Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([O:7][CH2:15][CH3:16])=[O:6]
Reactant: CCO
Reactant: CC1(C(=O)O)CC1(F)Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1(F)Cl
Yield: 79 %

Procedure:
44 ml of ethanol are added at room temperature and with stirring to 43 g (0.28 mol) of 2-fluoro-2-chloro-1-methyl-cyclopropanecarboxylic acid. After the addition of sulphuric acid, the reaction mixture is refluxed for 16 hours. Excess ethanol is subsequently distilled off and the residue is dried and distilled under reduced pressure. In this manner, 40 g (79% of theory) of ethyl 2-fluoro-2-chloro-1-methyl-cyclopropane-carboxylate are obtained in the form of a liquid of boiling point 62°-63° C./17 mbar.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16].C(OCC)C>O1CCCC1>[CH3:11][C:10]([O:9][C:7](=[O:8])[NH:3][CH2:4][CH2:5][CH2:6][C:2](=[O:1])[CH2:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(=O)CCCNC(=O)OC(C)(C)C

Procedure:
A solution of 1,1-dimethylethyl 2-oxo-1-pyrrolidinecarboxylate (7.5 g, 40.5 mmol) in dry tetrahydrofuran (150 ml) under a nitrogen atmosphere and at −78° C., was treated dropwise with a solution of isobutyl magnesium bromide in diethyl ether (2 molar, 22.5 ml, 45 mmol). The mixture was stirred at −78° C. for 2h then quenched into a saturated aqueous solution of ammonium chloride (100 ml). The products were extracted into ethyl acetate (2×250 ml) and the combined extracts dried over magnesium sulphate. Concentration of the extracts gave an oil which was purified on silica gel using isohexane/diethylether (1:1). The title compound was isolated as a colourless oil (2.3 g, 25%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:16]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]>CO.N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:16]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:4][O:2][CH3:3])[CH2:29][CH2:28]2)[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of methoxylamine hydrochloride (23 mg, 0.27 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 58, 80 mg, 0.18 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 35/65 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-methoxyimino-cyclohexyl)-N-pyrazin-2-yl-propionamide (68 mg, 81%) was a white foam: EI-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1364.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 4-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (23.6 mg, yield: quantitative).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13])(=O)[CH2:2][CH3:3].[CH2:14]([O:17][NH2:18])[CH:15]=[CH2:16]>CN(C)C=O>[CH2:14]([O:17][NH:18][C:1](=[C:5]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13])[CH2:2][CH3:3])[CH:15]=[CH2:16]
Reactant: C=CCON
Reactant: CCC(=O)C1C(=O)NC(=O)NC1=O
Solvent: CN(C)C=O
Product: C=CCONC(CC)=C1C(=O)NC(=O)NC1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
1.8 g of 5-propionylbarbituric acid was dissolved in 30 ml of dimethylformamide and after the temperature of said solution was raised to 40° C, 1.5 g of allyloxyamine was added to it and the resulting solution was stirred at 40° C during 3 hours and then, about 10 ml of said dimethylformamide was distilled off and after 50 ml of ethanol was added to it, the separated crystal was filtered and recrystallized from ethanol and thereby, 2.1 g of the desired compound was obtained as a white columns.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17]N(C=O)C.[H-].[Na+].CI>O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH3:17])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C(C)=O)c[nH]c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc2c(C(C)=O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 3-acetyl-1H-indole-6-carboxylate (0.92 g) and DMF (18 ml) was added sodium hydride (0.18 g) under ice-cooling, followed by stirring at room temperature for 0.5 hour. Next, methyl iodide (0.29 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 5 hours. Then, water was added thereto under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration, washed with water, and purified by silica gel column chromatography (hexane/THF=2:1→chloroform /THF=9:1) to obtain methyl 3-acetyl-1-methyl-1H-indole-6-carboxylate (0.98 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[S:8][CH:9]=[C:10]([CH3:12])[N:11]=1>>[Br:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:9]=[C:10]([CH3:12])[N:11]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)CBr)n1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 (Step 5) starting from bromoacetyl bromide and 2-amino-4-methylthiazole.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:16].[C@H:17]12C[C@H](NC1)CN2C(=O)C>>[ClH:16].[CH2:9]1[CH:10]2[CH2:11][NH:12][CH2:13][CH:14]2[CH2:15][N:8]1[C:6](=[O:5])[CH3:17]
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: Cl
Product: CC(=O)N1CC2CNCC2C1

