Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C@H:13]([C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C:7]2([S:11][CH2:10][CH2:9][S:8]2)[CH2:6]1)=[O:4].[CH3:30][NH:31][CH2:32][C:33](=[O:51])[CH:34]([NH:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:43]([NH:42][CH:34]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:33](=[O:51])[CH2:32][N:31]([CH2:2][C:3]([N:5]1[C@H:13]([C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C:7]2([S:11][CH2:10][CH2:9][S:8]2)[CH2:6]1)=[O:4])[CH3:30])(=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CNCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@@H]1CC2(CN1C(=O)CBr)SCCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the ester product from part (b) (2.4 g., 4.87 mmole), (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide (0.81 g., 2.43 mmole), prepared as set forth in Example 91(b), and diisopropylethylamine (0.85 ml., 4.87 mmole) in dimethylformamide (20 ml.) is stirred at room temperature overnight. The reaction mixture is poured into water (50 ml.), and extracted with ethyl acetate (3×100 ml.). The combined organic extracts are washed with saturated sodium bicarbonate, 10% potassium bisulfite, and water, dried (Na2SO4), and concentrated into a dark oily residue (2.8 g.). Flash chromatography (200 g. Merck silica gel, 10% ethyl acetate/methylene chloride, 20% methanol/ethyl acetate) affords 1.1 g. of (S)-7-[[[3-(benzoylamino-2-oxo-4-phenylbutyl]methylamino]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester as a yellow oil.
Reaction SMILES: [Mg].BrCC.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Br[CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:5]([OH:9])[CH2:6][C:7]#[C:8][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCO
Reactant: CCCCCC#CCC#CCBr
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCCCCC#CCC#CCC#CCCO
Reaction time: 1 h
Yield: 72.3 %

Procedure:
In a 1 L three-necked, flame-dried round. bottom flask fitted with a reflux condenser and a rubber septum was placed 3.86 g (159 mmol) of magnesium in 250 mL of anhydrous tetrahydrofuran. Bromoethane (17.3 g; 1586 mmol) in 250 mL anhydrous tetrahydrofuran was added dropwise, under argon, and the reflux rate was controlled with the aid of an ice-water bath. The mixture was heated to reflux and stirred for 1 hour. 3-Butyn-1-ol (5.56 g, 79.3 mmol), dissolved in 150 mL of anhydrous tetrahydrofuran, was slowly added dropwise with stirring (2 hours). Following addition, the reaction was heated to reflux. After stirring for 90 minutes, 0.5 g (2.63 mmol) of cuprous (I) iodide was added. After 75 minutes 9.0 g (39.65 mmol) of 1-bromo-2,5-undecadiyne dissolved in 150 mL of anhydrous tetrahydrofuran was added. The mixture was heated at reflux for 12 h and an additional 0.25 g (1.32 mmol) of cuprous (I) iodide was added. The mixture was heated at reflux for 7 hours, cooled and quenched by addition of 400 mL of ice-water saturated with ammonium chloride. After filtration (Celite), the filtrate was extracted with 3×400 mL of ether. The ether layers were washed with 2×300 mL of saturated ammonium chloride solution, 3×200 mL of water, 250 mL of brine, dried (Na2SO4), and concentrated in vacuo to yield 6.2 g of yellow-brown oil. The residue was partially purified by crystallization (petroleum ether) at -20° C. to produce 5.75 g (75%) of an unstable yellow oil (room temperature) which was utilized immediately in the next reaction. IR (neat, cm-1) 3365, 2956, 2933, 2225; 1H NMR (CDCl3) δ 3.70 (t, J=6.2 Hz, 2H), 3.17-3.13 (m, 4H), 2.45 (dt, J=1.5, 5.9, 12.0 Hz, 2H), 2.15 (dt, J=2.1, 6.9, 13.9 Hz, 2H), 1.68 (br, 1H), 1.55-1.43 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); HRMS calculated for C15H20O (M+) 216.1514, found 216.1519.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])O[C:9]=2[CH3:16])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[N:18]([CH3:17])[C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)o1
Reactant: CN
Solvent: CCO
Product: Cc1cc(=O)c(-c2ccc(Cl)cc2)c(C)n1C

