in an ice water bath. The reaction solution was stirred at ambient temperature for 1 hour and cooled again in the ice water bath. To the reaction solution was added triisopropylsilyl chloride (1.3 ml) slowly dropwise for 10 or more minutes. The reaction solution was stirred for 3 hours at ambient temperature and diluted with ethyl acetate (30 ml). The solution was washed with saturated aqueous sodium hydrogencarbonate (30 ml) and brine (20 ml). The solution was dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain 4-chloro-2-methyl-1-(triisopropylsilyl)-pyrrolo[2,3-b]pyridine (1.45 g) as a colorless transparent liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22](O)[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].C(N(CC)CC)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>C(#N)C.O>[N:47]([C:22]1[C:21]([F:25])=[CH:20][C:11]([C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:23]=1)=[N+:48]=[N-:49]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cc(F)c(N=[N+]=[N-])nc1Nc1ccc(F)cc1F
Yield: 48.9 %

Procedure:
In 10 ml of anhydrous acetonitrile was suspended 1.05 g of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and 450 mg of triethylamine and 1.22 g of diphenylphosphoryl azide were added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 4 hours. To this reaction mixture were added 50 ml of ethyl acetate and 50 ml of water, and the organic layer was separated, and then dried over anhydrous magnesium sulfate. The solvent was removed by ditillation under reduced pressure, and the residue thus obtained was purified by a column chromoatography [Wako Silica Gel C-200, eluant: benzene] to obtain 550 mg (yield 48.9%) of ethyl 2-[6-azido-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate having a melting point of 130°-131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:17][N:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a stirred solution of methyl 2-(4-methylphenylsulfonamido)acetate (3.10 g, 12.8 mmol) and Cs2CO3 (8.31 g, 25.5 mmol) in DMF (0.1 M) was added MeI (877 μL, 14.1 mmol). The reaction was allowed to stir overnight at rt. The reaction was then diluted with water and repeatedly extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to furnish 6 (2.80 g, 85%): δH (400 MHz, CDCl3) 2.42 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.66 (s, 3H, CH3), 3.97 (s, 2H, CH2), 7.31 (d, J=8.4 Hz, 2H, CH), 7.69 (d, J=8.4 Hz, 2H, CH); LRMS (ES+) calcd for [C11H15NO4S+H] 258.08. found 258.06 [M+H].
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=[C:8]([Br:18])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[N+:19]([O-])([OH:21])=[O:20]>>[N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=[C:8]([Br:18])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Br)c2c1CC(N=[N+]=[N-])CC2
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(N=[N+]=[N-])CC2
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of N-(7-azido-4-bromo-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (1.5 g) was cooled in an ice bath and treated with fuming nitric acid (2 mL). After stirring for 2 h the solvent was removed by rotoevaporation and water was added to the residue to give a solid. The product was collected by filtration and dried (1.1 g, 81% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([N:34]([CH3:44])[CH3:33])[CH:40]=2)=[CH:4][N:3]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2csc3c(-c4cccc(N(C)C)c4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 0.42 h
Yield: 20.3 %

Procedure:
A mixture of 1-Methyl-1H-indole-2-carboxylic acid [4-(4-amino-7-iodo-thieno[3,2-c]pyridin-3-yl)-2-methoxy-phenyl]-amide (0.100 g, 0.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was reacted with 3-(dimethylamino)phenylboronic acid (0.045 g, 0.27 mmol), sodium carbonate (0.06 g, 0.54 mmol) and tetrakis triphenylphosphine palladium (0) (0.017 g, 0.01 mmol) at reflux for two hours. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Hypersil-HS 100 A, C18, 8 μm, 100 Å, 25 cm; 5% acetonitrile—0.1M ammonium acetate 5–100% acetonitrile—0.1M ammonium acetate over 25 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the title compound (20 mg) as an off-white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.01 (t, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 7.58 (m, 2H), 7.34 (m, 3H), 7.23 (s, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 6.97 (s, 1H), 6.95 (d, 1H), 6.79 (d, 1H), 5.56 (bs, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.97 (s, 6H); LCMS (Conditions b), Rt=6.22 min, MS m/e: 548 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22](Cl)[CH:23]=[CH:24][C:9]1=2.[CH:40](OC(N1C2C(=CC3CCCC=3C=2)C(NCC2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)CCC1)=O)([CH3:42])[CH3:41]>>[CH:18]([O:17][C:15]([N:11]1[C:10]2[C:9](=[CH:24][C:23]3[CH2:41][CH2:40][CH2:42][C:22]=3[CH:21]=2)[CH:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:38])[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=2)[C:26]2[N:30]=[N:29][NH:28][N:27]=2)[CH2:14][CH2:13][CH2:12]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)CCC3
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)CCC3

