Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[CH3:13][CH2:14][OH:15].[H-].[Na+].C1C[O:21][CH2:20][CH2:19]1>C(OCC)C>[CH2:14]([O:15][C:20](=[O:21])[CH:19]=[C:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1)[CH3:13]
Reactant: C1CCOC1
Reactant: CCO
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C=C1CCc2ccc(OC)cc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
6-Methoxy-indan-1-one (5.02 g, 30.95 mmol) and triethyl phosphonoacetate (15.5 mL, 78.13 mmol) was dissolved in THF (20 mL) and added slowly to a mixture of EtOH (850 μL) and NaH (60% dispersion in oil, 2.5 g). The resulting slurry was stirred at 70° C. overnight. The crude mixture was diluted with diethyl ether and washed with water and brine, dried (Na2SO4), filtered and concentrated. The product was purified by silica gel flash column chromatography (5:1 hexanes in ethyl acetate) to afford (6-Methoxy-indan-1-ylidene)-acetic acid ethyl ester (3.18 g, 47%) as a mixture (˜1:1) of E/Z isomers. 1H NMR (400 MHz, CDCl3) mixture (˜1:1) of E/Z isomers 7.37 (d, 1H)7.27 (d, 1H), 7.09 (d, 1H), 6.99 (dd, 1H), 6.97 (d, 1H), 6.81 (dd, 1H), 6.50 (m, 1H), 6.31-6.30 (m, 1H), 4.27 (quart, 2H), 4.22 (quart, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.60 (m, 2H), 3.36-3.33 (m, 4H), 3.05-3.02 (m, 2H), 1.37 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[C:24]([C:27]#[CH:28])[CH:25]=2)[NH:20][C:19](=[O:30])[C:18]=1[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CC.Cl[C:44]1[CH:49]=[N:48][CH:47]=[CH:46][N:45]=1>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[C:24]([C:27]#[C:28][C:44]3[CH:49]=[N:48][CH:47]=[CH:46][N:45]=3)[CH:25]=2)[NH:20][C:19](=[O:30])[C:18]=1[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#Cc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Reactant: Clc1cnccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCN
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C#Cc4cnccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-ethynyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (123 mg in 1.5 mL N,N-dimethylformamide) was added tetrakis(triphenylphosphine)palladium (13 mg) followed by copper(I) iodide (22 mg), n-propylamine (0.19 mL) and chloropyrazine (0.026 mL) and the mixture heated to 90° C. on an oil bath. After 10 minutes, the mixture was cooled to room temperature, diluted with diethyl ether and washed successively with water and brine then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60; then 50:50) gave the title compound (69 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>ClCCl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22])[CH3:19]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 22.9 %

Procedure:
To a solution of 10.0 mg (0.0437 mMol) 6-amino-3 (dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 3.0 mL dichloromethane were added 6.2 mg (0.0874 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.15 gm (0.0874 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the filtrate washed with 1N hydrochloric acid. The aqueous phase was washed several times with dichloromethane and was then made basic with dilute aqueous sodium hydroxide. The aqueous phase was then extracted several times with an equal volume of dichloromethane. These organic extracts were dried over sodium sulfate and then concentrated under reduced pressure to give 3.0 mg (23%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C@@H:32]([OH:33])[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@@H:11]([CH2:13][O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH3:12].[C:37]([O:40]C(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([OH:40])(=[O:39])[CH3:38].[CH3:36][C:2]1([CH3:1])[C:32](=[O:33])[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C@@H:11]([CH2:13][O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:22]([CH3:23])[CH3:24])[CH3:12]
Reactant: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O
Product: CC(C)[Si](OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C)(C(C)C)C(C)C
Reaction time: 20 h

Procedure:
To a solution of 18.2 g (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3β-ol in 175 ml pyridine 6.24 ml of acetic anhydride were added at room temperature. The reaction mixture was stirred for 20 hours and then poured into an ice/hydrochloric acid mixture. This was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 16.2 g (20S)-4,4-dimethyl-20-[((triisopropylsilyl)oxy)methyl]-pregna-5-en-3-one acetate as a white solid, which was used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.ClC1C(C)=CN=[C:25]([C:30]([F:33])([F:32])[F:31])[N:24]=1.C([N:37]([CH:40]([CH3:42])[CH3:41])[CH2:38]C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:21])[CH2:14][CH2:13][N:12]([CH:15]3[CH:19]([OH:20])[CH2:18][N:17]([C:38]4[N:37]=[C:40]([CH3:41])[CH:42]=[C:25]([C:30]([F:33])([F:32])[F:31])[N:24]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: Cc1cnc(C(F)(F)F)nc1Cl
Reactant: O[C@@H]1CNC[C@H]1N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nc(N2CC(O)C(N3CCC(O)(c4ccc(Cl)cc4)CC3)C2)n1

Procedure:
The title compound was prepared following general procedures described above from trans-4-(4-chloro-phenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol hydrochloride and 4-chloro-5-methyl-2-trifluoromethyl-pyrimidine in the presence of diisopropylethylamine and DMF. 1H-NMR (300 MHz, DMSO): δ 1.58 (2H, m), 1.89 (2H, m), 2.40 (3H, s), 2.60 (3H, m), 2.95 (2H, m), 3.32 (1H, m), 3.44 (1 H, m), 3.80 (2H, m), 4.32 (1H, m), 4.90 (1H, s), 5.20 (1H, d), 6.92 (1H, s), 7.42 (4H, dd). Retention Time (LC, method, AA standard): 1.75 min. MS (M+H+): 457
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[O:28]=[C:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
The title compound was prepared from 4-(chlorosulfonyl) benzoic acid and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 2.36 (t, J=6.0 Hz, 4 H), 3.49 (t, J=6.0 Hz, 4 H), 6.87 (d, J=9.3 Hz, 2 H), 6.91 (d, J=9.3 Hz, 2 H), 7.77 (d, J=8.1 Hz, 2 H), 8.04 (d, J=8.1 Hz, 2 H), 9.97 (s, 1 H), 13.10 (brs, 1 H); MS (ES) m/z: 374.9 (MH+); HRMS Calcd. for C18H19N2O5S (MH+): 375.1009. Found: 375.1009.
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.[F:5][C:6]1[C:12]([F:13])=[CH:11][C:9](N)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1.N([O-])=[O:18].[Na+].Cl>O.Cl[Cu]>[F:5][C:6]1[C:12]([F:13])=[CH:11][C:9]([S:2]([Cl:4])(=[O:1])=[O:18])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: O=N[O-]
Reactant: O=S(Cl)Cl
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Cl
Yield: 208 %

Procedure:
In a similar fashion using route 3a general procedure 10, SOCl2 (1.15 ml, 15.7 mmol) in water (6 ml), CuCl (14 mg, 0.14 mmol), 4,5-difluoro-2nitroaniline (500 mg, 2.8 mmol), NaNO2 (285 mg, 7.5 mmol) and conc. HCl (5 ml) gave the title compound (1.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(Br)cc2nc(-c3ccccc3)nn12
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of 96 mg (0.51 mmol) 4-bromo-pyridine-2,6-diamine in 2.4 ml MeOH was added 121 mg (0.56 mmol) O-mesitylenesulfonylhydroxylamine (prepared from ethyl o-mesitylene-sulfonylacetohydroxamate and HClO4 (70%)) in 0.6 ml MeOH at −5° C. and after 15min 71 mg (0.56 mmol) benzaldehyde and stirred for 30 min. The addition of 4.8 ml 1N KOH was followed by extraction with ethylacetate, drying of the organic layer with Na2SO4, and removal of the volatile components. The residue was purified by column chromatography on silica eluting with ethylacetate and hexane (2:3). 58 mg(39%) of 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine were isolated, MS m/e (%): 290 (M++2, 44).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g, 0.448 mmol; prepared according to the procedure of Example 46, Step B), 4-fluorobenzenamine (0.056 ml, 0.582 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc. The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.132 g, 99%) as a pale yellow solid that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[C:18]1([S:24]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-nitro-4-chloroaniline (500 mg) and pyridine (2.1 ml in methylene chloride (10 ml), benzenesulfonylchloride (1.2 ml) was added dropwise at 0° C. under an atmosphere of argon. The reaction mixture was stirred for 3 days at room temperature. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The reside was recrystallized from AcOEt-hexane mixture solvent to give the by-product. The mother liquor was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-hexane) and recrystallized from AcOEt-hexane mixture solvent to give the title compound (175 mg) having the following physical data.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:20])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[CH3:21]N.[C:23](#[N:25])C>>[Cl:19][C:14]1[CH:13]=[C:12]([S:11][C:5]2[N:4]([CH3:20])[C:3]([CH2:2][N:25]([CH3:23])[CH3:21])=[N:7][C:6]=2[CH:8]([CH3:10])[CH3:9])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CC#N