Procedure:
3-(4-Chlorophenyl)-2,6-dimethylpyran-4-one (2.27 g) was heated at 150° with a solution of methylamine in ethanol (35 ml; 33% w/w) in an autoclave for 12 hr. The mixture was concentrated in vacuo, triturated with ether and filtered, to afford the title compound (1.2 g), m.p. 221°-222°, NMR δH (d6 -DMSO) 7.42 (2H, d, J 5 Hz), 7.1 (2H, d, J 5 Hz), 6.1 (1H, s), 3.5 (3H, s), 2.32 (3H, s), 2.15 (3H, s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH2:16])[C:10]([NH2:17])=[N:9]2.N1C=CC=CC=1.[O:24]1CC[CH2:26][CH2:25]1>>[C:1]([NH:16][C:11]1[C:10]([NH:17][C:25](=[O:24])[CH3:26])=[N:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([Cl:5])[CH:7]=2)[N:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Reactant: Nc1nc2ccc(Cl)cc2nc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Cl)cc2nc1NC(C)=O
Reaction time: 6 h

Procedure:
To a solution of 33 parts of acetyl chloride in 44 parts of tetrahydrofuran were added 10 parts of 6-chloro-2,3-diaminoquinoxaline. The temperature rose to 35°. The reaction mixture was cooled to 5° in an ice bath and stirred vigorously during the addition of a solution of 15 parts of pyridine in 22 parts of tetrahydrofuran. The cooling bath was removed and the reaction mixture was stirred for 6 hours. The solvent was evaporated and the residue was partitioned between 340 parts of methylene chloride and 200 parts of water. The methylene chloride layer was separated and washed in succession with 200 parts each of water, 10% aqueous sodium carbonate, water, 3% aqueous hydrochloric acid, and water. The methylene chloride solution was dried (MgSO4) and evaporated. The residue was triturated with ether, filtered off, and washed with ether to yield 1.6 parts of 2,3-bis-(acetamido)-6-chloroquinoxaline as a tan solid, m.p. 178° dec.
Reaction SMILES: [C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])#[N:2].[C:33](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:33])=[O:13])#[N:2]
Reactant: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2C(=O)O)C(C)C)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccccc1CCN(C)CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To 331 mg (0.839 mmol) of 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile in 8.3 mL of benzene was added 226 mg (1.01 mmol) of palladium(II)acetate and the mixture was stirred for 72 h at 22° C. under nitrogen. The solution was transferred into a pressure flask, 10 mL of methanol was added and the mixture was treated with carbon monoxide at 40 psi for 24 h. After addition of 175 μL (1.26 mmol) of triethylamine, the mixture was filtered through a pad of celite and evaporated to give a crude mixture of 3au and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile. In order to afford purification, a solution of 57 mg of the crude product was dissolved in 1 mL of methanol and treated with 63 μL of 10 N NaOH. After stirring for 1 h at 22° C., an additional 1264 of 10 N NaOH and 2 mL of methanol was added. The solution was heated to 50° C. then cooled to 22° C., evaporated and partitioned between ether and 0.5 N NaOH. The aqueous layer was acidified to about pH 6 with 12 N HCl then extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4) and evaporated to give 2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoic acid. The carboxylic acid was esterified by treating with 44 mg (0.24 mmol) of carbonyldiimidazole in 1 mL of THF for 3 h at 22° C. followed by addition of 8 mL of methanol and continued stirring for about 16 hours at 22° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with dichloromethane and then gradually increasing to 3% methanol/dichloromethane to give 3au. MS found M+H=453. Substitution of the ester group in the indicated ortho-position of the phenyl ring was confirmed by 1H NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][NH2:28])[NH:23][CH:22]=1.CN1CCOCC1>CO>[N:21]1[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[NH:23][CH:22]=1
Reactant: NCCc1cnc[nH]1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3cnc[nH]3)cc2s1
Yield: 6.6 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2-(3H-imidazol-4-yl)-ethylamine (68 mg, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 404.3 (M+1, 100%). Yield=6%.
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[C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.C(O)(=O)C>C(O)C.C(Cl)(Cl)Cl.[Fe]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Nc1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Yield: 43.9 %

