Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.O.[NH2:18][NH2:19]>C(O)C>[N:18]1[NH:19][C:14](=[O:16])[CH2:13][CH:3]2[CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=12
Reactant: NN
Reactant: O=C(O)CC1CCCc2ccccc2C1=O
Solvent: O
Solvent: CCO
Product: O=C1CC2CCCc3ccccc3C2=NN1

Procedure:
A mixture of the compound of formula (Dc), 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid, (5.7 g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20 mL of ethanol was refluxed for 2 h, cooled and filtered (washed with small amount of EtOH) to give the compound of formula (Dd), 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one, as a white solid (4.7 g, 84%); 1H NMR (300 MHz, CDCl3) δ: 8.61 (bs, 1H), 7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58 (dd, J=15.3, 16.8 Hz, 1H), 2.31 (dd, J=12.0, 16.8 Hz, 1H), 1.96-1.59 (m, 4H); LC-MS: purity: 100%; MS (m/e): 215 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:11].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1Cl)NCC2
Temperature: 15 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
6-Chloro-5-methylindole (D9) (0.109 g, 0.66 mmol) was stirred at 15° C. in glacial acetic acid (3 ml), and sodium cyanoborohydride (0.125 g, 1.98 mmol) was added. The mixture was stirred at 15° C. for 2 h, diluted with water (40 ml), basified with solid NaOH, and extracted with ether. The extract was dried (Na2SO4) and evaporated to give the title compound (0.105 g, 95%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][C:21](=[O:25])[C:20]2=[O:26])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]([O:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH:30]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:35]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)[CH2:36][C:37]([O:39][CH:40]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:38])[C:21](=[O:25])[C:20]2=[O:26])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCNC(=O)C2=O)cc1
Reactant: O=C(C=Cc1cccnc1)OC(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
In 7.5 ml of N,N-dimethylformamide was dissolved 2.5 g of 4-[3-(4-tert-butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazine, and to the solution were added 6.1 g of diphenylmethyl 3-(3-pyridyl)acrylate and 0.48 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting mixture was stirred overnight at room temperature and distilled under reduced pressure to remove the solvent. To the resulting residue were added 80 ml of ethyl acetate and 60 ml of water and the pH was adjusted to 7 with 2N hydrochloric acid. The organic layer was separated, washed with water and then a saturated aqueous sodium chloride solution, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent; chloroform:methanol 20:1) to obtain 2.34 g of diphenylmethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as a colorless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:4][CH2:3]1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][NH:10][CH2:23][CH2:24][CH2:25][O:26][CH3:27])[CH2:6][CH2:7]1
Reactant: COCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCCNCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(3-methoxypropyl)-2-nitrobenzenesulfonamide (0.510 g, 1.17 mmol) and thiophenol (0.387 g, 3.51 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.647 g, 4.68 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave a yellow oil (0.255 g, 87% yield). No further purification was performed and the mixture was carried forward to the next step. LCMS: m/z 251 (M+H+), 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.77 (quin, J=6.53 Hz, 2H) 2.13 (br. s., 2H) 2.62-2.68 (m, 2H) 2.68-2.75 (m, 4H) 2.93-3.11 (m, 8H) 3.32 (s, 3H) 3.44 (t, J=6.15 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:33]=[N:34][CH:35]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 198.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellow wax. UPLC-MS (Condition 3) tR=1.06 min, m/z=481.3 [M+H]+, m/z=479.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.89 (d, J=11.25 Hz, 1H) 3.19-3.29 (m, 2H) 3.35-3.46 (m, 1H) 4.21 (br. s, 1H) 4.86 (d, J=3.67 Hz, 1H) 7.55 (m, J=8.56 Hz, 1H) 7.61 (m, J=1.47 Hz, 1H) 7.83 (m, J=1.96 Hz, 1H) 7.98 (dd, J=13.20, 2.20 Hz, 1H) 8.07 (d, J=2.20 Hz, 1H) 8.51 (br. s, 1H) 8.60 (d, J=2.69 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 10.30 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Cl.[CH:18](OC(C)C)(C)C>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([O:9][CH3:18])=[O:8]
Reactant: CC(C)OC(C)C
Reactant: O=C(O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: COC(=O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
2.25 g of 3,4-dihydroxy-5-nitrocinnamic acid are dissolved in 50 ml of methanol and hydrochloric acid gas is introduced into this solution for 10 minutes. After 1 hour 50 ml of isopropyl ether are added thereto, and the separated precipitate is filtered under suction and washed with isopropyl ether. After recrystallization from methanol/ether there is obtained methyl 3,4-dihydroxy-5-nitrocinnamate in the form of yellow crystals of m.p. 186°-187°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:15])[CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:15])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CC(C)c1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CC(=O)O)c1ccccc1Br
Yield: 105.5 %

