Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18](C(O)=O)=[C:17]3[N:12]([N:13]=[CH:14][CH:15]=[CH:16]3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[I:22]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([I:22])=[C:17]3[N:12]([N:13]=[CH:14][CH:15]=[CH:16]3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2nn3ncccc3c2C(=O)O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nn3ncccc3c2I)cc1
Reaction time: 4 h
Yield: 46.9 %

Procedure:
A mixture of 2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylic acid (710 mg), N-iodosuccinimide (678 mg) and sodium bicarbonate (717 mg) in DMF (8 ml) was stirred for 4 h. A further quantity of N-iodosuccinimide(100 mg) was added and stirring continued for 2 h. Aqueous workup gave a dark brown solid which was purified by SPE with dichloromethane as eluant. This gave the title compound as an orange-brown solid (429 mg, 47%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([CH2:16][C:17]#[N:18])=[N:14][CH:15]=1)([O-:9])=[O:8].[CH3:23]I>CC#N>[N+:7]([C:10]1[CH:11]=[C:12]([C:19]([F:22])([F:20])[F:21])[C:13]([CH:16]([CH3:23])[C:17]#[N:18])=[N:14][CH:15]=1)([O-:9])=[O:8]
Reactant: N#CCc1ncc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 10 h
Yield: 34.7 %

Procedure:
K2CO3 (359 mg, 2.60 mmol) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridine-2-yl)acetonitrile (200 mg, 0.865 mmol) in MeCN (10 mL). MeI (3071 mg, 21.63 mmol) was added and the mixture was stirred at 40° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=5:1, Rf=0.5) to yield a light yellow solid of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg, 0.300 mmol, 34.7% yield): 1H NMR (400 MHz, CDCl3) δ: 9.65 (d, J=2.2 Hz, 1H), 9.54 (d, J=2.2 Hz, 1H), 8.86 (d, J=2.2 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 4.47 (q, J=7.1 Hz, 1H), 1.92 (s, 2H), 1.78 (d, J=7.1 Hz, 3H); ES-LCMS m/z 246.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C(=O)(O)[O-].[Na+]>ClCCl>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C[Si](C)(C)c1nccs1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (500 mg, 2.69 mmol) in dichloromethane (3 mL) at 0° C. was added oxalyl chloride (0.26 mL, 2.95 mmol) dropwise. The solution was stirred at 0° C. for 30 min and then allowed to warm to room temperature and stirred for one hour. The solution was then cooled back to 0° C. and 2-(trimethylsilyl)-1,3-thiazole (0.63 mL, 4.03 mmol) was added. The solution was allowed to warm to room temperature and then stirred for one hour. The solution was then poured into cold saturated sodium bicarbonate and then diluted with dichlormethane. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% ethyl acetate/hexanes) to provide methyl trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate. MS ESI calc'd. for C12H16NO3S [M+H]+ 254. found 254. 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J=1.6, 2.9 Hz, 1H), 7.67 (dd, J=1.7, 2.9 Hz, 1H), 3.77-3.67 (m, 3H), 3.62 (t, J=11.1 Hz, 1H), 2.35 (t, J=10.4 Hz, 1H), 2.18-2.06 (m, 4H), 1.68-1.48 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.[F-].[K+].Cl>CN(C)C=O.O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:17][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:16][CH2:15][C:14]=3[CH:13]=2)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)C2
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1

Procedure:
6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30 mg), 2-chloro-5-nitropyridine (21 mg) and potassium fluoride (23 mg) in dry dimethylformamide were heated at 120° C. until disappearance of the starting material. Water and 1 N HCl were added and the mixture extracted with ethyl acetate. Ethyl acetate was washed with brine and water, dried and evaporated. The product was recrystallised from toluene. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd, 1H, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m, 5H), 1.87-2.04 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH3:14].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][CH3:14])(=[O:25])=[O:24]
Reactant: CNc1nc2ccccc2n1CCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1nc2ccccc2n1CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a cooled (0° C.), stirred mixture of 1-(2-hydroxyethyl)-2-methylamino-1H-benzimidazole (8.05 g, 42.12 mmol), Et3N (4.26 g, 42.12 mmol), and CH2Cl2 (85 mL) was added a solution of MsCl (4.83 g, 42.12 mmol) in CH2Cl2 (10 mL). After 2 hours, H2O was added and the layers were separated. The aqueous phase was extracted with CH2Cl2. The combined extracts were washed with brine, dried, and concentrated to give 8.00 g (71%) of a white solid m.p. 48°-50° C.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CC(N(C)C)=O.O>[CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution (10 mL) of 4-(cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methoxy)benzoic acid (0.43 g) synthesized above in dimethylacetamide were added ethyl 3-(methylamino)propanoate (0.14 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.23 g) at room temperature, and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.44 g). This was dissolved in ethanol (2 mL), 1N sodium hydroxide (1.5 mL) was added and the mixture was stirred at room temperature for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue to give the title compound (0.40 g, 78%) as an amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:29][CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: Fc1ccc(N2CCN(CCCCc3[nH]nc4c3CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 4-(4,5,6,7-tetrahydro-2H-indazol-3-yl)-n-butyric acid obtained in Starting Material Synthesis Example 3 and 1-(4-fluorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-4,5,6,7-tetrahydro-2H-indazole was obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[S:12](Cl)([OH:15])(=O)=[O:13].[CH4:17].Cl>O>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][S:12]([CH3:17])(=[O:15])=[O:13])[CH3:11]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(CCCN)OCC
Reactant: C
Agent: Cl
Solvent: O
Product: CCOC(CCCNS(C)(=O)=O)OCC
Temperature: 0 °C
Yield: 88 %

