Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CCCCCCCCCC.C(OO)(C)(C)C.NC1C=CC=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C.O>[C:2]([CH:3]1[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]1[C:12]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:18])(=[O:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CCC(=O)c1ccccc1
Agent: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1C(=O)c1ccccc1
Yield: 76 %

Procedure:
A reactor was charged with 325 mg (1.0 mmol) of tert-butyl 2-(3-oxo-3-phenylpropyl)phenylcarbamate (an11) obtained in Synthesis Example 5, 36.9 mg (0.10 mmol) of tetrabutylammonium iodide (Bu4N+I−), and 50 mL of ethyl acetate as a solvent to prepare a solution. Subsequently, 364 μL of 5.5 M decane solution (manufactured by Aldrich) containing 2.0 mmol of tert-butyl hydroperoxide (TBHP) as an oxidizing agent was added to the solution in an amount corresponding to 2 equivalents based on the aniline derivative (an1). After adjusting the temperature of the reaction system to 50° C., the mixture was reacted for 10 hours with stirring. After cooling the reaction mixture including the reaction product to room temperature, the reaction mixture was added to 20 mL of water, and extracted twice with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium sulfite (Na2SO3) aqueous solution, an NaCl aqueous solution, and water, followed by the addition of anhydrous sodium sulfate (Na2SO4). The solvent was then evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=6/1) to obtain 246 mg (0.76 mmol) of tert-butyl 2-benzoylindoline-1-carboxylate represented by the formula (as1) (white solid). The yield was 76% (see Table 1-1). The analysis data for the resulting compound (as1) is shown below.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a white solid; mp 71-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.80 (t, 3H), 1.10-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.50-2.90 (m, 5H), 2.92 (s, 3H), 3.70-3.90 (m, 2H), 4.45-4.55 (m, 1H), 6.82 (d, 1H), 7.02 (d, 3H), 7.02 (d, 3H), 7.19 (d, 1H), 7.54 (d, 2H); MS (ES) m/z: 541.0 (MH+); HRMS Calcd. for C24H37N4O6S2 (MH+): 541.2155. Found: 541.2136.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]([CH2:12][CH3:13])[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[CH2:15](O)[CH3:16].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:15]([O:10][C:9](=[O:11])[CH2:8][N:7]([C:5]([O:4][C:2]([CH3:14])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH3:13])[CH3:16]
Reactant: CCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 3° C. solution of 86 g (423 mmole) of N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine, 21.4 g (465 mmole) of ethanol and 5.17 g (42.3 mmole) of 4-dimethylaminopyridine in 600 mL of dichloromethane is added 47 g (46.2 mmole) of triethylamine, followed by portionwise addition of 89.1 g (46.5 mmole) of 3-N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The stirred mixture is allowed to warm to ambient temperature and stir overnight. The reaction mixture is washed with water, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give N-[(1,1-dimethylethoxy)carbonyl]-N-ethylglycine ethyl ester (88 g) as an oil. MS (FAB) 232 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:35][CH2:36][CH2:37][Cl:38])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C2(C)CC2)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C2(C)CC2)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
7 g of 2-tert-butyl-4-piperazin-1-yl-6-(1-methylcyclopropyl)-pyrimidine (25.5 mmol; prepared by analogy to steps a.2.1 to a.2.4 starting from 1-methylcyclopropyl carbonic acid chloride) were dissolved in 50 ml of dimethyl formamide. 2.58 of triethylamine (25.5 mmol), and 3.53 g of potassium carbonate were added, followed by dropwise addition of 4.62 g of 1-bromo-3-chloropropane. After stirring for 1.5 h at 50° C. the reaction mixture was stirred overnight at room temperature. The precipitate was filtered off and washed with dimethylformamide. The filtrate was partitioned between 150 ml of ethyl acetate and 50 ml of water. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (ethyl acetate) to yield 4.6 g of the title compound.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:32][CH:31]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Br-]