Procedure:
To a solution of 28.04 g of ethyl 3-(2-bromophenyl)-3-methylpropionate (109.1 mmole) in ethanol (200 ml) and water (100 ml) was added 12.2 g of potassium hydroxide (218.2 mmole), and the mixture was heated under reflux for 5 hours. After the mixture was left standing at room temperature, it was concentrated to a half of the volume by distillation and diluted again with dilute hydrochloric acid. Dichloromethane was then added, and an aqueous ammonium chloride solution was added before extraction. The organic layer was dried over magnesium sulfate, and the solvent was removed by distillation to give 27.97 g of 3-(2-bromophenyl)-3-methylpropionic acid (quantitatively).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:16]2[C@@H:12]([O:13][C:14](C)([CH3:17])[O:15]2)[O:11][C@@:10]1([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:32][C:33]([O:35]C(C)=O)=[O:34]>CC(O)=O.OS(O)(=O)=O>[C:14]([O:13][CH:12]1[C@H:16]([O:35][C:33](=[O:34])[CH3:32])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:10]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH:19]([F:20])[F:21])[O:11]1)(=[O:15])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)O[C@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound (3aR,5R,6S,6aR)-6-(benzyloxy)-5-(benzyloxymethyl)-5-(difluoromethyl)-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole (1.0 g, 6.3 mmol) in Ac2O (2.5 mL) and AcOH (10 mL) was added H2SO4 (3 drops). The mixture was stirred at room temperature for 3 hrs. TLC showed the reaction was complete. The mixture was poured to water, extracted with EtOAc, dried (Na2SO4) and purified by silica gel chromatography [ethyl acetate:petroleum ether (1:3)] to afford compound 5 (1.0 g, crude) as a light-color oil. LC-MS (M+H)+=465.1
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)=[O:4].[CH:24]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][C:25]=1[O:37][CH2:38][CH2:39][NH2:40]>CO.C(Cl)(Cl)Cl>[CH:24]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][C:25]=1[O:37][CH2:38][CH2:39][NH:40][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cc(OCc2ccccc2)cc(C(=O)CBr)c1
Reactant: NCCOc1ccc2c(c1)[nH]c1ccccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cc(OCc2ccccc2)cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)c1

Procedure:
170 mg of Intermediate 62 and 95 mg of Intermediate 2. Rf=0.28 (methanol/chloroform of 1/9).
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].O[Li].O.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CO.O>[CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH2:10][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCCCCCCCCO
Reactant: C=CCOC(C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C=CCCCCCCCCOC(=O)C(C)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
3,5 g of crude ethyl (RS)-2-allyloxy-propionate are introduced into 24 ml of MeOH/H2O=3:1, cooled to 0° C., and then 2.2 g (30 mmol) of LiOH·H2O are added in portions. The mixture is further stirred for 5 minutes before the ice cooling is removed and the mixture is stirred for a further 1 h at room temperature. Methanol is then removed on a rotary evaporator and the residue is taken up in water. The aqueous phase is firstly extracted with Et2O in order then to be acidified to pH 1 with 6N HCl. The aqueous phase is then saturated with NaCl and extracted three times with EtOAc. The combined organic phases are dried over Na2SO4, filtered and freed from solvent on a rotary evaporator. The resulting carboxylic acid is dissolved in 40 ml of toluene and treated with 4.7 g (30 mmol) of 9-decen-1-ol and 0.38 g (2 mmol) of p-toluenesulfonic acid. The mixture is then heated using a water separator until visible amounts of water no longer separate out. After cooling to room temperature, the reaction solution is once again wash ed with saturated NaHCO3 solution, then dried over Na2SO4, filtered and freed from solvent on a rotary evaporator. Flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.31) over silica gel gives 2.8 g (52.2%) of dec-9-enyl (RS)-2-allyloxy-propionate as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH3:13])=[O:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]=2[C:10]([O:12][CH3:13])=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Br)sc2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)sc2c1CCC2
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a suspension of methyl 2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate, phenyl boronic acid, and Pd(PPh3)4 in dioxane was added a 2 M aqueous Na2CO3 solution, followed by stirring at 90° C. for 15 hours. Water was added thereto, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate as a colorless liquid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:18][CH2:19][P:20]([O:24][CH3:25])([O:22][CH3:23])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][CH2:19][P:20]([O:24][CH3:25])([O:22][CH3:23])=[O:21])[C:3]([OH:26])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(OC)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-3-(Biphenyl-4-yl)-2-[(dimethylphosphonomethyl)-amino]-propionic acid methyl ester (5 g, 13.2 mmol) is dissolved in methanol (60 mL) and cooled to 0°. 1N Sodium hydroxide (19.8 mL, 19.8 mmol) is added dropwise. The solution is stirred at room temperature for 4 hours, then neutralized with 1N hydrochloric acid (20.2 mL, 20.2 mmol). The solvent is removed in vacuo at 10° from the gelatinous solution. The residue is extracted with methylene chloride (3×20 mL). The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude solid is triturated with acetonitrile, filtered and washed with ether. (S)-3-(Biphenyl-4-yl)-2-[(dimethylphosphonomethyl)-amino]-propionic acid is obtained as a white solid that is dried under vacuum at 60° for 16 hours, [α]D =+77.34 (c 0.83, MeOH).
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:20]1[C:21]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=2[N:23]=[N:24][N:25]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH2:32])=[O:31])[C:22]=3[N:23]=[N:24][N:25]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(C(F)(F)F)c3)nnnc12