Procedure:
The titled compound was prepared in a manner analogous to the procedure for the preparation of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, from Step 2 to Step 3) by replacing isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with (+/−)-isopropyl-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (prepared above) in Example 46 Step 2. MS (ES−): 581 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:30])[C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH:23]C(=O)C(C)(C)C)[N:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+].ClC1C2C3C(=CC=CC=3)NC=2N=C(NC(=O)C(C)(C)C)N=1.COC1C=C(C=CC=1)NC>Cl.C(Cl)(Cl)Cl.CO.C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:30])[C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[N:13]=[C:12]([NH2:23])[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)cc1
Agent: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Agent: CNc1cccc(OC)c1
Agent: Cl
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(N(C)c2nc(N)nc3[nH]c4ccccc4c23)cc1
Yield: 73 %

Procedure:
Using the general procedure described above, the reaction of 11 (100 mg, 0.24 mmol) and 1 N NaOH provided 58 mg of AAG107 as a white solid in 73% yield. Alternatively, AAG107 can also be synthesized by treating 6 (90 mg, 0.3 mmol) with 3-methoxy-N-methylaniline (306 mg, 2.23 mmol) in presence of 3 drops HCl and solvent n-butanol under reflux conditions for 14 hours. The yield from 6 to AAG107 using this method is 53%. TLC Rf 0.34 (chloroform-methanol 15:1); mp 233.6° C.; 1H NMR (DMSO-d6) δ 3.55 (s, 3H, OCH3), 3.58 (s, 3H, NCH3), 6.19 (s, 2H, NH2, exch), 5.87-7.18 (m, 8H, Ar—H), 11.27 (s, 1H, 9-NH, exch).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:38][CH:39]=[CH2:40]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH2:40][CH:39]=[CH2:38])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: C=CCBr
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred and heated to 110° C. for a while. After cooling to 20° C., 3.63 parts of 3-bromo-1-propene are added dropwise. Upon completion, stirring is continued for 20 hours at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from hexane, yielding 2-propenyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 57.2° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[C:5]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:26]([S:23]([C:4]1[C:5]([C:8]([N:10]([CH3:22])[C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=[C:2]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1)(=[O:25])=[O:24])[CH3:27]
Reactant: CCS(=O)(=O)c1cc(Cl)cnc1C(=O)N(C)c1ccc(SC(F)(F)F)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCS(=O)(=O)c1cc(-c2ccccc2)cnc1C(=O)N(C)c1ccc(SC(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
A mixture of 250 mg of 5-chloro-3-ethylsulfonyl-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide (Compound of Present Invention 118), 104 mg of phenylboronic acid, 10 mg of tris(dibenzylideneacetone)dipalladium(0), 25 mg of 2-dicyclohexylphosphino-2′-4′-6′-triisopropylphenyl, 242 mg of tripotassium phosphate and 3 ml of dimethoxyethane was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 112 mg of 3-ethylsulfonyl-5-phenyl-N-methyl-N-(4-trifluoromethylsulfanylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 124).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([N:32](CC)[C:33]2[C:38](NCC)=CC=CN=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]([CH2:33][CH3:38])[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(c1ncnc(Cl)c1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
4,6-Dichloro-5-nitropyrimidine (8.88 g) is dissolved in 400 ml of methylene chloride and cooled to -78°. Then triethylamine (6.7 ml) and 1-benzyl-4-N-ethylaminopiperidine (EXAMPLE 205, 10.00 g) is added and the reaction is stirred 1 hr at -78° and slowly warmed to 20°-25°. The reaction is poured into saturated aqueous sodium bicarbonate, extracted with methylene chloride, washed with saline, dried and concentrated under reduced pressure. Purification by flash column chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) gives the title compound.