Procedure:
A mixture of 2-[3-(2-naphthyl)phenylamino]-3-nitropyridine (3.0 g), iron (2.46 g) and acetic acid (5.28 g) in ethanol (14 ml) was stirred under reflux for 6 hours. The reaction mixture was diluted with chloroform, filtered and treated with saturated sodium bicarbonate solution. The chloroform layer was separated, dried, evaporated and chromatographed on silica gel to give 2-[3-(2-naphthyl)phenylamino]-3-aminopyridine (1.2 g, 43.9%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][C:20]1([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:19][C:20]1([C:26]([F:29])([F:27])[F:28])[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1
Reactant: OC1(C(F)(F)F)CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC(O)(C(F)(F)F)CC3)s2)noc1C(F)(F)F
Yield: 49 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxy-4-trifluoromethyl-piperidine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford product as a colorless solid (53 mg, 49%). 1H NMR (DMSO-d6) 1.70-1.72 (m, 4H), 2.34 (d, J=1.8, 3H), 3.24 (br, 2H), 4.19 (br, 2H), 6.17 (s, 1H), 7.56 (d, J=4.0, 1H), 7.65 (d, J=4.0, 1H). 19F NMR −83.5, −63.1. LC/MS 6.40 min, [M+1]+ 429.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:31][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:12][CH:11]=3)[N:15]=[C:16]([NH:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][O:27]3)[C:17]=2[CH2:23]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@@H]4CCCO4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
(5)-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (55 mg, 0.14 mmol) was dissolved in methanol (3 mL). Acetic acid (7.76 μL, 0.14 mmol) was added followed by formaldehyde (10.10 μL, 0.14 mmol) and sodium cyanoborohydride (8.52 mg, 0.14 mmol). The reaction mixture was stirred for 1 h at room temperature and the solvent was evaporated under reduced pressure. The crude was purified by preparative HPLC yielding (S)-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (19.30 mg, 33.9%). MS (ES+) m/z 417.8 (M−H)−
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24](O)=[O:25])[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH3:27][S:28]([Cl:31])(=[O:30])=[O:29].Cl.[C:33]([C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)#[N:34]>>[ClH:31].[NH2:16][C@H:15]([C:24](=[O:25])[N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:33]#[N:34])[CH2:14][CH2:13][CH2:12][NH:11][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: N#C[C@@H]1CCCN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)NCCC[C@H](N)C(=O)N1CCC[C@H]1C#N

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, methanesulphonyl chloride and (S)-2-cyano-pyrrolidine hydrochloride, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[N+:10]([C:13]1[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[Al]>>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH:13]1[CH:18]=[CH:17][C:1]([N:3]([C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(N(c2ccccc2)c2ccc([N+](=O)[O-])cc2)cc1
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 195 °C
Reaction time: 2.25 h
Yield: 90 %

Procedure:
0.83 mol of formanilide, 0.50 mol of p-nitrochlorobenzene, 0.34 mol of potassium carbonate and 0.20 mol of aluminium granules were introduced into a reaction vessel and heated to 195° C. and the mixture was stirred at this temperature for 135 minutes. Volatile constituents were distilled off with steam and the residue was washed with a little sodium hydroxide solution and water. 0.45 mol (90% of theory) of 4-nitrodiphenylamine and 0.02 mol of 4,4'-dinitrotriphenylamine were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][C:10](=[O:19])[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[CH3:22][N:23](/[CH:25]=[C:9]1\[C:10](=[O:19])[N:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:8]\1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1
Solvent: CO
Product: CN(C)/C=C1\C(=O)N(c2ccccc2)N=C1c1ccccc1F
Reaction time: 1 h