Product: O=C(O)CCCCC=Cc1ccc(F)cc1
Yield: 85.4 %

Procedure:
5-Carboxypentyl-triphenylphosphonium bromide (20 g) and 4-fluorobenzaldehyde (6.5 g) were subjected to substantially the same reaction as in Reference Example 1. The reaction product was isolated by means of a silica gel chromatography to afford 7-(4-fluorophenyl)-6-heptenoic acid (8.3 g) as white crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].ClCCl.[CH:8]1([CH2:14][CH:15]2[CH2:26][C:25]3[C:17](=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=3)[C:16]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:28]Br>>[CH:8]1([CH2:14][CH:15]2[CH2:26][C:25]3[C:17](=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][C:23]=4[C:24]=3[Br:28])[C:16]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1c2cc3c(cc2CC1CC1CCCCC1)CCC3
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2cc3c(c(Br)c2CC1CC1CCCCC1)CCC3
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 40.9 g (0.305 mol) of AlCl3 in 180 ml of dichloromethane 32.7 g (0.122 mol) of 2-(cyclohexylmethyl)-3,5,6,7-tetrahydro-s-indacen-1(2H)-one was added. To this mixture cooled to 0° C. 21.5 g (0.134 mol) of bromine was added dropwise by vigorous stirring for 45 min at 0-5° C. The resulting mixture was stirred for 12 h at ambient temperature and then poured on 1000 cm3 of ice. The organic layer was separated, and the aqueous layer was extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. This product was further used without an additional purification. Yield 39.5 g (93%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:5][N:4]=[C:3]1[CH3:16]>CO.[Pd]>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])=[CH:5][N:4]=[C:3]1[CH3:16]
Reactant: Cc1ncc(-c2cccc([N+](=O)[O-])c2)n1C
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(-c2cccc(N)c2)n1C
Yield: 88.5 %

Procedure:
A suspension of 3-(1,2-dimethyl-1H-imidazol-5-yl)nitrobenzene (19.2 g) in methanol (200 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 5 g) under hydrogen atmosphere for 10 hours. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure. The residue was triturated with ethyl acetate and diisopropyl ether to give 3-(1,2-dimethyl-imidazol-5-yl)aniline (14.65 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[Cl:15]N1C(=O)CCC1=O>C1COCC1>[Cl:15][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1csc(C(=O)O)c1
Reaction time: 1 h

Procedure:
A solution of 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (600 mg, 2.88 mmol) and N-chlorosuccinimide (384 mg, 2.88 mmol) in THF (14 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM, the aqueous phase was adjusted to pH 3 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (698 mg, quant.): LCMS (ES) m/z=243 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:21]([CH2:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:29][CH2:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCCc1ccccc1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NCCc1ccccc1
Yield: 87.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and benzylmethylamine (65 μL, 0.5 mmol) to give 170 mg of the title compound (87%): mp 120°~125° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 and 12.04 (two s, 1H), 7.10~7.41 (m, 7H), 5.09~5.21 (m, 1H), total 2H of 4.63 (s), 4.58 (d, J=16.2 Hz), and 4.47 (d, J=16.2 Hz), 2.95~3.12 (m, 1H), J=2.92 and 2.82 (two s, 3H), 2.78 (dm, 1H, J=17.1 Hz), 2.61~2.73 (m, 2H), 2.22 (dm, 1H, J=13.5 Hz), 1.79~1.94 (m, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[C:29]([N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(=O)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 43 h
