Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(Cl)cc2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 4-chlorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(4-chloro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH3:35]>CS(C)=O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][C:14]2[CH:15]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH:30]([CH3:35])[CH2:31]4)=[CH:7][N:6]=3)=[O:9])[NH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CC1CNCCN1C
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1.00 mmol) was added in one portion to 1,2-dimethyl-piperazine (228 mg, 2.00 mmol) in anhydrous dimethylsulfoxide (2.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (375 mg, 81%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>COCCOC>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: COCCCN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COCCCN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 74 %

Procedure:
A solution of chloride 21 (1.62 g, 7.3 mmol), Et3N (2.0 mL, 14.0 mmol) and N1-(3-methoxypropyl)-N1-methyl-1,2-ethanediamine (274) (1.24 g, 8.8 mmol) in DME (50 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×120 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 32 (1.79 g, 74%) as a yellow solid: mp 41-42° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.83 (br s, 1H, NH), 3.55 (dt, J=5.9, 5.5 Hz, 2H, NCH2), 3.43 (t, J=6.3 Hz, 2H, OCH2), 3.33 (s, 3H, OCH3), 3.01 (t, J=7.4 Hz, 2H, H-8), 2.99 (t, J=7.8 Hz, 2H, H-6), 2.64 (t, J=5.9 Hz, 2H, NCH2), 2.50 (t, J=7.2 Hz, 2H, NCH2), 2.27 (s, 3H, NCH3), 2.14 (p, J=7.4 Hz, 2H, H-7), 1.76 (tt, J=7.2, 6.4 Hz, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 70.8, 58.6, 55.8, 54.4, 41.6, 38.6, 33.1, 32.3, 27.4, 25.7; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C17H25N5O2: C, 61.6; H, 7.6; N, 21.1. Found: C, 61.4; H, 7.4; N, 21.4%.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][C:19]=2[S:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)(=[O:18])=[O:17])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The mixture of 2-(quinoline-8-sulfonylamino)-indan-2-carboxylic acid ethyl ester (35) (210 mg, 0.53 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (36) as white solid (195 mg, 100%).
Reaction SMILES: [CH2:1]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[S:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25]([C:30](O)=[O:31])#[C:26][C:27]([OH:29])=[O:28]>>[CH2:15]([N:14]1[C:30](=[O:31])[C:25](=[CH:26][C:27]([OH:29])=[O:28])[S:13][C:12]1=[N:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCCCCCNC(=S)NCCCCCCCCCC
Product: CCCCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCCCC
Yield: 93.1 %

Procedure:
Prepared by the method described in Example 16 from N,N'-didecylthiourea (15.0 g, 42 mmoles) and acetylenedicarboxylic acid (5.0 g, 42 mmoles). Recrystallization from hexane gave the product (17.7 g), mp 68°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=[O:8].C(C1C(=O)C(Cl)=C(Cl)[C:21](=[O:22])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[CH:6][C:7]([O:22][CH3:21])=[O:8]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1cc(OC)c(OC)cc1C=CC=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cc(OC)c(OC)cc1OC
Yield: 84 %

