Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1)[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[S:30](=[O:34])(=[O:33])([OH:32])[NH2:31]>>[CH:10]1([NH:31][S:30](=[O:33])(=[O:32])[OH:34])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:17]=1)[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: NS(=O)(=O)O
Agent: COc1ccc(C(C#Cc2ccccc2)CNC(=O)CN)cc1OC1CCCC1
Product: O=S(=O)(O)NC1CCCCC1

Procedure:
A solution of 4-t-butoxycarbonylaminomethylcarbonylamino-3-(3-cyclopentyloxy-4methoxyphenyl)-1-phenyl-1-butyne (290 mg, 0.59 mmol) in CH2Cl2 (5 ml) at 0° was treated with trifluoroacetic acid (4 ml). After 1 hr, all the solvents were evaporated. The residue was partitioned between H2O and Et2O, basified with aqueous NaOH, and the Et2O layer seperated, dried, and the solvent evaporated, and gave 4-aminomethylcarbonylamino-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne, 200 mg (86%). The salt was formed by treating this amine (180 mg) in Me2CO (2 ml) with sulfamic acid (82 mg). The solution was concentrated to almost dryness, and the resultant crystals were triturated with Me2CO, and gave the titled compound, mp 119-124°. 1H NMR (400 MHz, CDCl3) δ 8.22 (t, 1 H), 7.44 (m, 3 H), 7.28 (m, 3 H), 7.02 (d, 1 H), 6.94 (m, 1 H), 6.82 (d, 1 H), 4.80 (m, 1 H), 4.04 (t, 1 H), 3.80 (s, 3 H), 3.76 (m, 2 H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.18 (m, 1 H), 2.04 (m, 2 H), 1.80-1.98 (m, 6 H), 1.52-1.72 (m, 4 H), 1.08-1.32 (m, 6 H).
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].C(OO)(=[O:20])C>C1(C)C=CC=CC=1>[CH2:1]([N+:5]1([O-:20])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OO
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Solvent: Cc1ccccc1
Product: CC(C)C[N+]1([O-])C=Nc2cnc3ccccc3c21

Procedure:
The oxidation of 1-isobutyl-1H-imidazo[4,5-c]quinoline produced in Example 3 is carried out in toluene at 40-45° C. using peracetic acid as oxidant to produce 1-isobutyl-1H-imidazo[4,5-c]quinoline N-oxide. The product is isolated by filtration after addition of a sodium sulfate solution and ammonium hydroxide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].CI.[C:15](OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: CCOC(C)=O
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromoindole (5 g, TCI) in DMF (30 ml) was added with 60% sodium hydride (1.14 g) under ice cooling and stirred for 10 minutes. The mixture was added dropwise with methyl iodide (3.18 ml, TCI), stirred for 10 minutes, then warmed to room temperature and further stirred for 30 minutes. The reaction mixture was poured into ice water and added with ethyl acetate (300 ml) for extraction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 51, 4.95 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=NO)[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2].[N+](C1C=CC=C2C=1C(=O)C=CC2=NO)([O-])=[O:18].[N+](C1C=CC=C2C=1C(N)=CC=C2O)([O-])=O>[Fe+2]>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:18])[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2]
Reactant: O=C1C=CC(=NO)c2cccc([N+](=O)[O-])c21
Reactant: O=C1C=CC(=NO)c2c1cccc2[N+](=O)[O-]
Agent: [Fe+2]
Agent: Nc1ccc(O)c2cccc([N+](=O)[O-])c12
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
5-Nitro-1,4-naphthoquinone is prepared by reducing 8-nitro-1,4-naphthoquinone-1-oxime and/or 5-nitro-1,4-naphthoquinone-1-oxime in an aqueous and/or organic reaction medium in the presence of iron (II) ions and a hydrogen halide at a temperature in the range of from -20° to 100°C, and thereafter oxidizing the 8- and and/or 5-nitro-4-amino-1-naphthol formed, or the corresponding salt, optionally without intermediate isolation, at a temperature in the range of from -10° to 100°C to form the desired 5-nitro-1,4-naphthoquinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.O>CC(C)=O>[F:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Fc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(-c2cccc(F)c2)cc1
Temperature: 40 °C
Yield: 86.6 %