Yield: 72.7 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (5.87 g, 20 mmol) and 4-dimethylaminopyridine (60 mg) in dichloromethane (25 ml) and triethylamine (3.1 ml, 22 mmol) is added pivaloyl chloride (2.46 g, 21 mmol). The mixture is stirred 43 h at room temperature, diluted with hexane (200 ml), washed with water (4×20 ml), dried over MgSO4 and evaporated. The residue is chromatographed on silica gel (hexanes-ethyl acetate 4:1) to afford 5.49 g of the title compound as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:39](=[O:40])[N:12]2[C:13]([C:36]([OH:38])=[O:37])=[C:14]([CH2:17]OC(=O)C3C=CC=CC=3S(=O)(=O)NC(OCC)=O)[CH2:15][S:16][C@H:11]12)=[O:8].[N-:41]=[N+:42]=[N-:43].[Na+].C(=O)(O)[O-].[Na+].P(=O)(O)(O)O>P([O-])([O-])([O-])=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:39](=[O:40])[N:12]2[C:13]([C:36]([OH:38])=[O:37])=[C:14]([CH2:17][N:41]=[N+:42]=[N-:43])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
7β-(Thienylacetamido)-3-[2-(N-carboethoxysulfamoyl)-benzoyloxy]methyl-3-cephem-4-carboxylic acid-etherate (619 mg), sodium azide (100 mg) and sodium bicarbonate (84 mg) are dissolved in phosphate buffer solution (pH 6.4) (10 ml) and the mixture is stirred at 60° C. for one hour. After cooling, the reaction mixture is acidified by phosphoric acid and extracted with ethyl acetate. The ethyl acetate layer is dried and concentrated under reduced pressure. The residue is triturated with ether. The procedure provides 7β-(thienylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ccncc2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from 3-pyridin-4-yl-benzoic acid methyl ester [CAS-No. 126179-78-0] (3.60 g, 16.88 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (3.88 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([NH:16][CH:17]([CH3:19])[CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:9]([N:16]([CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)NCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)N(Cc1ccccc1)c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 2,6-dichloropyrazine (7.45 g), N-benzylpropan-2-amine (12.5 mL), potassium carbonate (10.4 g) and DMA (50 mL) was stirred at 80° C. for 15 hr. Water (100 mL) was added, and the mixture was extracted with ethyl acetate.
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl.CN.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH:14]1[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: O=C1CCC(c2ccncc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC1CCC(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Acetic acid (0.2 ml) was added catalytically to an ice-cooled (0° C.) solution of 4-(pyridin-4-yl)cyclohexanone (500 mg, 2.857 mmol, 1 eq) and methylamine hydrochloride (957 mg, 14.28 mmol, 5 eq) in MeOH (10 ml), and stirring was carried out for 1 h at RT. NaCNBH3 (358 mg, 5.714 mmol, 2 eq) was added at 0° C. and stirring was carried out for a further 14 h at RT. The reaction mixture was concentrated, diluted with dichloromethane (100 ml) and washed with sat. sodium hydrogen carbonate solution (60 ml) and sat. NaCl solution (60 ml). The organic phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Alox neutral, 6% MeOH in dichloromethane). The desired amine was obtained in the form of a light-yellow solid. Yield: 27% (150 mg, 1.26 mmol).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1[N:49]=[N:48][C:43]2[CH:44]=[CH:45][CH:46]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1(N)CCCC1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][N:48]5[CH2:43][CH2:44][CH2:45][CH2:46]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCC1
Product: COc1cc(C(=O)NN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and pyrrolidin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.75 (m, 6H) 1.90-2.02 (m, 2H) 2.67-3.03 (m, 4H) 3.57 (s, 3H) 3.95 (s, 3H) 4.05 (t, 2H) 4.73-4.81 (m, 1H) 7.48-7.54 (m, 2H) 8.00 (s, 1H) 8.20 (d, 1H) 8.27 (s, 1H) 8.30 (d, 1H). [M+H] calc'd for C25H31F2N7O3, 516. found 516.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:15](=[O:17])[C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)C#Cc1ccc(CN2CCCC2)cc1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C#Cc1ccc(CN2CCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 0.3 g (1.30 mmol) of (4-pyrrolidin-1-ylmethylphenyl)propynoic acid, 0.27 g (1.32 mmol) of 4′-chlorobiphenyl-4-ylamine, 0.42 g (1.32 mmol) of TBTU, and 0.18 mL (1.32 mmol) of triethylamine in 30 mL of DMF is stirred for 14 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (10:1)). Yield: 0.095 g (17.5% of theory); melting point: from 180° C.; C26H23ClN2O (M=414.93); calc.: molecular ion peak (M+H)+: 415/417; found: molecular ion peak (M+H)+: 415/417; Rf value: 0.3 (silica gel, dichloromethane/ethanol (5:1)).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Cl.[Cl:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.CN1C(=O)CCC1>[ClH:11].[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[N:4]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Nc1cc(F)ccc1F
