Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[I-].[K+].[OH-].[K+].C1CO[C:21]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)([CH2:22][CH2:23][CH2:24]Cl)[O:20]1>C1(C)C=CC=CC=1.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:24][CH2:23][CH2:22][C:21]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:20])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cl
Product: O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere 4.87 parts of 4-(4-chlorophenyl)piperidin-4-ol, 1.91 parts of potassium iodide and 25 parts of deionized water is combined and gently warmed. 1.65 Parts of potassium hydroxide, followed by 6.12 parts of 1,1-ethylenedioxy-1-(4-fluorophenyl)-4-chlorobutane is added, and the mixture is heated to reflux. After refluxing for 3.75 hours, the reaction mixture is cooled to room temperature, and 55 parts of toluene is added. The aqueous and organic layers are separated, and the aqueous layer discarded. 5.1 Parts of methanol is added to the organic layer and the mixture cooled to about 25° C. While stirring vigorously, 3.1 parts of concentrated hydrochloric acid is added. The resultant precipitate is filtered and washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol. The filtrate, after standing for about 18 hours, affords additional precipitate. This is filtered and combined with the initially isolated precipitate. The solid is then washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol and twice with 22 parts by volume portions of a 10:1 mixture of acetone-methanol. The solid is air-dried to give, in 75.5% yield, 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone hydrochloride as a white solid melting at about 226° - 228° C., and identical to the product of Example 2.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH:19]4[CH2:23][CH:22]=[CH:21][N:20]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:18]=2)[O:15][C:14]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:13][C:12]3=[O:37])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1(C(C2C=C3C(=C(C4C=CCN4C(OC(C)(C)C)=O)C=2)OC(N2CCOCC2)=CC3=O)=O)CCOCC1>C(O)C.[Pt](=O)=O>[N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH:18]=2)[O:15][C:14]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)=[CH:13][C:12]3=[O:37])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C=CCC1c1cc(C(=O)N2CCOCC2)cc2c(=O)cc(N3CCOCC3)oc12
Agent: O=[Pt]=O
Agent: CC(C)(C)OC(=O)N1CC=CC1c1cc(C(=O)N2CCOCC2)cc2c(=O)cc(N3CCOCC3)oc12
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1cc(C(=O)N2CCOCC2)cc2c(=O)cc(N3CCOCC3)oc12
Reaction time: 4 h
Yield: 76 %

Procedure:
The above mixture of tert-butyl 2-(6-(morpholine-4-carbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate compound and tert-butyl 2-(6-(morpholine-4-carbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1:1) (2.1 g, 2.05 mmol) and platinum(IV) oxide (0.093 g, 0.41 mmol) in ethanol (30 ml) was hydrogenated under 1.2 atm at room temperature for 4 h. The resulting solution was filtered and the filtrate was concentrated to dryness to afford the crude tert-butyl 2-(6-(morpholine-4-carbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (1.60 g, 76%) as an orange solid. Mass Spectrum: m/z [M+H]+=514.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=1.B([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][C@@H:28]([C:30]([OH:32])=[O:31])[NH2:29])=[CH:25][CH:24]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:29][CH:28]([CH2:27][C:26]1[CH:33]=[CH:34][C:23]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[C:30]([OH:32])=[O:31]
Reactant: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(Cc1ccc(-c2cc(OC(c3ccccc3)C(F)(F)F)ncn2)cc1)C(=O)O
Temperature: 120 °C
Yield: 10.5 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with 4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine (30 mg, 0.11 mmol), 4-borono-L-phenylalanine (32 mg, 0.16 mmol), 1 ml of acetonitrile and 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, 1M) was added to above solution followed by 10 mol percent of POPd2 (dihydrogen di-μ-chlorodichlorobis(di-tert-butylphosphinito-κP) dipalladate. The reaction vessel was sealed and heated to 120° C. for 30 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 4.8 mg of 2-amino-3-{4-[6-(2,2,2-trifluoro-1phenyl-ethoxy)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 11%. 1H-NMR (400 MHz, CD3OD): δ 3.20 (m, 1H), 3.40 (m, 1H), 4.25 (t, 1H), 6.82 (dd, 1H), 7.43 (m, 5H), 7.57 (s, 1H), 7.60 (m, 2H), 8.10 (d, 2H), 8.75 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[CH2:22](N)[C:23]#[CH:24]>O1CCCC1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:24][C:23]#[CH:22])[CH2:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CC([N+](=O)[O-])=C(Cl)c2ccccc21
Reaction time: 1.5 h