Procedure:
The title product KK is prepared from hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester according to the procedure described for the synthesis of Intermediate O.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:19](=[O:21])=[O:20].CCOCC>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[C:11]([F:13])[C:12]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: CCCCCc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCc1cc(F)c(C(=O)O)c(F)c1

Procedure:
A solution of n-butyllithium (10.5M in hexane; 2.70 ml, 0.028 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 13 (5.10 g, 0.028 mol) in dry THF (30 ml) under dry nitrogen. The stirred mixture was maintained under these conditions for 2.5 h and then poured onto a slurry of solid carbon dioxide and dry ether. The product was extracted into 10% sodium hydroxide which was then acidified with 36% hydrochloric acid. The acidic mixture was washed with ether (twice), and the combined ethereal layers were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a colourless solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:12][C:13]([C:15]1[C:16](=[O:29])[N:17]([CH3:28])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][CH:19]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]([C:15]1[C:16](=[O:29])[N:17]([CH3:28])[C:18]2[C:23]([C:24]=1[OH:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][CH:19]=2)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Reactant: CCNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=O)c1c(O)c2c(OC)cccc2n(C)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
N-Ethylaniline (3.0 g, 25 mmol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled off in order to obtain a dry solution. To this boiling solution was added 1,2-dihydro-4hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (2.7 g, 10 mmol). The ethanol formed during the reaction was distilled off together with some toluene for about 4 hours. The reaction mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), yield 80%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:37][CH:38]1[CH:45]2[CH2:46][C:41]3([OH:48])[CH2:42][CH:43]([CH2:47][CH:39]1[CH2:40]3)[CH2:44]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:48][C:41]12[CH2:46][CH:45]3[CH2:44][CH:43]([CH2:47][CH:39]([CH:38]3[NH:37][C:15]([C:13]3[CH:12]=[CH:11][C:10]4[N:6]([CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH:7]=[N:8][C:9]=4[CH:14]=3)=[O:17])[CH2:40]1)[CH2:42]2
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.65 g, 0.0028 mol) in dry DMF (5.0 mL) was added with stirring HOBt (0.46 g, 0.0034 mol), DIPEA (2.5 mL, 0.014 mol), 4-aminoadamantan-1-ol (0.685 g, 0.0034 mol) at 0° C. To the resulting mixture was added EDCl (0.65 g, 0.0034 mol) and stirred for 15 h at ambient temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water, dried (Na2SO4) and the solvent evaporated affording (1.0 g, 93.5%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide. MS-ESI m/z 381 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M17) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (62 mg).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[Na].C(O)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=1)[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.9 g (10 mmol) 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4 thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3), 0.4 g (10 mmol) sodium hydroxyde and 100 ml ethanol were refluxed 30mn. After evaporation of the solvent, the residue was dissolved in 50 ml DMF and 1.86 g (10 mmol) p-nitrobenzoyl chloride were added while keeping the temperature under 30° C. The mixture was stirred 2 hrs at room temperature, diluted with 100 ml water, extracted with ethyl acetate. The organic layers were washed with brine and dried over magnesium sulfate. The residue was purified by column chfomatography on silica (eluent:ethylacetate/hexane:1/1) and the major fraction was triturated in isopropyl ether and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:3]=1.[NH4+:16].[OH-]>>[N:10]1([CH:8]([C:4]2[N:3]=[C:2]([NH2:16])[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [NH4+]
Reactant: CC(c1cccc(Br)n1)N1CCCCC1
Agent: [OH-]
Product: CC(c1cccc(N)n1)N1CCCCC1