Procedure:
1-Bromo-3-fluorobenzene (28.8 g, 0.165 mol), potassium carbonate (50 g, 0.362 mol), 4-methoxybenzene boronic acid (27.6 g, 0.182 mol), water (100 ml) and acetone (300 ml) were placed in 1 L round-bottom three necked flask equipped with condenser, thermometer, mechanical stirrer and nitrogen inlet and outlet. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was heated up to the boiling point to 40° C. to degas the reaction system and then cooled down and the catalyst palladium acetate (0.1 g) was added. The temperature has increased of few degrees and the solution turned brown. The mixture was refluxed for 6 hours, then was cooled down, poured on cold water and the precipitated gray solid was filtered off. The raw product was recrystallized from ethanol (500 ml). The product (28.9 g) in a form of white crystals was obtained, 88% of theor. yield. The melting point 63-64° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1)\[CH3:21])[CH3:16]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(F)c1
Temperature: 23 °C
Yield: 85.3 %

Procedure:
Potassium t-butoxide (7.40 g, 0.066 mol) was added to a stirred solution of 3-fluoro-phenol (3.78 g, 0.034 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (6.50 g, 86%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH3:39])[CH2:34][C:35]([CH3:38])([OH:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CCOC(C)=O.C(#N)C>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:23])[CH3:39]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)CC(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(CC(C)(C)O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (98 mg, 0.22 mmol), 4-amino-2-methylpentan-2-ol [prepared according to US 2003/0171584 A1] (27 mg, 0.23 mmol), and HATU (89 mg, 0.23 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.2 mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight then diluted with EtOAc and washed with water (3×). The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 75 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide as an off-white solid. MS: [M+H]+=541.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:16][CH2:15][CH2:14][C@:11]3([O:13][CH2:12]3)[CH2:10]2)[C:5]([F:17])=[CH:4][N:3]=1.[OH-].[NH4+:19]>O>[NH2:19][CH2:12][C@:11]1([OH:13])[CH2:14][CH2:15][CH2:16][C@H:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1
Reactant: [NH4+]
Reactant: Fc1cnc(Cl)nc1N[C@H]1CCC[C@@]2(CO2)C1
Agent: [OH-]
Solvent: O
Product: NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-fluoro-N-[(3S,5S)-1-oxaspiro[2.5]octan-5-yl]pyrimidin-4-amine, 46a, (0.19 g, 0.73 mmol) was dissolved in water (75 mL) and treated with 30% ammonium hydroxide (10 mL, 86.0 mmol). The suspension was heated to 50° C. for 5 hrs then allowed to stir at room temperature overnight. The volatiles were evaporated under reduced pressure, and the residue, (1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)cyclohexanol, was taken into the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:12].COC(C1C=CC(C(CC2OC(COC3C=CC=CC=3)=CC=2)C(NCC2C=CC3C(=CC=CC=3)C=2)C)=CC=1)=O.[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([CH:61]([CH:73](NCC2C=CC=C(Cl)C=2Cl)[CH3:74])[CH2:62][C:63]2[O:67][C:66]([C:68]([O:70][CH2:71][CH3:72])=[O:69])=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH:73]([CH3:74])[CH:61]([C:58]1[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=1)[CH2:62][C:63]1[O:67][C:66]([C:68]([O:70][CH2:71][CH3:72])=[O:69])=[CH:65][CH:64]=1
Reactant: NCc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)NCc2cccc(Cl)c2Cl)o1
Agent: COC(=O)c1ccc(C(Cc2ccc(COc3ccccc3)o2)C(C)NCc2ccc3ccccc3c2)cc1
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)NCc2ccc3ccccc3c2)o1

