Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=1.Br[CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Br:26])[C:25]=1[CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Brc1cncc(Br)c1
Reactant: BrCCCOCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Brc1cncc(Br)c1CCCOCc1ccccc1
Temperature: -60 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
Diisopropylamine (5.1 g, 50 mmol) is dissolved in THF (100 ml), and thereto is added with stirring a solution of n-butyl lithium in hexane (27.3 ml, 45 mmol) at −70° C. Ten minutes thereafter, a solution of 3,5-dibromopyridine (10.0 g, 42 mmol) in THF (30 ml) is added dropwise over a period of time for 20 minutes during which the bulk temperature should not be raised over −60° C., and the mixture is further stirred for 5 minutes. Subsequently, 1-bromo-3-benzyloxypropane (10.0 g, 44 mmol) is added to the mixture, and the mixture is stirred at −70° C. for 2 hours. The mixture is warmed to 20° C. over a period of time for 2 hours. The reaction is quenched with a saturated brine (200 ml), and the mixture is extracted with ethyl acetate (300 ml×2). The extract is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (9.0 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:15]([NH:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:16])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:25](OC=O)(=[O:27])C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:15]([N:17]([CH:25]=[O:27])[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:16])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccc(Cl)cc1)C(=O)O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1ccc(Cl)cc1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (380 mg, 1.07 mmol) in pyridine (4 mL) at 0° C. is added formic acetic anhydride (0.9 mL). The resulting solution is allowed to warm to 25° C., stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (385 mg, 94% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CS(C)=O.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of indole (11.7 g, 0.1 mol) in THF is added to a stirred mixture of NaH (60% dispersion in mineral oil, 4.2, g 0.105 mol), DMSO and THF. The reaction mixture is stirred for 1 h at room temperature, cooled to 0° C., treated with phenylsulfonyl chloride (13.3 mL, 0.15 mol), stirred at ambient temperatures for 3 h, quenched with water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized in ethanol and filtered. The filtercake is air-dried to give 1-phenylsulfonylindole. A portion of this 1-phenylsulfonylindole (257 mg, 1.0 mmol) and cyclohexylcarbonyl chloride (0.175 mL, 1.3 mmol) in methylene chloride is treated with tin tetrachloride (97 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethylacetate. The extracts are combined and concentrated in vacuo to give a residue. The residue is suspended in isopropanol, treated sequentially with concentrated HCl (50 μL) and aminoguanidine bicarbonate (100 mg, 0.5 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product 37.7 mg (17% yield), identified by HPLC1 and mass spectral analyses.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[CH3:10].[OH-].[K+]>C(O)C>[CH3:10][C:9]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: Br[Mg]c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)c1ccccc1
Temperature: 50 °C

Procedure:
Diethyl (α, α-dimethylbenzyl)malonate was prepared by the congugate addition of phenyl magnesium bromide to diethyl isopropylidenemalonate as described by C. Holmberg [Liebigs Ann. Chem., 748 (1981)]. A solution of this diester (42.1 g, 0.15 mole) in ethanol (100 mL) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mole) in 100 mL of ethanol. After heating at 90° C. for 1 h and at 50° C. for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5° C., acidified to pH 3, with 6N HCl and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate. Evaporation of the solvent gave 27.3 g (84%) of liquid product. NMR (CDCl3): 1.05 (3H, t), 1.6 (6H, s), 3.78 (1H, s), 3.96 (2H, m), 7.2-7.4 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(OC(C)C)(=O)C.[Br:22]([O-])(=O)=O.[Na+].S([O-])(O)=O.[Na+]>O>[Br:22][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To 60.0 g of 4-methyl-3-trifluoromethylbenzoic acid was added 600 ml of isopropyl acetate. Under stirring at room temperature, a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water were added in turn. The mixture was gradually heated from 30° C. up to 50° C. at intervals of 10° C. and stirred until the color of the reaction solution disappeared. The aqueous layer was separated to remove, and to the organic layer were added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and then the mixture was gradually heated up to 60° C. as above. After separation, to the organic layer were further added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and the mixture was gradually heated as above and heated to the temperature the mixture was finally refluxed. After the completion of the reaction, the reaction solution was separated, the organic layer was washed twice with a 5% aqueous sodium thiosulfate solution and twice with 15% saline, dried over anhydrous magnesium sulfate, and, then the solvent was distilled off under reduced pressure. To the residue was added 120 ml of n-heptane, the mixture was stirred, and then the crystals were collected by filtration to obtain 50.0 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:33][C:32]([C:34](O)([CH3:36])[CH3:35])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:34]([C:32]1[S:33][C:29]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[O:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:19]=2)=[CH:30][CH:31]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(C)(C)O)s3)ccc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(C)C)s3)ccc2c1