Procedure:
A homogeneous mixture containing 2,4,5-trimethoxycinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLITE® IR 120 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl 2,4,5-trimethoxycinnamate (from formula I where X1═OCH3, X2═H, X3═OCH3, X4═OCH3, X5═H, R═CH3) is isolated in 84% yield. 1H-NMR (CDCl3, 300 MHz) δ7.91 (1H, d, J=16.10 Hz), 7.01 (1H, s), 6.50 (1H, s), 6.37 (1H, d, J=16.10 Hz), 3.93 (3H, s), 3.88 (3H, s), 3.87 (3H, s), 3.80 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ168.2, 153.9, 151.9, 143.4, 139.7, 116.6, 115.4, 112.6, 96.9, 56.5, 56.4, 56.1, 51.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[OH-].[Na+].Br[C:13]1([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[NH:15][C:14]1=[O:23].Cl>O.O1CCOCC1>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]3)([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:14](=[O:23])[NH:15]2)=[CH:20][CH:19]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CCCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of piperidine-3-carboxylic acid (600 mg, 4.5 mmol) and NaOH (360 mg, 9 mmol) in water (5 mL) and dioxane (5 mL) was added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.1 g, 3 mmol). The mixture was stirred at room temperature for 1 h and then diluted by water (30 mL). The resulting solution was neutralized to pH=7 with hydrochloride acid and extracted by dichloromethane. The organic phase was dried over Na2SO4, filtered and concentrated to give rac-1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-3-carboxylic acid yield: (0.9 g, 71%). MS: [M−H]−=417.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:82])[CH3:81]>CN(C=O)C>[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:27](=[O:28])[C@@H:2]([NH:1][C:30]([O:32][CH2:33][CH:34]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]2[C:13]([CH3:14])=[C:15]([CH3:16])[C:17]3[O:18][C:19]([CH3:21])([CH3:20])[CH2:22][C:23]=3[C:24]=2[CH3:25])(=[O:10])=[O:11])[CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:81])[CH3:82]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-Arg(Pbf)-OH 1 (25.0 g, 38.5 mmol) in DMF (200 mL) at room temperature was added DIEA (13.41 mL, 77.1 mmol). After stirring at room temperature for 10 min, the reaction mixture was cooled to ˜5° C. To the reaction mixture was added HATU (16.11 g, 42.4 mmol) in portions and stirred for 20 min and a solution of tert-butyl-1-piperazine carboxylate (7.18 g, 38.5 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 5 min. The mixture reaction was then allowed to warm to room temperature and stirred for 2 h. Solvent was removed in vacuo and the residue was dissolved in EtOAc (500 mL), washed with water (2×750 mL), 1% H2SO4 (300 mL) and brine (750 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to a total volume of 100 mL. Compound A was taken to the next step as EtOAc solution (100 mL). LC-MS [M+H] 817.5 (C43H56N6O8S+H, calc: 817.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[CH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.I[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:23][Si:22]([C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:15][CH:16]=1)([CH3:24])[CH3:25]
Reactant: C#Cc1cc(OC)cc(OC)c1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 1.31 g (0.0081 mole) of 3.5-dimethoxyphenylacetylene, 2.25 g (0.0075 mole) of 4-iodophenyl-trimethylsilylacetylene, 0.016 g (0.084 mmole) of CuI, 0.155 g (0.22 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 15 ml of THF and 15 ml of triethylamine. The light brown solution turned to a suspension within a minute. After ˜40 min, the reaction mixture turned to an orange solution with some white ppt. The reaction was followed by TLC. The mixture was stirred at room temperature under nitrogen overnight. TLC showed presence of staring material still. The reaction was stirred continuously overnight at room temp. Not much further reaction had occurred. It was then stirred overnight at 50° C. TLC indicated that only a trace of starting material was present. The reaction was then terminated and the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 15 ml of chloroform and the solution was washed two times with water (15 ml each) and dried over anhydrous MgSO4, filtered and concentrated. 2.27 g (90.4% yield) of solid was obtained. 1HNMR: 0.26 ppm (s, 9H); 3.83 ppm (s, 6H); 6.49 ppm (s, 1H); 6.70 ppm (s, 2H); 7.47 ppm (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:9]([N:1]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCN(CCCCCC)c1ccccc1

Procedure:
A mixture of aniline (5.90 ml, 6.47×10−2 mol), 1-iodohexane (20.0 ml, 0.136 mol) and K2CO3 (18.80 g, 0.136 mol) in 80 ml of EtOH was refluxed for 27 h under Ar. The precipitate was filtered off and washed with CH2Cl2. The filtrate was washed with water and dried over Na2SO4. The residue was chromatographed on silica gel with 4:1 hexane:CHCl3 as the eluent. Yield=14.735 g (87% based on 5.90 ml of aniline). 1H NMR (250 MHz, CDCl3): δ 7.20 (dd, 2H, J=7.1, 8.8 Hz, Ph), 6.57-6.66 (m, 3H, Ph), 3.24 (t, 4H, J=7.7 Hz, —NCH2—), 1.48-1.65 (m, 4H, —NCH2CH2—), 1.22-1.40 (m, 12H, —CH2—), 0.90 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 262.253 ((M+H)+) (calcd 262.253).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[CH:24][CH:23]=3)[C:18](=[O:19])[N:17]([CH3:20])[C:16]([NH2:21])=[N:15]2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:21][C:16]1[N:17]([CH3:20])[C:18](=[O:19])[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH2:7])[CH:9]=2)([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[CH:24][CH:23]=2)[N:15]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(NC(=O)OC(C)(C)C)c2)N=C1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(N)c2)N=C1N
Reaction time: 4.5 h
Yield: 99.3 %

Procedure:
{3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-phenyl}-carbamic acid tert-butyl ester (15.3 g, 34.3 mmol) was dissolved in trifluoroacetic acid/methylene chloride (1:1) (20 mL) and allowed to stir for 4.5 h. Additional trifluoroacetic acid (3.0 mL) was added and the reaction was allowed to stir for an additional hour and concentrated. To the residue was added Na2CO3 followed by extraction with methylene chloride. The organic layer was dried over Na2SO4 and concentrated in vacuo to provide the title compound (11.8 g, 99%), characterized by NMR and mass spectral analyses. MS (ES+) m/e 347 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:7]=1[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)cc3c21
Solvent: CC#N
Product: CC(=O)NCC[C@@H]1CCc2ccc3nn(C)c(Cl)c3c21
Temperature: 50 °C
Reaction time: 5 h
Yield: 22.2 %