Procedure:
The reactions were carried out in the same manner as in Reference Example 1 except that instead of p-nitrophenylacetone and/or ethyl 5-chloromethyl-2-furancarboxylate and/or 2-naphthoaldehyde used as the starting material in the above reaction, the corresponding arylacetone derivative and/or halide and/or arylaldehyde derivative was used, to obtain ethyl 5-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl}-2-furancarboxylate, ethyl 3-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyllbenzoate, ethyl 5-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl}-3-isoxazolecarboxylate, ethyl 2-{(2RS,3RS)-2-(4-chlorophenyl)-3-(2-naphthylmethylamino)butyl}-5-pyridinecarboxylate, ethyl 5-{(2RS,3RS)-3-(2-benzo[b]thienylmethylamino)-2-(3,4-methylenedioxyphenyl)butyl}-2-furancarboxylate, N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(3-phenoxymethylphenyl)propyl}-2-naphthylmethylamine, N-[(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{5-(phenoxymethyl)-3-(1,2,4-oxadiazolyl)}propyl]-2-naphthylmethylamine, N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-{(E)-3-styrylphenyl}propyl!-2-naphthylmethylamine, N-{(1RS,2RS)-2-(4-chlorophenyl)-1-methyl-3-{(E)-3-styrylphenyl}propyl!-2-naphthylmethylamine, N-{(1RS,2RS)-2-(4-methoxycarbonylphenyl)-1-methyl-3-(5-phenoxymethyl-2-furyl)propyl}-2-naphthylmethylamine and ethyl 5-{(2RS,3RS)-2-(4-nitrophenyl)-3-(2,3-dichlorobenzylamino)butyl}-2-furancarboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C:11](O)(=O)[C:12]([OH:14])=[O:13]>C1COCC1>[C:3]([O:13][C:12]([CH2:11][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:11][C:12]([O:14][C:6]([CH3:9])([CH3:7])[CH3:5])=[O:13])=[CH:5][CH:4]=1)=[O:14])([CH3:8])([CH3:4])[CH3:2]
Reactant: BrCc1ccc(CBr)cc1
Reactant: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(CCC(=O)OC(C)(C)C)cc1
Reaction time: 12 h
Yield: 75 %

