Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1[O:8][C:7]2[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:6]=2[C:5]2[CH:21]=[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[O:3]1.[OH2:33].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:33]=[PH:2]1[O:8][C:7]2[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:6]=2[C:5]2[CH:21]=[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Reactant: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c-2cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6.32 g (13 mmol) of the compound of Example 1 in 150 mL of toluene at ambient temperature is added dropwise a solution of 0.24 mL (13 mmol) of distilled water in 3.0 mL (22 mmol) of triethylamine. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 minutes. The reaction solvent is removed in vacue and the reaction mass is then recrystallized twice with 50 mL of acetonitrile. The recrystallization solvent is removed under vacuum and the residue is dried under vacuum to afford the title compound in a yield of 5.2 g (86.3%) as an off-white solid melting at 218° C.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:7]1([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:9]=[CH:10][S:6]1)[CH2:26][CH2:27][CH3:28]
Reactant: c1csc(-c2cccs2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(c2cccs2)CC=CS1
Temperature: -40 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
n-Butyllithium (22.0 mL, 55.0 mmol, 2.5 M solution in hexane) was added dropwise at -78° C. to a solution of 2,2'-bithiophene (9.44 g, 56.78 mmol) in anhydrous THF (600 mL) under nitrogen. The solution was stirred for 1 h and warmed to -40° C. Tributylstannyl chloride (17.90 g, 55.00 mmol) was added and the entire solution was finally allowed to warm to room temperature. At room temperature the mixture was filtered using Celite and the solvent was stripped. The organo-tin compound was vacuum dried to give 2-(tributylstannyl)-2,2'-bithiophene, obtained as a dark yellow liquid, yield=99%. MS(EI) m/z (rel int): 456 [(M)+, 18%] and 399 [(M)+ --C4H9, 76%].
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:13][CH:14]=2)=[O:19])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
Benzenesulfonyl chloride (0.26 mL, 2.03 mmol) was slowly added to an ice-cooled solution of (4-amino-phenyl)-(4-methoxy-phenyl)-methanone (178) (0.42 g, 1.85 mmol) and pyridine (0.16 mL, 2.03 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 20 h then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give a solid. The solid was recrystallized from hot dichloromethane and methanol to give 0.451 g (66%) of the title compound 182. 1H NMR (400 MHz, DMSO-d6): δ 3.82 (s, 3 H), 7.03 (d, J=8.8 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H), 7.57-7.65 (m, 7 H), 7.84 (d, J=7.3 Hz, 2 H), 10.87 (s, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@@H:11](O)[C@H:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3=[O:23])[C:9]=2[CH:24]=1)#[N:4]>O1CCCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3=[O:23])[C:9]=2[CH:24]=1)#[N:4]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCCC2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C=C(N2CCCCC2=O)c2cc(C#N)ccc2O1
Yield: 4.3 %

Procedure:
Sodium hydride (170 mg, 80% dispersion in oil) was added to a solution of trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxo-1-piperidinyl)-2H-1-benzopyran-3-ol (1.65 g) in anhydrous tetrahydrofuran (25 ml) and the reaction mixture stirred and heated under reflux for 48 hours. Work up as in Example 1, followed by chromatography (chromatotron--2 mm Silica gel HF254 --elution with ethyl acetate at 6 ml/min) gave one fraction (312 mg) which on recrystallisation from ethyl acetate gave the title compound as crystals (66 mg) of m.p. 162°-163° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[N:40](COCC[Si](C)(C)C)[C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[NH:40][C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cn4)cc3)cc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cn4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-[4-(5-Cyclohexyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (16 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{4-[2-[4-(5-cyclohexyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1, 1-dioxide.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].[CH3:32]I.O>O1CCCC1>[CH3:32][N:3]1[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Reaction time: 0.33 h

Procedure:
Under an atmosphere of argon, 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 200 mg, 0.50 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 24 mg, 0.60 mmol) in dry tetrahydrofuran. After 20 min, methyl iodide (41 μL, 0.66 mmol) is added. After 20 min water is added and the mixture is concentrated. The residue is purified by flash a) chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 49 mg; ESI mass spectrum [M+H]+=412; Retention time HPLC: 0.59 min (X012_S01).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccco1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Yield: 83 %