Procedure:
Triethylamine (8.0 mL, 1.2 eq.) was added to a mixture of 4-chloro-3-nitroquinoline (10.0 g, 47.9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 200 mL). Propargylamine (3.4 mL, 1.1 eq.) was added and the reaction mixture was stirred vigorously for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between chloroform (700 mL) and water (200 mL). The organic layer was washed with water (1×200 mL). The combined aqueous layers were back extracted with chloroform (2×150 mL). The combined organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 10.59 g of 4-chloro-3-nitro-N-(2-propynyl)quinoline as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][N:17]([CH2:19][CH2:20][OH:21])[CH2:16][N:15]([CH3:22])[C:14]1=[S:23].C(OCC)C>C1(C)C=CC=CC=1>[C:1]([O:21][CH2:20][CH2:19][N:17]1[CH2:18][N:13]([C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[CH3:5])[C:14](=[S:23])[N:15]([CH3:22])[CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N2CN(CCO)CN(C)C2=S)c(C)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)OCCN1CN(C)C(=S)N(c2ccc(C)cc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Acetyl chloride (0.168 g, 1.5 mmole) was added dropwise with stirring to a cooled solution of 1-(2,4-dimethylphenyl)-5-(2-hydroxyethyl)-3-methyl-tetrahydro-s-triazin-2[1H]-thione (0.60 g, 1 mmole) in dry toluene (30 ml). After 10 minutes the solution was allowed to warm to room temperature and stirring was continued for a further 3 hours. The solution was filtered and the solvent removed under vacuum. The product was chromatographed on a column of silica eluting with dichloromethane containing 2% methanol to yield an oil. Trituration with diethyl ether gave 5-(2-acetoxyethyl)-1-(2,4-dimethylphenyl)-3-methyl-tetrahydro-s-triazin-2[1H]-thione (0.24 g, 35%), m.p. 80°-83° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[O:18][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=1)=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:25][N:23]([CH2:22][C:19]1[O:18][C:17]([CH2:16][S:15][CH2:14][CH2:13][NH:12][C:10]([NH2:9])=[S:11])=[CH:21][CH:20]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(CSCCNC(=S)NC(=O)c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC(N)=S)o1
Temperature: 65 °C