Procedure:
In a manner similar to that described in Preparation BW, 2-bromo-6-(1-piperidin-1-yl-ethyl)-pyridine (370 mg, 1.37 mmol) was heated with NH4OH (18 mL), IpOH (10 mL), and Cu (30 mg) in sealed tube to give a brown oil. MS m/z: 206.1 (M+H). Calc'd. for C12H19N3-205.16.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].I[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>[Cu](Br)Br.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: Br[Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 0.5 h

Procedure:
5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol and 70 ml of pyridine were introduced into a three-necked flask under a nitrogen stream, and 430 mg (15 mmol) of sodium hydride (80% in oil) were added in small amounts. The mixture was stirred for 30 minutes, 3.9 g (15 mmol) of methyl 4-iodobenzoate and 4.6 g (22.5 mmol) of a copper bromide and dimethyl sulfide complex were added successively and the resulting mixture was heated at reflux for 16 hours. The reaction medium was evaporated to dryness, taken up in water and ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH2:1]([CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][NH2:3].[F:10][C:11]([F:18])([F:17])[C:12]([O:14]CC)=O>O1CCCC1>[F:18][C:11]([F:10])([F:17])[C:12]([NH:3][CH2:2][CH2:1][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][NH:9][C:12](=[O:14])[C:11]([F:18])([F:17])[F:10])=[O:14]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCNCCCN
Solvent: C1CCOC1
Product: O=C(NCCCNCCCNC(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C

Procedure:
35 g of 3,3′-iminobispropylamine (266.7 mmol) were solubilized in 150 ml of anhydrous tetrahydrofuran under an argon stream. The reaction mixture was then cooled to 0° C. on an ice bath and 65 ml of ethyl trifluoroacetate (546.8 mmol) were added dropwise (very slowly) using a dropping funnel. At the end of the addition (3 hours later), the reaction mixture was allowed to return to room temperature and the stirring was maintained for a few hours under argon.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[C:25]([O:29][C:30]([NH:32][C:33]([CH3:51])([CH3:50])[CH2:34][C:35]([NH:37][C@@H:38]1[CH2:44][CH2:43][C:42]2[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=2[NH:40][C:39]1=[O:49])=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:40]3[C:41]4[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=4[CH2:43][CH2:44][C@@H:38]([NH:37][C:35](=[O:36])[CH2:34][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:50])[CH3:51])[C:39]3=[O:49])=[CH:4][CH:5]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccc(CBr)cc2)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3Oc3ccc([N+](=O)[O-])cc3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 4'-bromomethyl-2-(4-nitrophenoxy)-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.78 (m,1H), 2.3-2.7 (m,5H), 4.47 (m,1H), 4.75 (d,15 Hz,1H), 5.13 (d,15 Hz,1H), 6.63 (d,7 Hz,1H), 6.75 (d,8 Hz,2H), 7.05-7.50 (m,/11H), 7.97 (s,1H), 7.98 (d,8 Hz,2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([F:17])[CH:11]=1.CN(CCN(C)C)C.C([Li])CCC.[O:31]=[C:32]1[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:35]([C:44]([O:46][CH3:47])=[O:45])[CH2:34][CH2:33]1>C1COCC1>[CH3:43][C:40]([O:39][C:37]([NH:36][C@@H:35]([CH2:34][CH2:33][C:32]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:11][C:12]=1[F:17])=[O:31])[C:44]([O:46][CH3:47])=[O:45])=[O:38])([CH3:41])[CH3:42]
Reactant: Fc1cc(OCc2ccccc2F)ccc1Br
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2F)cc1F)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.4 %