Procedure:
48.2 g 4-amino butyraldehyde diethyl acetal are dissolved in 48.2 g water-free pyridine at 20 ° C. under stirring in a three-necked flask, equipped with a thermometer, reflux condenser, tap funnel and magnetic stirrer. Subsequently, the mixture is cooled to 10° to 15° C. by means of external cooling and at these temperatures 34,6 g methane sulfochloride is added drop-wise at such a rate that the temperature of the reaction mixture does not rise beyond the given range. Subsequently, the mixture is heated to 40° to 50° C. for 1 hour and then stirred into 300 g ice water, to which 20 g of concentrated hydrochloric acid were added, under intensive stirring. The resulting substance is a two-phase, yellow-brown mixture, which is extracted with ether and further processed as explained in Preparation Example 1. Yield: 88% based on the amino acetal used.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].O>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A mixture of 2-bromo-4-chloro-1-methoxybenzene (1 g, 4.5 mmol), CuI (43 mg, 0.23 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.23 mmol) in NEt3 (10 mL) was degassed, Then ethynyltrimethylsilane (0.5 g, 5 mmol) was added to the solution, the mixture was stirred at 80° C. for 6 hours. Then the mixture was cooled to 25° C., and added to H2O (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=10:1) to provide the product of ((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane (1 g, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H), 7.21˜7.23 (m, 1H), 6.76˜6.78 (d, J=9.2 Hz, 1H), 3.86 (s, 3H), 0.26 (s, 9H). MS (M+H)+: 239/241
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[NH:23][CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[NH:23][CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([CH:39]3[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C1CCOCC1
Reaction time: 12 h

Procedure:
Secondary amine 24 (200 mg, 0.41 mmol) was dissolved in 1,2-dichloroethane (4 mL) at ambient temperature and tetrahydro-4H-pyran-4-one (84 μL, 0.90 mmol), HOAc (50 μL, 0.82 mmol), and sodium triacetoxyborohydride (172 mg, 0.78 mmol) were added. After 12 h, the reaction mixture was diluted with EtOAc, washed successively with saturated aqueous NaHCO3 (3×), and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude orange mixture was purified by reverse-phase HPLC (2″ Dynamax® C18, 10-100% ACN/water containing 0.1% HOAc over 25 min; Flow: 40 mL/min) to give 100 mg of 24 and 90 mg of 25 as a colorless oil. Mass spectrum, m/z [572.0] (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:31]([C:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>[Cu]I.CN(C=O)C>[NH2:39][C:33]1([C:31]#[C:32][C:2]2[N:3]([CH3:23])[C:4]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=4[N:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C#CC1(N)CCCCC1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C#CC2(N)CCCCC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 90 °C
Yield: 41 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (0.02 g), PdCl2dppf (3.5 mg), triethylamine (0.1 mL), DMF (5 mL), copper(I) iodide (1 mg) and 1-ethynylcyclohexylamine (0.034 mL) was heated at 90° C., under an inert atmosphere, for 1.5 hours. The solvent was evaporated in vacuo then purification by flash chromatography on silica eluting with DCM:MeOH (9:1) gave the title compound as a beige solid (9 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
2,5-Diamino-benzenesulfonamide (4.20 kg, 22.4 mol) was dissolved in dichloromethane (120 L) and pyridine (8.00 kg, 89.9 mol), and the resulting solution was cooled to 0° C. Methanesulfonyl chloride (2.80 kg, 24.4 mol) was added slowly, and the resulting mixture was allowed to warm to 23° C. and stirred for 2 days. The mixture was filtered and the resulting solid was washed with dichloromethane (2×20 L). The solid was diluted with water (100 L) and 1.0 M aqueous hydrochloric acid solution (25 L), and was then stirred at 23° C. for 1 h. The mixture was filtered and the resulting solid was washed with water (20 L) and then with methyl-tert-butyl ether (2×10 L). The solid was further dried in vacuo at 45° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (4.39 kg, 16.5 mol, 73%) as a pale pink solid. 1H NMR (400 MHz, CD3OD) δ: 2.89 (3H, s), 6.82 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.58 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C7H11N3O4S2 265.02, found 266.0[M+H+].
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][OH:34]>O.C(Cl)(Cl)Cl>[OH:34][CH2:33][CH2:32][CH2:31][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH2:8][CH2:7]1
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OCCCC2CCN(CCCO)CC2)cc1
Reaction time: 0.25 h