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: Fc1ccc(F)c(N2CCNCC2)c1
Temperature: 130 °C

Procedure:
0.03 Mol of 2,5-difluoroaniline and 0.03 mol of bis-(2-chloroethyl)amine hydrochloride are suspended in 50 mL of xylene and 15 mL of NMP. The mixture is heated at 130° C. for 25 h while stirring, then cooled to RT and the solvents are evaporated. The residue is dissolved in water and 1 equivalent of 2N aqueous sodium hydroxide (NaOH) is added. The mixture is extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous MgSO4, filtered and evaporated to dryness in vacuo. The residue is dissolved in acetone and 1 equivalent of HCL in diethyl ether (Et2O) is added. The precipitated product is collected by filtration and recrystallized from isopropanol to afford 1-(2,5-difluorophenyl)piperazine hydrochloride: m.p. 195° C. LC/MS (M+1=199.1). 1H NMR (DMSO-d6, 400 MHz) δ 3.22 (m, 4H), 3.28 (m, 4H), 6.83 (m, 1H), 6.97 (m, 1H), 7.22 (m, 1H), 9.46 (br s, NH).
Reaction SMILES: Cl[C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClC1C2SC(S)=NC=2C=CC=1.[Cl:21][C:22]1[S:23]C2C=CC(Cl)=CC=2N=1>>[Cl:21][C:22]1[S:23][C:2]2[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1cccc(Cl)c1Cl
Agent: Sc1nc2cccc(Cl)c2s1
Product: Clc1nc2cccc(Cl)c2s1

Procedure:
The title compound was prepared from 2,3-dichloroaniline via 7-chloro-2-mercaptobenzothiazole as described for 2,5-dichloro-1,3-benzothiazole.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.CN(C)CCN(C)C.C([Li])CCC.[Li].C([Cu])#CCCCC.[C:39]1(=[O:45])[CH2:44][CH2:43][CH2:42][CH:41]=[CH:40]1.[Cl-].[NH4+].[OH-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)C>[CH3:17][Si:2]([CH3:1])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:41]2[CH2:42][CH2:43][CH2:44][C:39](=[O:45])[CH2:40]2)=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: O=C1C=CCCC1
Reactant: CCCCCC[Si](C)(C)c1cccc(OC)c1
Agent: CCCCC#C[Cu]
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCC[Si](C)(C)c1ccc(C2CCCC(=O)C2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
To a 25° C. solution of 2.00 g. (8.0 mmole) of 3-(dimethyl-n-hexylsilyl)-1-methoxybenzene and 1.32 ml. (8.8 mmole) of N,N,N',N'-tetramethylethylenediamine in 8 ml. diethyl ether was added 3.2 ml. of 2.5 M n-butyllithium in hexane. The reaction solution was heated at reflux for 1 hr and then cooled to -78° C. To the -78° C. solution was added 9.68 mmole of 1-hexynyl copper lithium in 20 ml. tetrahydrofuran. The resultant yellow mixture was stirred 5 minute at -78° C. and then 768 mg. (8.0 mmole) of cyclohex-2-en-1-one was slowly added. The reaction mixture was stirred for 5 minute longer at -78° C. and then warmed to -20° C. and stirred for 5 minute. The reaction mixture was added to 500 ml. saturated aqueous ammonium chloride adjusted to pH 9 with saturated aqueous ammonium hydroxide. The quenched reaction was extracted five times with 500 ml. diethyl ether. The diethyl ether extracts were dried over magnesium sulfate and evaporated to an oil. The crude oil was purified by column chromatography on 200 g. of silica gel eluted with 10% diethyl ether-hexane to yield 1.0 g. (36%) of the title compound as an oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.CO>C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:13])[CH2:14][NH:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NCc1ccccc1
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(CNCc1ccccc1)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, benzylamine and ethanol essentially as described above in Example 94 except that the reaction mixture is heated for 15.5 hours and the column chromatography is performed with a graded solvent mixture from 5% methanol in ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=390.