Reactant: CN
Reactant: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CN(C)C)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 0.15 g (0.43 mmol)of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (28a), 1 ml of acetonitrile and 1.5 ml of a 50% methylamine aqueous solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with diethyl ether. The extract was washed with water and with saturated brine and dried over potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:4)to obtain 0.148 g of (Compound I-78)(yield 95%). Oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH3:19][O:20][CH2:21]CCl>>[CH3:19][O:20][CH2:21][CH2:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)C
Reactant: COCCCl
Product: COCCc1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 45, 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline (2 g 8.4 mmol,) was reacted with 2-chloroethyl methyl ether (0.76 mL, 10 mmol) to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1]C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=O.[F:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]4[C:37](=[O:38])[C:36]5=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]5[C:34]4=[O:43])[CH2:27][CH2:26]3)=[N:21][NH:22]2)=[CH:18][CH:17]=1>CCOCC>[ClH:1].[CH2:5]([O:4][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([F:15])[CH:24]=2)[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]3[C:34](=[O:43])[C:35]4=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]4[C:37]3=[O:38])[CH2:27][CH2:26]2)=[N:21]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCOC(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CCOCC
Product: CCCCCCCCCCOn1nc(N2CCN(CCN3C(=O)c4ccccc4C3=O)CC2)c2ccc(F)cc21
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of decanyl chloroformate (2.4 g, 11 mmol), and N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (3.9 g, 10 mmol) was warmed on the steam bath for 15 minutes. The reaction was allowed to cool to ambient temperature, and then ether was added to the residue. The resulting solid was filtered to afford N-[2-[4-(1-decanoxy-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide hydrochloride.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]=O.[CH2:13]([CH:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][NH:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:14]>CO>[CH2:24]([CH:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][N:17]([CH2:11][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[S:1])[CH2:16][CH:15]([CH2:13][CH3:14])[CH2:26][CH2:27][CH2:28][CH3:29])[CH3:25]
Reactant: C=O
Reactant: Sc1nc2ccccc2s1
Reactant: CCCCC(CC)CNCC(CC)CCCC
Solvent: CO
Product: CCCCC(CC)CN(CC(CC)CCCC)Cn1c(=S)sc2ccccc21
Temperature: 50 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
To a suspension of 250.8 g (1.5 moles) of 2-mercaptobenzothiazole in 1500 ml of methanol are added 112.8 ml (1.5 moles) of 37% aqueous formaldehyde, followed by the dropwise addition, with stirring, of 362.4 g (1.5 moles) of bis(2-ethylhexyl)amine. The mixture is stirred for 15 hours at 50° C. and then concentrated by evaporation in vacuo, affording as residue 618 g of 3-[bis(2-ethylhexyl)aminomethyl]benzothiazoline-2-thione as a reddish brown oil
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CS(C)=O>[C:6]1(=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH:2]=[O:1])=[N:4][NH:5]1