Yield: 93.7 %

Procedure:
Add 2-(5-(6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl)thiophen-2-yl)propan-2-ol (84 mg; 0.16 mmol), triethylsilane (1.7 mL) and dichloromethane (0.85 mL) to a flask under argon. Add trifluoroacetic acid (0.81 mL) and stir the resulting mixture for 45 minutes. Load the mixture onto an SCX acidic ion exchange column. Flush the column with 1:2 methanol/dichloromethane and elute with 1:2 2M ammonia in methanol/dichloromethane. Concentrate the ammonia containing eluent in vacuo to give the title compound (73.1 mg; 0.15 mmol): Mass spectrum (m/z): 502 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 81.1 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.1%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([NH:1][C:2]2[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1cnc(N)c(I)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To a solution of 2-amino-3-iodo-5-methylthiopyridine (7.63 g) in pyridine (30 ml), benzenesulfonyl chloride (7.9 ml) was added at 15 to 30° C. under nitrogen atmosphere and the mixture was stirred at 60° C. for 15 hours. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. A solution of the resulting crude bis(benzenesulfonyl) product in a mixture of methanol/dioxane (1:1, 200 ml) was added a 1N aqueous potassium hydroxide solution (64 ml) at 15 to 30° C. and the mixture was stirred at 60° C. for 1 hour. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol chloroform=1:50) to obtain 6.4 g (56%) of the desired product as a white powder.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([OH:20])=O)=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([NH:41][CH2:42][C:43]2[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=2[CH3:49])=[O:20])=[C:10]1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(=O)c3ccccc3)c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 26.9 %

Procedure:
To a solution of 1-benzoyl-2-methyl-1H-indole-3-carboxylic acid (125 mg, 0.45 mmol), 1-hydroxybenzotriozole (122 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (173 mg, 0.9 mmol), triethylamine (0.4 mL) in dichloromethane (20 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (137 mg, 0.9 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 1-benzoyl-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (50 mg, 53%). LRMS (M+H+) m/z: calcd 413.17. found 413. HPLC Purity (214 nm): 96%. 1H NMR (300 MHz, do-DMSO): (11.57 (s, 1H), 8.13 (q, J=5.1 Hz, 1H), 7.74-7.70 (m, 4H), 7.60-7.58 (m, 2H), 7.20-7.00 (m, 3H), 5.88 (s, 1H), 4.32 (d, J=5.1 Hz, 2H), 2.37 (s, 3H), 2.267 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: N[C:2]1C(N)=CC=CN=1.C[O:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].OC1C=C(O)C=CC=1C(OC)=O.C(Cl)C#C>>[OH:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:2])=[O:14]
Reactant: C#CCOc1ccc(C(=O)O)c(OC)c1
Reactant: Nc1cccnc1N
Agent: C#CCCl
Agent: COC(=O)c1ccc(O)cc1O
Product: C#CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
A mixture of 10.9 g of 2,3-diaminopyridine (IIa) and 20.6 g of 2-methoxy-4-propargyloxybenzoic acid (m.p.142°; obtainable by the reaction of methyl 2,4-dihydroxybenzoate with propargyl chloride to give methyl 2-hydroxy-4-propargyloxybenzoate (m.p. 100°); reaction of this with methyl iodide to give methyl 2-methoxy-4-propargyloxybenzoate (m.p. 88°) and hydrolysis) is added in portions with stirring to 500 ml of POCl3. The mixture is boiled for 4 hours, concentrated, and the residue is treated with 375 ml of 10% hydrochloric acid. The precipitated 2-(2-methoxy-4-propargyloxyphenyl)imidazo(4,5-b)pyridine hydrochloride ("M") is filtered off. M.p. 247° (from methanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34]C=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NC1(C#N)CC1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:37][C:32]1([C:31]#[N:36])[CH2:34][CH2:33]1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-(3-chloro-4-hydroxyphenyl)propanoic acid (3.86 g, 12.2 mmol, Eq: 1.00) was dissolved in DMF (50 mL). HATU (9.3 g, 24.4 mmol, Eq: 2.00), 1-amino-1-cyclopropanecarbonitrile hydrochloride (1.74 g, 14.7 mmol, Eq: 1.20) and Hunig's Base (3.16 g, 4.27 mL, 24.4 mmol, Eq: 2.00) were added to the obtained suspension. The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was poured into aqueous 0.1M HCl (300 mL), extracted with dichloromethane (3×125 mL), dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 65% AcOEt in n-heptane) to yield a white solid (3.13 g; 67%). m/z=378.1 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:25]=3[O:24][CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1.C(=O)(O)[O-].[K+].CCN(C(C)C)C(C)C>CC(N(C)C)=O.O>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[C:29]([C:2]4[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=4)[CH:30]=[CH:31][C:25]=3[O:24][CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC1CCN(C(=O)N2CCOc3ccc(B(O)O)cc3C2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c([N+](=O)[O-])c4)cc3C2)CC1