Procedure:
A mixture of 24.76 g (65.6 mmol) of N-benzoyl-N'-(2-(((5-(dimethylamino)methyl-2-furanyl)methyl)thio)ethyl)-thiourea and 5.6 g (40.5 mmol) of potassium carbonate in 160 ml ethanol and 100 ml water is heated under stirring at 65° C. An additional amount of 3.45 g (25 mmol) potassium carbonate is added after 30 and 75 minutes respectively. After 90 minutes the ethanol is eliminated by vacuum distillation. A reaction mixture is diluted with 200 ml 5% sodium carbonate and extracted with dichloromethane (3×250 ml). The organic compound is washed with 5% sodium carbonate (2×500 ml), dried over anhydrous magnesium sulfate and concentrated to a brown oil. After chromatography on 500 g silica gel in dichloromethane/methanol 9:1, 16.8 g of N-(2-(((5-(dimethylamino)methyl-2-furanyl)methyl)thio)ethyl-thiourea oil is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](=[O:26])(=[O:25])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:9][CH:8]=1)=[O:5].[C:31](Cl)(=[O:35])[CH2:32][CH2:33][CH3:34].C(N(CC)CC)C>C1COCC1>[C:31]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][S:17]([C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=3[CH3:1])=[CH:8][CH:9]=2)(=[O:26])=[O:25])[CH2:20][CH2:21]1)(=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)NC2CCNCC2)c2c1CCCC2
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3c2CCCC3)CC1
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To a 25° C. mixture of sulfonamide (26) (134 mg, 0.29 mmol) in THF (10 mL) was added butyryl chloride (77 mg, 0.725 mmol) and triethylamine (367 mg, 3.625 mmol). The mixture was stirred for 18 hours, followed by filtration to remove the precipitate. The filtrate was concentrated in vacuo and purified via chromatography, resulting in the title compound as white solid (50 mg). 1H NMR (300 MHz, MeOD) δ 7.91 (d, 1H), 7.55 (m, 2H), 7.41 (m, 1H), 7.31 (m, 2H), 4.30 (m, 1H), 3.89 (m, 1H), 3.21 (m, 2H), 3.09 (m, 1H), 2.85 (m, 2H), 2.61 (m, 1H), 2.55 (s, 3H), 2.34 (t, 2H), 1.88 (m, 7H), 1.62 (m, 2H), 1.39 (m, 2H), 0.95 (t, 3H) ); LC/MS (M+H)+ m/z 498.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][C:27]4[N:28]([C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=4)[N:29]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O>CN(C=O)C>[N:3]1([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][C:27]5[N:28]([C:30]([C:33]([F:36])([F:34])[F:35])=[N:31][N:32]=5)[N:29]=4)[CH2:22][CH2:23]3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCBr)cc4)CC3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCn5cccn5)cc4)CC3)nn12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 16.97 mg, 0.42 mmol) was added to 1H-pyrazole (28.9 mg, 0.42 mmol) in DMF (2 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 20° C. for 20 minutes. 6-[4-[4-(2-Bromoethoxy)phenyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.21 mmol) was added and the reaction stirred at 20° C. for 1 hour. Water (25 mL) was then added and the resulting precipitate filtered off, washed with ether and dried overnight under vacuum at 50° C. to give 6-[4-[4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (66.0 mg, 68%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1I)[CH3:21].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[CH:24][C:23]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)[CH3:21]
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: CCc1c(I)cnn1-c1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1c(C#Cc2cnn3cc(-c4cnn(C)c4)cc(OC)c23)cnn1-c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20 mg, 0.080 mmol), 5-ethyl-4-iodo-1-phenyl-1H-pyrazole (24 mg, 0.08 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.2 mg, 0.0079 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.022 ml, 0.16 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-ethyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[F:23][C:24]([F:60])([F:59])[C:25]1[CH:26]=[C:27]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[C:28]([N:30]1[CH2:34][C@@:33]([CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[O:32][CH2:31]1)=[O:29].C(OCC)(=O)C>O1CCCC1>[F:59][C:24]([F:23])([F:60])[C:25]1[CH:26]=[C:27]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[C:28]([N:30]1[CH2:34][C@@:33]([CH2:42][CH2:43][OH:44])([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[O:32][CH2:31]1)=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@]1(c2ccc(F)cc2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CO[C@](CCO)(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 508 mL) and acetic acid (70 mL, 1.27 mol) were added to a solution of the compound (131.76 g, 0.254 mol) obtained in Example 1b in tetrahydrofuran (500 mL), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (1000 mL) was added to the reaction mixture, washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane, 30%→50%) to give the title compound (102.11 g; yield, 99%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH:21]=[O:22])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][OH:22])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC[C@@H](CC=O)CCCCOCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC[C@@H](CCO)CCCCOCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of the crude methyl (S)-8-(benzyloxy)-4-(formylmethyl)octanoate (2.44 g crude) in ethanol (22 ml) is added sodium borohydride (0.307 g, 8.1 mmol). The reaction is stirred for 15 minutes and then poured into water. The pH of the mixture is adjusted to 8.0 using saturated sodium bicarbonate solution. The mixture is extracted with methylene chloride (3×30 ml) and the combined organic extracts are dried, filtered and evaporated to give an oil. This is purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent to yield methyl (S)-8-(benzyloxy)-4-(2-hydroxyethyl)-octanoate (oil), [alpha]D25 -1.22° (c 1.02 in methanol).
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[C:7]1([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:25].[ClH:5].[C:7]1([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:3])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: SCCCN1CCN(CCCc2ccccc2)CC1
Yield: 81.9 %

Procedure:
The procedure described in Example 1(b) was followed, using 19.0 g of thiourea, 44.0 g of 1-(3-phenylpropyl)-4-(3-chloropropyl)piperazine dihydrochloride, 25 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 35.8 g (82% of theory) of 3-[4-(3-phenylpropyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 237°-239° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=4[F:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cccc(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccc(F)c1F
Reaction time: 0.05 h
Yield: 13.7 %