Procedure:
To a mixture of 200 ml of THF and 44 ml (0.315 mol) of diisopropylamine was added 168 ml (286 mmols) of hexane solution of 1.70 mol dm-3 butyl lithium at 0° C. The mixture was stirred at 0° C. for 10 minutes and then cooled to -78° C. To the mixture was added 35 ml (260 mmols) of t-butyl acetate, followed by stirring for 1 hour. To the lithium enolate thus formed was added 300 ml of THF solution of 26.4 g (0.1 mol) of α,α'-dibromo-p-xylene. The reaction mixture was stirred at -78° C. to room temperature for 12 hours, and 100 ml of saturated aqueous solution of oxalic acid was thereafter added thereto. The organic layer was separated off and subjected to extraction with ether. The organic layer was dried over MgSO4 and concentrated to obtain an oil, which was then subjected to silica gel column chromatography (90:10 hexane-ether), affording 25.0 g (yield 75%) of t-butyl 3-[4-(2-t-butoxycarbonylethyl)phenyl]propionate in the form of an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([N:16]1[CH2:15][CH2:14][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:18][CH2:17]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
Methanesulfonyl chloride (34.38 ml, 443 mmol, 1.1 equiv.) was added slowly to a solution of 1-(tert-butoxycarbonyl)piperazine 6 (BOC-piperazine, 75 g, 403 mmol, 1.0 equiv.) and triethylamine (67.4 ml, 483 mmol, 1.2 equiv.) in methylene chloride (750 ml) while maintaining the internal temperature below 20° C. The solution was stirred at ambient temperature for 24 hours. The solution was poured onto a mixture of ice and water (1.5 L). The phases were separated and the aq. phase was extracted with methylene chloride (800 ml×2). The organic phases were combined, dried over MgSO4, filtered and concentrated to give tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate 7 as an off-white solid (105 g).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Solvent: O
Product: CC(C)(C)c1nc2cc(N3CCN(c4ccccc4)CC3)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 7 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, in 8.2 g of N-phenylpiperazine is heated at 150°-160° for 12 hours, cooled and poured into water. The paste is extracted with methylene chloride, washed with 2N HCl, then with 10% NaOH and then with water. The organic layer is dried, the solvent evaporated and the solid crystallised from isopropyl alcohol to give 2-tert-butyl-6-nitro-5-[4-phenylpiperazin-1-yl]benzothiazole, melting at 152°-155°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH:25]N(C)C)[C:20](OCC)=[O:21])=[CH:15][CH:14]=1)#[N:12].Cl.CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([N:8]2[C:20]([OH:21])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=3)[CH:25]=[N:9]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Reactant: Cc1cc(NN)ncc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Combined 5-bromo-2-hydrazinyl-4-methylpyridine (6.0 g, 29.85 mmol) and isopropanol (100 mL) and added ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (8.02 g, 32.84 mmol) and HCl solution (aqueous, 1.85%, 49.75 mL) and stirred at room temperature for 2 h, then DIEA (19.40 g, 149.25 mmol) was added. After about 30 minutes the reaction was evaporated to give a residue which was extracted with EtOAc (50 mL×2) and water (50 mL×2), the EtOAc layers were combined and washed with brine, dried over Na2SO4 to give a residue which was purified by flash chromatography (petroleum ether: EtOAc 5:1-1:8) to give the title compound (8.67 g, 82.04%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[F:17][C:18]([F:30])([F:29])[C:19]1[N:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:25]([C:22]3[CH:23]=[N:24][C:19]([C:18]([F:30])([F:17])[F:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 42.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-trifluoromethoxy-quinolin-8-ylamine (Intermediate 46) (75 mg, 0.32 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (96 mg, 0.39 mmol), DMAP (cat.), pyridine (0.05 ml, 0.65 mmol) and DCM (2 ml) gave the title compound (60 mg, 42%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:10]1([CH2:16][S:17][CH:18]([C:22](O)=[O:23])[C:19](O)=[O:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:23][C:22]1[CH:2]=[C:1]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[O:3][C:19](=[O:20])[C:18]=1[S:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccnc1
Product: O=c1oc(-c2cccnc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared from the condensation of the trimethylsilyl enol ether of 3-acetyl pyridine and diethyl ester of [(phenylmethyl)thio]propanedioic acid following the same procedure outlined in Method A; m.p. 183°-184° C. NMR (DMSO-d6) δ 4.02 (s, 2 H), 6.83 (s, 1 H), 7.20 (m, 1 H), 7.26 (d, 4 H), 7.55 (m, 1 H), 8.16 (m, 1 H), 8.69 (m, 1 H), 8.98 (d, 1 H).
Reaction SMILES: I[CH2:2][CH3:3].[NH:4]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]#[N:11])[CH2:5]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:2]([N:4]1[CH2:8][CH2:7][C@H:6]([CH2:9][C:10]#[N:11])[CH2:5]1)[CH3:3]
Reactant: CCI
Reactant: N#CC[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC[C@H](CC#N)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
Iodoethane (6.46 g) was added in portions to a cooled mixture of 2-((R)-pyrrolidin-3-yl)acetonitrile (Intermediate 210, 4.6 g) and potassium carbonate (8.6 g) in acetonitrile (30 mL) at 0° C. The mixture was stirred for 3 hours at 0° C. then concentrated under vacuum. The residue was partitioned between water and DCM. The organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-((R)-1-ethylpyrrolidin-3-yl)acetonitrile (2.1 g) as a colourless liquid which was used without further characterisation.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:18]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:8]=1)=[O:20])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=384.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[O:9][N:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:11]=[C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[O:9][N:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cc(Cn3ncc(N)n3)on2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)on1

Procedure:
Following general procedure A followed by L (with a reaction time of 3 weeks), starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-isoxazol-5-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:14]=[N:13][C:6]2[NH:7][C:8](=O)[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:2][C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=C1CNCc2cc(Br)cnc2N1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)CNCCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A suspension of 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one hydrochloride (1.16 g, 4.16 mmol) in THF (35 ml) was cooled in an ice bath and treated dropwise with LiAlH4 (8.4 mL of a 1.0 M solution in THF, 8.4 mmol). After stirring for 30 min, the ice bath was removed and the solution was allowed to warm to room temperature. After heating to reflux overnight, the mixture was cooled in an ice bath. The reaction was quenched sequentially with H2O (0.3 mL), 15% NaOH (0.3 mL) and H2O (0.9 mL). After 5 min, the ice bath was removed and the mixture was stirred at room temperature for 2.5 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give a yellow syrup. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 95:5 to 90:10) gave the title compound (0.42 g, 44%) as a white solid: 1NMR (300 MHz, CDCl3) δ8.03 (d, J=2.3 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 4.96 (br s, 1H), 3.82 (s, 2H), 3.22-3.15 (m, 2H), 3.08-3.05 (m, 2H), 1.97 (br s, 1H); MS (ESI) m/e 228 (M+H)+.