Procedure:
To a solution of 4-bromo-3-fluorophenyl (2-fluorophenyl)methyl ether (D41, 500 mg, 1.67 mmol) and TMEDA (178 mg, 1.53 mmol) in dry THF (7 ml) at −78° C. under nitrogen atmosphere was added n-butyllithium 1.6M solution in hexanes (1 ml, 1.6 mmol) dropwise. The resulting suspension was stirred at −78° C. for 15 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D5, 338 mg, 1.39 mmol) in dry THF (2 ml). The mixture was stirred at −78° C. for 1 h, then it was quenched with a saturated ammonium chloride aqueous solution. The phases were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (9:1 to 85:15) affording the title compound as a white solid (254 mg, 39%); 1H NMR (300 MHz, CDCl3-d) δ (ppm): 8.00-7.80 (m, 1H); 7.53-7.42 (m, 1H); 7.42-7.25 (m, 1H); 7.23-7.05 (m, 2H); 6.90-6.80 (m, 1H); 6.75-6.65 (m, 1H); 5.18 (s, 2H); 4.50-4.30 (m, 1H); 3.71 (s, 3H); 3.18-2.85 (m, 2H); 2.40-2.20 (m, 1H); 2.15-1.90 (m, 1H); 1.40 (s, 9H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Li]CCCC.CCCCCC.CN([CH:29]=[O:30])C1C=CC=CC=1>CCOCC>[S:9]1[C:8]([CH:29]=[O:30])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cc2ccccc2s1
Temperature: -15 °C
Reaction time: 1.75 h
Yield: 73.1 %

Procedure:
To a solution of thianaphthene (1.45 g, 10.5 mmol (97% pure)) in anhydrous Et2O (20 mL) at -15° C. was added dropwise a 1.6M solution of n-BuLi in hexane (9.9 mL, 15.7 mmol). The mixture was stirred at -15° C. (1.75 h) and at 25° C. (15 min). After recooling to -15° C., anhydrous N-methylformanilide (1.6 mL, 12.7 mmol) (distilled from CaH2) was added dropwise and the mixture was heated at reflux (30 min). The reaction mixture was quenched by addition of a mixture of 3N HCl (9 mL) and ice chips (20 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (3×75 mL). The combined organic layers were washed with 1N HCl (3×40 mL), saturated aq. NaHCO3 (40 mL), dried (MgSO4), and evaporated to dryness. The residue was dissolved in EtOH (3 mL) and mixed with saturated aq. NaHSO3 (15 mL). The resulting mixture was allowed to stand for 30 min and the crystalline bisulfite addition product was collected by filtration, washing with Et2O (50 mL) and dried in a vacuum desicator. The yellow solid was dissolved in warm H2O (30 mL) and cooled to 0° C. Saturated aq. Na2CO3 was added and the mixture was stirred at 25° C. for 15 min. Filtration, washing with H2O and drying afforded benzo[b]thiophene-2-carboxaldehyde as an amorphous solid (1.25 g, 7.68 mmol) in 73% yield.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([CH:11]3[CH2:13][CH2:12]3)=[N:6][C:5]=2[N:14]=1.N([O-])=O.[Na+].[ClH:19]>[OH-].[Na+]>[Cl:19][C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([CH:11]3[CH2:13][CH2:12]3)=[N:6][C:5]=2[N:14]=1
Reactant: Nc1nc2nc(C3CC3)nc(O)c2s1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(C2CC2)nc2nc(Cl)sc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The compound (1.2 g) obtained in Step 3 was suspended in 2N aqueous sodium hydroxide solution (18 ml) and, under ice-cooling, sodium nitrite (1.2 g) was added in several portions. The obtained suspension was slowly added dropwise to a concentrated aqueous hydrochloric acid solution (18 ml) heated to 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.60 g). The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure to give a crude product (0.34 g) containing the title compound as a main component. The obtained crude crystals were suspended in a mixed solvent of hexane and ethyl acetate, collected by filtration and dried to give the title compound (0.26 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:15]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cc(F)c(F)cc1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(F)c(F)cc2[nH]1
Yield: 53 %

Procedure:
4,5-Difluoro-1,2-phenylenediamine (2.87 g, 19.91 mmol), isopropyl isothiocyanate (2.19 g, 21.65 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (11.38 g, 26.87 mmol) and pyridine (75 mL) were used according to general method I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid; m.p. 188-189° C.