Procedure:
To a stirred solution of 0.350 g of 2,3-difluorobenzoyl chloride in 5 ml of methylene chloride is added 0.346 ml of triethylamine. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours. The reaction mixture is filtered and the solid washed with methylene chloride. The solid is saved. The combined filtrate is washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give 100 mg of a solid. The two solids are combined and dried to afford 790 mg of the desired product as a solid, m.p. 252°-258° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C>>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:32][C@@H:28]3[CH2:29][CH2:30][CH2:31][NH:27]3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Product: c1ccc(Cc2ccc(-c3ccc(OC[C@@H]4CCCN4)cc3)s2)cc1
Yield: 85 %

Procedure:
The title compound was prepared from the product of example 170, step 4 (0.3 g, 1.1 mmol) and (S)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.4 mmol) using the procedure of Example 159, step 5 with 85% yield (360 mg). 1HNMR (CD3OD) 7.50 (d, J=8.8 Hz, 2H), 7.39-7.18 (d, J=3.6 Hz, 5H), 7.08 (d, J=3.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 4.58 (m, 1H), 4.32 (m, 1H), 4.12 (s, 2H), 4.03 (m, 2H), 3.34 (m, 2H), 2.26 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), LC/MS (ESI+) m/z: 99%; 351 (M+1, 100). Elemental analysis
Reaction SMILES: O.[Y:2].OC1C=C[C:7]([C:8]([OH:10])=[O:9])=CC=1>C(O)CC.CCCO.CCCO.CCCO.CCCO.[Zr]>[C:8]([O-:10])(=[O:9])[CH3:7].[Y+3:2].[C:8]([O-:10])(=[O:9])[CH3:7].[C:8]([O-:10])(=[O:9])[CH3:7]
Reactant: [Y]
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Zr]
Solvent: O
Solvent: CCCO
Product: CC(=O)[O-]
Product: [Y+3]
Reaction time: 0.5 h

Procedure:
A preferred method for the production of the admixture needed to produce an 8 wt % Y2O3 /ZrO2 spray dried material is described herein. A clear solution of yttrium acetate was prepared by dissolving 247 g of the Y(acetate)3. 3.5 H2O (0.76 mole) in 500 cc (28 mole) of 90° C. distilled water. This solution was added to an equal volume of hot (80° C.) n-propanol. This solution must be kept hot during the synthesis. Using a heated dropping funnel, the yttrium solution was slowly added to 2.66 kg (6.3 mole) of zirconium n-propoxide. An air driven propellor stirrer was used throughout the addition, and the stirring continued for an extra 30 min. The suspension was quite thick and was improved by the addition of one gram of p-hydroxybenzoic acid (0.2 wt % of the ZrO2) in 1.3 l of n-propanol to the zirconium alkoxide prior to the addition of the yttrium solution.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>CO.O>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCCBr
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1N1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of o-toluidine (2.0 g; 18.7 mmol) in methanol (62 mL) was added sodium carbonate (4.95 g; 46.75 mmol) followed by 1,4-dibromobutane (4.85 g; 22.4 mmol). The resulting mixture was stirred at 50° C. under a nitrogen atmosphere overnight and then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to yield the title product as a dark yellow-orange oil (1.24 g).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1)C.Cl>CN(C)C=O.O>[NH:15]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]([CH2:12][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14]1
Reactant: O=Cc1ccccc1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 131.9 %

Procedure:
NaCN (1.4 g, 29 mmol) was provided in absolute dimethylformamide (10 ml) in argon. At a bath temperature of 35° C. benzaldehyde (3 ml, 29 mmol) dissolved in absolute dimethylformamide (10 ml) was added in drops within 1.5 h and stirred for a further 0.5 h at this temperature. Gramine (10.1 g, 58 mmol) dissolved in absolute dimethylformamide (30 ml) was added in drops to this reaction solution within 2 h at an inside temperature of 70° C. The mixture was stirred a further 1 h at this temperature. For work up the vessel contents were placed in water (150 ml). The aqueous phase was acidified with 2N HCl to separate non-converted gramine as, a water-soluble hydrochloride. The aqueous phase was then extracted with chloroform (3×50 ml). The combined extracts were washed with NaHCO3 solution (50 ml) and dried over Na2SO4. The volatile constituents were then completely removed in a vacuum. The residue (9 g) obtained after distilling off the solvent was purified by column chromatography [silica gel 60 (300 g); cyclohexane/ethyl acetate 6:1 (1500 ml)].