Procedure:
8.0 g of (2-furylcarbonyl)methylamine hydrochloride, 10.5 g of sodium bicarbonate and 9.2 g of 4-methylbenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 10.0 g of N-(4-methylbenzoyl)-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 83.3%
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:35][CH2:36][CH:37]=[CH2:38])[CH:33]=[CH2:34]>C(Cl)Cl>[CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C:11](=[O:12])[C@@:7]2([CH3:31])[CH2:6]1)/[C:17](=[CH:18]\[N:35]([CH2:36][CH:37]=[CH2:38])[CH2:32][CH:33]=[CH2:34])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[O:3]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C=CCNCC=C
Solvent: ClCCl
Product: C=CCN(/C=C1/C(=O)O[C@H](COC)[C@@]2(C)C1=C(O)C(=O)C1=C2[C@H](OC(C)=O)C[C@]2(C)C(=O)CC[C@@H]12)CC=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of wortmannin (10.7 mg, 25.0 μmol) in CH2Cl2 (125 μL) was added a freshly prepared 0.2 M stock solution of diallylamine (138 μL, 27.5 μmol) in CH2Cl2. The reaction mixture was stirred at room temperature for 1 h. The solvent and excess amine were removed in vacuo, and the product was purified via chromatography on SiO2 (hexanes/ethyl acetate, 1:9) to give PX-866 (9.0 mg, 17 μmol, 68%) as an orange oil. The product was analyzed by several experimental methods and shown to be of the correct structure and of high purity as: [α]D −630 (c 0.0015, CH2Cl2, 23° C.); IR (KBr) 3391, 1743, 1695, 1685, 1622, 1569, 1222, 1111, 1100 cm−1; 1H NMR δ 8.20 (s, 1H), 6.81 (s, 1H), 6.06 (dd, 1H, J=7.4, 4.8 Hz), 5.85 (br s, 1H), 5.62 (br, 1H), 5.44-5.04 (m, 4H), 4.48 (dd, 1H, J=7.2, 1.9 Hz), 4.05-3.60 (m, 4H), 3.26 (s, 3H), 3.27-3.20 (m, 1H), 3.16 (dd, 1H, J=10.9, 7.2 Hz), 3.00-2.90 (m, 2H), 2.59 (dd, 1H, J=19.4, 8.6 Hz), 2.40 (dd, 1H, J=14.4, 7.7 Hz), 2.35-2.07 (m, 2H), 2.07 (s, 3H), 1.83 (dd, 1H, J=14.4, 4.7 Hz), 1.54 (s, 3H), 0.86 (s, 3H); 13C NMR δ 217.0, 178.5, 169.6, 164.8, 156.3, 151.5, 139.0, 136.9, 132.2, 131.3, 127.7 (2 C), 119.2, 89.0, 81.9, 73.1, 67.6, 59.1, 50.9 (2 C), 48.9, 42.3, 42.2, 37.5, 36.0, 24.6, 22.2, 20.8, 16.1; MS (EI) m/z (rel. intensity) 525 (M′, 11), 466 (17), 391 (15), 350 (14), 323 (13), 266 (17), 239 (17), 60 (100); HRMS (EI) calculated for C29H35NO8 525.2363; found 525.2386.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:14]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, can be stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-1,3,5-triazine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature, filtered and purified by prep-HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]2[C@@H:8]([N:9]2[P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:26][CH2:27][CH:28]([OH:31])[CH2:29][CH3:30].B(F)(F)F.CCOCC>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C@@H:10]([NH:9][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C@H:8]([O:31][CH:28]([CH2:29][CH3:30])[CH2:27][CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@H]2[C@@H]([C@H](OS(C)(=O)=O)C1)N2P(=O)(OCC)OCC
Reactant: CCC(O)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.94 g of 16 and 3-pentanol (20 mL) cooled to 0-5° C. in a 50 mL round-bottom flask equipped with a magnetic stirrer and an argon gas supply was added 736 μl boron trifluoride ethyl etherate. The reaction mixture was stirred for 16 h at RT and the reaction mixture was then diluted with 50 mL of EtOAc and twice extracted with 70 mL of water. The organic phase was separated, dried (Na2SO4, 25 g) filtered and concentrated in a rotary evaporator at 40° C./70-10 mbar to afford 2.18 g of the crude product as a yellow oil. The crude product was purified by SiO2 column chromatography eluting with tert-butyl methyl ether. The combined fractions were evaporated and dried on a rotary evaporator at 40° C./250-10 mbar to afford 1.47 g of 18 as a light yellow solid.
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH3:20].CO.[BH4-].[Na+]>CCO>[NH2:20][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (5.35 g, 20.0 mmol) in EtOH (40 mL) were added a solution of NH3 in MeOH (7M, 40 mL, 280.0 mmol) and Ti(Oi-Pr)4 (11.30 g, 40.0 mmol), the mixture was stirred at room temperature overnight. And then NaBH4 (1.51 g, 40.0 mmol) was added portionwise. After addition, the resulting mixture was stirred at room temperature for another 5 h, then quenched with water (40 mL), stirred for 1 h and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/25) to give the product as a light yellow solid (1.20 g, 22.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[NH3:24]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:24][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: N
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC1CNCCN21
Yield: 59 %

Procedure:
10 g 7-chloro-1-(β-chlorethyl)-2-chlormethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were reacted in 200 ml methanol with 20 g ammonia gas in a gas autoclave for 16 hours at 90° to 95° C. After heating of the solution under vacuum, the reaction material is yielded in chloroform and washed with dilute aqueous sodium hydroxide solution. After drying and evaporating of the solvent under vacuum the resultive oily reaction product is dissolved in ether. From the concentrated solution, 5 g of 1,2,3,4,4a,5-hexahydro-9-chloro-7-phenyl-pyrazino[1,2-a]-[1,4]benzodiazepine having a melting point of 132°-135° C. are obtained by crystallization.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[C:24](=O)([O:33]N1C(=O)CCC1=O)[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:1]1[C:4]2([CH2:5][CH2:6][N:7]([C:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:33])[CH2:8][CH2:9]2)[CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 100.2 %