Procedure:
To a solution of N-{2-[(8S)-2-methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl]ethyl}acetamide (80 mg, 0.311 mmol) in acetonitrile (3.1 mL) was added N-chlorosuccinimide (45.7 mg, 0.342 mmol), and the mixture was stirred at 50° C. for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90), preparative HPLC (acetonitrile/water=10/90→90/10) and recrystallization (ethyl acetate/hexane) to give the title compound (20.1 mg, yield 22%).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.O>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[N:25]=2)[CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (10.5 g, 30.8 mmol) in N,N-dimethylacetamide (40 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (8.39 mL, 92.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, trifluoroacetic acid (50 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in water. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (7.44 g, 78%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:38])[NH:15][C:16]1[C:17]([CH3:37])=[N:18][CH:19]=[C:20]([NH:22][C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[CH:25][N:24]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[N:24][C:23]([NH:22][C:20]3[CH:21]=[C:16]([NH:15][C:14]([CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]4)=[O:38])[C:17]([CH3:37])=[N:18][CH:19]=3)=[N:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)C4CCCCN4C(=O)OC(C)(C)C)c3)nc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(NC(=O)C4CCCCN4)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-{5-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-ylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester 20 is dissolved in DCM (1 mL) and TFA is added (2 mL). The yellow solution is stirred at rt for 2 h. The solvent and the excess of TFA are removed under vacuum and the residue is purified by preparative LCMS to afford piperidine-2-carboxylic acid {5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-amide C1. 1H NMR (400 MHz, d6-DMSO) δ 1H NMR (400 MHz, d4-CH3OH) δ 9.27 (d, J=4.0 Hz, 1H), 8.85 (d, J=4.0 Hz, 1H), 8.80 (s, 2H), 7.59-7.57 (m, 2H), 7.06-7.06 (m, 2H), 4.14 (dd, J=4.0 and 12.0 Hz, 1H), 3.86 (s, 3H), 3.52-3.48 (m, 1H), 3.15-3.12 (m, 1H), 2.62 (s, 3H), 2.45-2.44 (m, 1H), 2.07-2.06 (m, 1H), 1.98-1.95 (m, 1H), 1.89-1.85 (m, 1H), 1.79-1.75 (m, 2H). MS (m/z) (M+1)+: 419.2.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:31]=[N:32][N:33]([CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:34]=4)=[CH:28][N:27](C(OC(C)(C)C)=O)[C:24]3=[N:25][CH:26]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C>Cl.CCOCC.CO>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:31]=[N:32][N:33]([CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:34]=4)=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)=[CH:14][C:13]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccnc4)c2)cn3C(=O)OC(C)(C)C)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccnc5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 12.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxyphenyl)-3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (60 mg, 0.219 mmol) was deprotected in HCl in ether/MeOH (1/3 ml) to afford 13 mg (29% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.78 (s, 2H), 8.53 (s, 2H), 8.42-8.37 (m, 2H), 8.02 (s, 1H), 8.00-7.94 (m, 1H), 7.77-7.76 (m, 2H), 7.62-7.59 (dd, 1H), 7.24-7.21 (d, 1H), 5.66 (s, 2H), 3.98 (s, 3H), 2.99 (s, 3H). MS: m/z=475.1 (M+1), HPLC: 97.36% in method A.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([N:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:12][CH3:13])[CH3:10].[OH-].[Na+]>CO>[CH2:9]([N:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4](=[CH:18][C:17]3[CH:20]=[CH:21][C:14]([N:11]([CH2:9][CH3:10])[CH2:12][CH3:13])=[CH:15][CH:16]=3)[C:5]2=[O:8])=[CH:16][CH:15]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CN1CCC(=O)CC1
Reactant: CCN(CC)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)c1ccc(C=C2CN(C)CC(=Cc3ccc(N(CC)CC)cc3)C2=O)cc1

Procedure:
Two grams (17.7 mmoles) of N-methyl-4-piperidone and 6.26 g (35.4 mmoles) of p-N,N-diethylaminobenzaldehyde were introduced into a 100 ml eggplant type flask, to which was added a solution of 0.5 g of sodium hydroxide in 50 ml methanol. The contents of the flask equipped with a reflux condenser were heated under reflux for about one hour with stirring by means of a magnetic stirrer. After allowing the reaction mixture to cool, the deposited organge-colored crystalline product was collected by filtration and thoroughly washed with methanol. Then, it was purified by recrystallization from benzene/chloroform.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)=O>O>[N+:18]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:11])[CH:3]=[CH:2][C:1]2=[O:12])([O-:20])=[O:19]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 15 °C

Procedure:
In the same apparatus as in Example 1, 20 g of 1,4-naphthoquinone was added, with stirring, to 70 g of a mixed acid consisting of 66 percent by weight of sulfuric acid, 19 percent by weight of nitric acid and 15 percent by weight of sulfur trioxide while maintaining the mixed acid at 0° to 5°C. The temperature of the mixture was gradually raised to 15°C over 30 minutes and maintained at 15°C for 3 hours to complete reaction. The reaction mixture was then stirred into 400 ml of water at 20°C in 5 minutes to precipitate crystals, while cooling the water as to maintain a liquid temperature at 40°C. The state of dispersion of the precipitated crystals was good. The precipitate was processed in the same manner as in Example 5 to obtain 22.7 g of crude 5-nitro-1,4-naphthoquinone of a melting point of 155°C. The crystals were of a nearly equal particle size not exceeding 0.2 mm. The amount of acidic matter remaining in the crystals was 0.4 percent by weight in sulfuric acid equivalent.