Reactant: O=c1[nH]nc(CO)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1n[nH]c(=O)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under N2 atmosphere, 50 g (284 mmol) 4-hydroxymethylphthalazin-1(2H)-one is dissolved in 900 ml DMSO and 119 ml (851 mmol) triethylamine. A solution of 90.3 g (567 mmol) sulfur trioxide pyridine complex in 733 ml DMSO is added and the mixture stirred for about 2 h. After the reaction is completed (TLC control), the mixture is poured onto a mixture of 2 l 5% Na2CO3 solution with 2 kg ice and 5 l EtOAc and then stirred. The aqueous phase of the resulting suspension is separated off and twice extracted with 2 l EtOAc. The first organic phase comprises crystalline product, this is filtered off and washed with water and EtOAc. The organic phase is separated off from the filtrate and, together with the second and third organic phase, washed with water and brine, dried (Na2SO4) and evaporated. The evaporation residue is combined with the above crystalline product, stirred in EtOAc, and hexane added before being filtered. This yields the title compound; m.p. 262-265° C.; 1H-NMR (DMSO-d6) 9.82 (s, HCO), 8.88 (d, 1H), 8.27 (d, 1H), 7.95 (m, 2H); FAB-MS (M+H)+=175, (M+H+MeOH)+=207.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[F:31][C:32]1[CH:33]=[CH:34][C:35](Br)=[N:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:35]1[CH:34]=[CH:33][C:32]([F:31])=[CH:37][N:36]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(F)cn2)c1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (˜1 mmol) was used in Procedure A with 5-fluoro-2-bromopyridine (1 mmol). Purified by silica gel chromatography (5-45% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-fluoropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: MS (Q1) 409 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[Cl:20]CCCl.CN(C)C=O.S(Cl)(Cl)=O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([Cl:20])=[O:19])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12
Reactant: ClCCCl
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)Cl
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 4 g (12.9 mmol) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylic acid 40 mL of 1,2-dichloroethane and 0.1 mL dimethyl formamide was carefully added 4.7 mL (64.4 mmol) of thionyl chloride. The reaction was heated to 90° C. for five hours. The reaction was cooled to room temperature and dry ethyl ether was added. The resulting brown precipitate was collected by vacuum filtration, washed with diethyl ether and dried to afford 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonyl chloride (3.31 g) in 78% yield. C12H6Cl2N2OS2: APCI m/z (in methanol to give methyl ester) 325.1/327.1 (pos.); 1H NMR (d6-DMSO): δ 8.68 (d, 1H, J=5.0 Hz), 8.32 (s, 1H), 8.65 (d, 1H, J=5.0 Hz), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.O(C(C)C)C(C)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid methyl ester (15.0 g, 68 mmol), 4-aminothiophenol (8.8 g, 68 mmol) and K2CO3 (11.8 g, 85 mmol) in DMF (150 mL) was heated at 90° C. for 1.5 hours, cooled to room temperature, and then poured into H2O (450 mL) under stirring. The aqueous mixture was extracted with ethyl acetate (400 mL). The extract was washed with H2O (3 times) and brine, dried over MgSO4, and evaporated to give the crude produce as orange crystal. The crude product was suspended in 150 mL of i-Pr2O and stirred at room temperature for 1 hour. The crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. for 3 days under reduced pressure gave purified title compound as orange crystal (18.6 g, 90% yield).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15]C)=O)[CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:18][NH2:19]>CCO>[N+:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:18][NH2:19])=[O:15])[CH:11]=2)[NH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a suspension of methyl 3-nitro-1H-indole-5-carboxylate (2.0 g, 9.09 mmol) in EtOH (40 mL) was added hydrazine hydrate (6 mL) and the reaction mixture was heated to reflux for 30 h. The mixture was cooled to RT and EtOH was removed in vacuo. Petroleum ether was added to the residue to get a yellow precipitate. The precipitate was filtered, washed with petroleum ether (3×40 mL) and dried to afford 3-nitro-1H-indole-5-carbohydrazide (1.0 g, 50%) as a yellow solid. MS (ESI, pos. ion) m/z: 221.0 (M+1); 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.71 (s, 1H), 8.57 (s, 1H), 7.77 (dd, 1H, J=8.7, 1.2 Hz), 7.58 (d, 1H, J=8.7 Hz), 4.49 (brs, 2H).