Procedure:
To an N,N-dimethylformamide (70 mL) solution of 9.81 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile were added 8.02 g of potassium carbonate and 2.62 mL of 3-bromo-1-propanol at room temperature, which was then stirred at the same temperature for 2 hours and 15 minutes. Thereto was added 2.62 mL of 3-bromo-1-propanol, which was then stirred at the same temperature for 1 hour and 45 minutes. Chloroform and water were added to the reaction mixture. The organic layer was separated, washed sequentially with a 1 mol/L sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution, and then dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=4:1) to provide 4.28 g of 4-{3-[1-(3-hydroxypropyl)-4-piperidinyl]propoxy}benzonitrile as white solid form.
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([OH:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1>C(OC(C)C)(C)C.[Ag-]=O.[Ag]=O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([O:17][CH2:1][CH3:2])[C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=1
Reactant: CCI
Reactant: COC(=O)[C@@H](O)Cc1ccc(Br)cc1
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: CC(C)OC(C)C
Product: CCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Temperature: 70 °C
Yield: 79 %

Procedure:
11 ml of ethyl iodide are added dropwise to a solution of 23.5 g (91 mmol) of methyl 3-(4-bromophenyl)-2(S)-hydroxypropanoate and 35.6 g (155 mmol) of silver(I) oxide in 120 ml of isopropyl ether. The reaction medium is heated at 70° C. overnight. 10 g (45 mmol) of silver oxide and 3.7 ml (45 mmol) of ethyl iodide are added and the reaction medium is heated for a further 4 hours and then filtered through Celite, the precipitate is rinsed with ethyl acetate and the filtrate is concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 95/5 and then 90/10 heptane/ethyl acetate mixture. 20 g (79%) of methyl 3-(4-bromophenyl)-2(S)-ethoxypropanoate are obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:16][C:17]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:19]1[N:23]([CH3:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:21][N:20]=1)[CH3:18].Cl>[Cl-].[Na+].O.C(Cl)(Cl)Cl>[CH3:18][C:17]([N:32]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:19]1[N:23]([CH3:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[N:21][N:20]=1)[CH3:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1-c1nnc(C(C)(C)Nc2ccccc2)n1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1-c1nnc(C(C)(C)N(C(=O)c2ccccc2)c2ccccc2)n1C
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Benzoyl chloride (0.21 ml) and N,N-dimethylaminopyridine (40 mg) were added to a pyridine (15 ml) solution of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}aniline (500 mg), followed by stirring at 80° C. for 3 days. After the reaction solution and chloroform were added to 1M hydrochloric acid, the reaction solution and chloroform were added to brine and then the organic layer was separated. Furthermore, the organic layer washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution successively, dried over anhydrous magnesium-sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=99:1 to 98:2) and then the resulting solid washed with ether to obtain 523 mg of N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]ethyl}-N-phenylbenzamide (colorless solid).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN=C=[N:27][CH2:28][CH2:29][CH2:30][N:31]([CH3:33])C.[CH:34]1C=CC2N(O)N=NC=2[CH:39]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:33]=[CH:34][CH:39]=4)=[O:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)O)ccc32)c1
Reactant: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1-[3-(acetylamino)phenyl]-1H-benzimidazole-5-carboxylic acid (0.83 g, 2.8 mmol), EDCI (0.81 g, 4.22 mmol), HOBt (0.57 g, 4.22 mmol) in anhydrous DMA (10 mL) was added DIPEA (0.75 mL, 4.31 mmol) at rt. The reaction mixture was stirred for 0.5 h and then (3-aminomethyl)pyridine (0.57 mL, 5.62 mmol) was added drop-wise. Stirring was continued for an additional 25 h. The solvent was evaporated in vacuo and the crude material was purified by silica gel chromatography (5%-15% MeOH in CH2Cl2) and then recrystallized from acetone to afford 1-[3-(acetylamino)phenyl]-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.09 (3H, s), 4.54 (d, J=6.0 Hz, 2H), 7.35-7.40 (m, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.4 Hz, 1.2 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 8.46 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.58 (1H, J=1.6 Hz, 1H), 8.68 (s, 1H), 9.21 (t, J=5.6 Hz, 1H), 10.33 (s, 1H). MS (ES+): m/z 386 [MH+].
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.1 h
Yield: 68 %

Procedure:
208 g of anthraquinone are introduced into 955 g of 99% nitric acid at 0° with stirring (mole ratio 15:1). The temperature of the reaction mixture rises to 55° in about 6 minutes. This temperature is maintained by cooling until the total reaction time is 10 minutes. 316 g of 99% nitric acid (γHNO3 = 0.791) are then distilled off very rapidly at this temperature under vacuum. 100 ml of water are then slowly added to the sump product (crystallisation acid 82%, γHNO3 = 0.532). The precipitated product is suction-filtered, washed with a little 75% nitric acid and then with water, dried and subjected to fractional vacuum distillation at 10 Torr and a head temperature of 281°. 172.1 g of 98.7% pure 1-nitroanthraquinone (67.1% of the theoretical amount) are obtained as distillate.