Procedure:
Tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (21.0 g, 92.8 mmol) and triethylamine (20 mL, 186 mmol) were dissolved in dichloromethane (200 mL). The reaction was cooled to 0° C. and a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (23.1 g, 92.8 mmol) in dichloromethane (25 mL) was added dropwise. The ice-bath was removed and the reaction was stirred at room temperature for 6 hours. The reaction was diluted with dichloromethane (100 mL), washed with 10% aqueous citric acid solution (100 mL), water (100 mL) and brine (100 mL). The organic solution was dried over MgSO4, filtered and concentrated to afford 7-benzyl 2-tert-butyl 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate (33.5 g, 100%) as colorless oil, which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:42]([C:39]3[CH:40]=[CH:41][C:36]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[CH:37][CH:38]=3)=[O:43])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3ccc(-c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester HCl salt (50 mg, 0.141 mmol), EDCI (67.54 mg, 0.352 mmol), biphenyl-4-carboxylic acid (30.73 mg, 0.155 mmol), HOBt (28.56 mg, 0.211 mmol) and ethyldiisopropylamine (63.90 mg, 0.493 mmol) were put into dichloromethane solvent (10 mL) and stirred at room temperature for 24 hours. After the reaction, aqueous NaHCO3 was added thereto, and extracted with dichloromethane. The organic layer was washed with brine, then the product was dried with anhydrous sodium sulfate, and the solvent was removed. A column chromatography was conducted on the crude material to obtain trans-[4-(4-{3-[(biphenyl-4-carbonyl)-amino]-propionylamino}-phenyl)-cyclohexyl]-acetic acid methyl ester (64 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])[O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(Br)cc3o2)c(F)c1
Temperature: 195 °C
Yield: 13.2 %

Procedure:
2-amino-5-bromophenol (1.72 g, 9.2 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) were dissolved in polyposphoric acid (30 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Solid that formed was filtered and dried to obtain the crude. Crude was purified by combiflash using a gradient mixture of EtOAc and Petether (1:3) as eluent to afford the titled compound (450 mg) as a dark brown solid.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[N:11]=[N:10][C:9]([CH2:12][OH:13])=[N:8]2)[CH:2]=1.[H-].[Na+].[CH:17]1([N:20]2[C:24](S(C)(=O)=O)=[N:23][N:22]=[C:21]2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:19][CH2:18]1>>[CH:17]1([N:20]2[C:24]([O:13][CH2:12][C:9]3[N:10]=[N:11][N:7]([C:3]4[CH:2]=[C:1]([CH3:14])[CH:6]=[CH:5][CH:4]=4)[N:8]=3)=[N:23][N:22]=[C:21]2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH2:19][CH2:18]1
Reactant: Cc1cccc(-n2nnc(CO)n2)c1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1
Yield: 1.2 %

Procedure:
The title compound (4.6 mg, 11%, yellow solid) was prepared from (2-m-tolyl-2H-tetrazol-5-yl)-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol). 1H NMR (CDCl3) δ (ppm): 8.77 (s br, 2H), 7.97 (m, 2H), 7.79 (d, 2H), 7.47 (t, 1H), 7.35 (d, 1H), 5.94 (s, 2H), 3.21 (m, 1H), 2.50 (s, 3H), 1.12 (m, 2H), 0.86 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[CH2:34][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: O=C1CCCCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1CCCCC1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (0.44 mL, 3.1 mmol) in THF (5 mL) at 0° C. was added n-butyllithium (1.6 M in hexane, 1.94 mL, 3.1 mmol) dropwise and the solution is stirred for 20 min. After cooling the solution to −78° C., a solution of cyclohexanone (0.32 ml., 3.1 mmol) in THF (2 mL) is added dropwise. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (1.0 g, 3.1 mmol) in THF (3 mL) is added dropwise. The solution was warmed to RT and stirred for 18 h. Saturated NaHCO3 is added and the mixture is extracted with EtOAc. The organic layer is washed with water then brine and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 20-33% EtOAc/hexane as eluent to give the title compound as a yellow liquid. NMR (CDCl3): δ 7.79-7.77 (d, J=8.33 Hz, 1H), 7.46-7.31 (m, 5H), 6.93 (d, J=1.51 Hz, 1H), 6.81-6.79 (dd, J=1.52 Hz, 8.34 Hz, 1 H), 5.22 (s, 2H), 3.20-3.16 (m, 1H), 2.53-2.39 (m, 2H), 2.33-2.25 (m, 1H), 2.11-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.85-1.79 (m, 1H), 1.66-1.55 (m, 2H), 1.35-1.25 (m, 2H).