Procedure:
5-(2-Fluorophenyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2.5 g, 8.1 mmol) and N,N-dimethylformamide dimethylacetal (1.2 g, 9.7 mmol, 1.2 equiv) were combined in methanol (3 mL) and placed into a preheated oil bath at 60° C. for 1 hour. The mixture was cooled to ambient and concentrated in vacuo, providing the titled compound.
Reaction SMILES: O=[C:2]1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:71]([OH:73])=O)[CH2:67][CH:68](C)C)=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:61][C:59]1[CH:58]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:71]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:73])[CH:67]([CH3:68])[CH3:2])=[O:64])[CH:56]=[C:55]([F:54])[CH:60]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Br
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cis)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-L-leucine (108b) (85 mg) was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (107 mg), white solid, m.p.180-190° C. 1H NMR (300 MHz, d6-DMSO) δ 4.76 (t, 1H, J=7 Hz), 5.12 (d, 1H, J=7 Hz), 6.91-7.49(m, 12H), 7.67 (d, 1H, J=7 Hz), 8.25 (s, 1H),10.49 (s, 1H). MS APCI, m/z=538(M+1). LC/MS: 2.65 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:11]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[NH:31][C:32]2[CH:38]=[C:37]([C:39]([NH:41][NH2:42])=[O:40])[CH:36]=[CH:35][C:33]=2[N:34]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[NH:31][C:32]2[CH:38]=[C:37]([C:39]3[O:40][C:11]([NH:1][C:2]4[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=4)=[N:42][N:41]=3)[CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Temperature: 80 °C

Procedure:
Combine 3-amino-6-methoxy-pyridine (64 uL, 0.606 mmol) and di -imidazol-1-yl-methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir for 3 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1 mL). Heat to 80° C. for 1 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling, dilute the reaction with EtOAc (50 mL) and extract with water (10 mL). Dry the organic phase over Na2SO4 and concentrate. Triturate the concentrate with hot EtOAc/toluene to obtain a white solid. Suspend the solid in saturated NaHCO3 and stir vigorously. Collect the solid and purify by silica gel chromatography (10-100% EtOAc/HEP, 0-50% MeOH/DCM) to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 3.84 (s, 3 H) 6.89 (d, J=8.84 Hz, 1 H) 7.62-7.67 (m, 1 H) 7.70 (s, 1 H) 7.72 (d, J=1.64 Hz, 1 H) 7.76 (tautomer, d, J=8.46 Hz, 1 H) 7.81 (tautomer, dd, J=8.46, 1.26 Hz, 1 H) 7.85-7.92 (mixture of tautomers, m, 1H) 7.96-8.01 (m, 1 H) 8.03 (tautomer, s, 1 H) 8.16 (tautomer, s, 1 H) 8.44 (s, 1 H) 10.63 (s, 1 H) 13.28 (s, 1 H); MS m/z=453.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CNC.CN(C)[P:17](N(C)C)N(C)C>>[N:1]12[P:17]3[N:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH2:11]1)[CH2:3][CH2:2]2
Reactant: C1CNCCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Product: C1CN2CCCN3CCN(C1)P23
Temperature: 125 °C
Yield: 75.2 %

Procedure:
A mixture of 3.62 g of 1,4,8-triazacycloundecane and 3.75 g of hexamethylphosphorous triamide is heated to 125° C with stirring and held at this temperature for 2 hours, by which time evolution of dimethylamine is complete. Evolution is vigorous for the first 45 minutes. Distillation affords 3.20 g (75%) 1,4,8-triaza-12-phosphatricyclo-[6.3.1.04,12 ]dodecane as a water-white liquid which boils at 73°-75° C at 0.30 mm.
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F.[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)(C)C>[N:27]1([C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][C:6]2[CH2:10][CH2:9][CH2:8][N:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[CH3:22][S:23]([O-:26])(=[O:25])=[O:24]
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)O
Agent: F[B-](F)(F)F
Solvent: CC(C)O
Product: C(=C(c1ccccc1)N1CCCCC1)C1=NCCC1
Product: CS(=O)(=O)[O-]

Procedure:
Crude 2-[2-(1-piperidyl)-2-phenyl-ethenyl]-1-pyrroline is produced by refluxing for 12 hours the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 25 ml of piperidine, and processing the reaction mixture analogously to Example 1. By the addition of 2.8 g of methanesulphonic acid to the solution of the crude base in isopropanol, concentration of this solution in the rotary evaporator and recrystallisation of the residue from acetone/hexane, there is obtained 2-[2-(1-piperidyl-2-phenylethenyl]-1-pyrroline-(1:1)-methanesulphonate, m.p. 123°-124°.