Procedure:
Compound 14 was prepared following general synthetic scheme 7 wherein (S)-2-(Azetidin-1-yl)-1-(4-chloro-3-(trifluoromethyl)phenyl)ethan-1-amine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [451 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.87 (d, 1H), 8.63 (d, 1H), 8.54 (d, 1H), 8.05-8.01 (m, 3H), 7.81 (d, 1H), 7.70 (d, 1H), 5.59 (d, 1H), 3.21-3.14 (m, 4H), 3.02 (t, 1H), 2.99-2.78 (m, 1H), 1.92 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[C:18]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH:17]=3)[N:11]=2)[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CN1CCN(Cc2ccc(N)c(C(N)=O)c2)CC1
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(CN4CCN(C)CC4)cc3c(=O)[nH]2)cc(C)n1
Temperature: 115 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-dimethylpyridine-4-carbaldehyde (0.14 g, 1.00 mmol) in N,N-dimethyl acetamide (8 mL) were added 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzamide (0.25 g, 1.00 mmol), sodium hydrogensulfite (0.18 g, 1.20 mmol), and p-toluenesulfonic acid (0.057 g, 0.30 mmol). The reaction mixture was stirred at 115° C. for 20 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with sat. NaHCO3, water, then brine, and dried over anhydrous sodium sulfate. Solvent was evaporated and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-3% 7 M ammonia in methanol and dichloromethane as eluent) to give the title compound. Yield: 0.035 g (9.6%). MP 229-230° C. 1H NMR (400 MHz, CDCl3): δ 8.30 (br s, 1H), 7.88 (s, 2H), 7.84 (m, 2H), 3.66 (s, 2H), 2.72 (s, 6H), 2.50 (br s, 8H), 2.30 (s, 3H). MS (ES) m/z: 364.17 (M+1), 182.67 (100%).
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.CI>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18](/[CH:21]=[CH:22]/[CH2:23][O:24][CH3:4])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: OC/C=C/[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC/C=C/[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of sodium hydride and 50 ml of tetrahydrofuran was treated with 2.6 g of 1-bromo-4-[trans-4-[(E)-3-hydroxypropenyl]cyclohexyl]benzene while gassing with nitrogen, stirred for 2 hours, treated with 1.6 g of methyl iodide and subsequently stirred at room temperature overnight. The reaction mixture was treated with 500 ml of water and extracted four times with 50 ml of hexane each time, the combined organic phases were washed twice with 500 ml of water each time, dried over magnesium sulphate, the suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel with hexane and the product obtained was recrystallized from hexane at -78° C. to give 2.4 g of 1-bromo-4-[trans-4-[(E)-3-methoxypropenyl]cyclohexyl]benzene, m.p. (C-I) 47° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Cn2cnc(-c3cccnc3)c2)cc1
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
To a solution of 34 (35 mg, 0.25 mmol) in THF (5 mL) under argon was added sodium hydride (12 mg, 0.29 mmol) in one portion and the resultant slurry was stirred for 20 min. Benzyl bromide (26 μL, 0.32 mmol) was added and the resultant solution was stirred for 10 min. The reaction was quenched by the slow addition of HCl(aq) (1 N, 2 mL), diluted with 13 mL of water and washed with ethyl acetate (3×15 ml). Dichloromethane was added (25 mL) and the aqueous fraction was adjusted to pH 9 with NaOH(aq) (10 N). The organic fraction was collected and the aqueous was extracted with dichloromethane (20 mL), the combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 2.5/97.5, Rf=0.26) to afford the title compound 60 (43 mg, 74% yield) as a white semisolid: 1H NMR (CDCl3) δ 8.95 (br s, 1H), 8.47 (br s, 1H), 8.10 (m, 1H) 7.64 (m, 1H) 7.42-7.17 (m, 7H) 5.17 (s, 2H); LRMS (ESI) m/z calcd for C15H14N3 [M+H]+ 236. found 236; HRMS (ESI) m/z calcd for C15H14N3 [M+H]+ 236.1188. found 236.1198; HPLC>99% (tR=10 min, 60 (A):40 (B): 0.02 (C); tR=6.12 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:8]1[CH2:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1
Reactant: O=C(O)C1=CCNCC1
Reactant: Clc1ncccn1
Solvent: O
Product: O=C(O)C1=CCN(c2ncccn2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
2-Chloropyrimidine (0.570 g, 4.98 mmol) and 1,2,3,6-tetrahydro-4-pyridinecarboxylic acid (1.22 g) were combined in water (7 mL) and heated at 90° C. After 4 hours, the mixture was treated with additional 1,2,3,6-tetrahydro-4-pyridinecarboxylic acid (0.52 g) and stirred overnight. The mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was acidified with concentrated HCl (pH˜3) and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:1][CH2:2][C:3]([C:9]1[CH:10]=[CH:11][C:6]([CH3:12])=[CH:7][CH:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1
Product: Cc1ccc(C(=O)CCl)cc1

Procedure:
reacting toluene with chloroacetyl chloride in the presence of a Friedel-Crafts catalyst in a suitable solvent to produce 4-(2-chloroacetyl)toluene,