Temperature: 99 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a mixture of 5-bromo-3-nitropyridin-2-amine (0.69 g, 3.2 mmol), {4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-yl}boronic acid (1.0 g, 3.2 mmol) (example 2, step 4), potassium bicarbonate (1.3 g, 2.3 mmol) and DIPEA (1.1 mL, 6.3 mmol) in DMA (12 mL) and water (3 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.12 g, 0.16 mmol). The reaction mixture was stirred at 99° C. for 12 hours and then partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting brown residue was suspended in methanol (20 mL), filtered and washed with ethyl ether (2×30 mL) to afford 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-3-nitropyridin-2-amine (1.0 g, 77% yield) as a yellow solid. MS (EI) for C21H25N5O4: 412 (MH+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1>ClCCl>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[CH3:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a suspension of potassium carbonate (1.79 g, 10 mmol, 1.30 equiv) and 2-amino-3-methyl-5-chloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (3.00 g, 9.97 mmol) in dichloromethane (20 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (4.000 g, 10.97 mmol, 1.10 equiv.) in dichloromethane (10 mL) at room temperature. After 2 h at this temperature, the solids were filtered off. The resulting filtrate was washed with water and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diisopropyl ether to yield the title compound (3.1 g, 54%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH:22]=[CH:23][CH:24]=3)[N:17]=2)[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])[CH:22]=[CH:23][CH:24]=3)[N:17]=2)[NH:12][CH:11]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(n2)c(-c2cc4ccccc4[nH]2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cc5ccccc5[nH]4)c3n2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of compound 13 (90 mg, 1.449 mmol) in chloroform was added trifluoroacetic acid. The reaction was stirred overnight at 45° C., distilled off TFA and diluted with water and pH was adjusted to 9-10 with 1M NaOH solution at 20-25° C. The aqueous layer was extracted with dichloromethane (25 mL) twice. The organic layer was dried over sodium sulphate, filtered and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using gradient of 50% Ethyl acetate in hexane to afford brown colour solid Compound 14. MS-ES+379.41, 1H NMR (400 MHz, DMSO-D6-d6) 14: 11.36 (d, 1H), 10.40 (d, 1H), 8.89 (d, 1H), 8.54 (d, 1H), 8.38 (d, 1H), 7.94 (d, 2H), 7.55 (d, 2H), 7.43 (d, 2H), 7.13 (d, 2H), 6.56 (d, 1H), 6.36 (d,1H), 5.83 (d, 1H), 5.31 (d, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH3:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:26]#[CH:27].BrC(C1C=CC=CC=1)C.C([Si](C)(C)C)#C.[N-]=[N+]=[N-]>>[C:28]1([CH:25]([C:26]2[N:1]([C@H:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:27]=2)[CH3:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CC(C)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Agent: C#C[Si](C)(C)C
Agent: CC(Br)c1ccccc1
Agent: [N-]=[N+]=[N-]
Product: CC(c1ccccc1)c1cnnn1[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from both enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and (1-methylprop-2-yn-1-yl)benzene prepared from (1-bromoethyl)benzene and ethynyltrimethylsilane. The resulting diastereoisomeric esters derived from the chiral azide with the retention time of 10.3 min from EXAMPLE 6 were separated by flash chromatography using a gradient of 10-70% EA/Hex to afford after standard hydrolysis EXAMPLE 29.1 and 29.2. The resulting diastereoisomeric esters derived from the chiral azide with the retention time of 11.5 min from EXAMPLE 6 were separated by flash chromatography using a gradient of 10-70% EA/Hex to afford after standard hydrolysis EXAMPLE 29.3 and 29.4 respectively. MS (+ESI) m/z: 405.1.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:30])[CH2:25][O:26]C(=O)C)[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1>C(=O)([O-])[O-].[Na+].[Na+].CO.O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:30])[CH2:25][OH:26])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)COC(C)=O)cccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)CO)cccn12
Reaction time: 4 h
Yield: 98.1 %

Procedure:
8-[2Methyl-6-(2-acetoxyacetyl)aminobenzylamino]3-(2-propynyl)-2 -methylimidazo[1,2-a]pyridine (0.33 g) was dissolved in a mixture of an aqueous solution (0.7 ml) of sodium carbonate (0.0118 g) and methanol (6.6 ml) at room temperature and then the mixture was stirred for 4 hours. The mixture was diluted with water and the resultant solid was collected to give 8-[2-methyl- 6-(2-hydroxyacetyl)aminobenzylamino]-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.29 g).