Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]([C@H:18]([CH3:22])[CH2:19][CH:20]=[O:21])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].O>C(OC(C)C)(C)C>[O:10]([C@H:18]([CH3:22])[CH2:19][CH:20]([C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[OH:21])[Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: Clc1cnc(Cl)c(Br)c1
Reactant: C[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CC(C)OC(C)C
Product: C[C@H](CC(O)c1cc(Cl)cnc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a cooled (-70° C.) solution of n-butylithium (129.3 mL of 1.18 M hexanes solution, 0.153 mol) in isopropyl ether was added a solution of 3-bromo-2,5-dichloropyridine (36.45 g, 0.161 mol) in isopropyl ether (225 mL) over a period of 30 minutes. The resulting white suspension was then treated with a solution of 3(R)-t-butyldimethylsiloxybutyraldehyde (34.14 g, 0.169 mol) in isopropyl ether (106 mL) and allowed to stir for an additional 30 minutes at -70° C. followed by warming to room temperature. After the addition of 480 mL of water, the biphasic mixture was separated and the organic layer was extracted with isopropyl ether (2×200 mL). The combined organic layers were washed once with water, heated with decolorizing carbon [G-60 DARCO (trademark)] filtered through diatomateous earth [Celite (trademark)] and condensed on a rotary evaporator. The resulting hazy yellow liquid was heated at 80° C. under high vacuum overnight to yield the desired product (mixture of diastereomers) as an amber oil (40.52 g, 72%): Rf 0.36 (25% Et2O in hexanes); 1H NMR (60 MHz, CDCl3) δ 0.1 (s, 6H), 0.82 (s, 9H), 1.18 (m, 3H), 1.72 (m, 2H), 4.16 (m, 1H), 4.42 (m, 1H), 5.10 (m, 1H), 7.92 (d, 1H, J=2.6 Hz), 8.13 (d, 1H, J=2.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH3:42])[C:33]2=[O:43])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[C:33](=[O:43])[N:34]([CH3:42])[CH:35]=2)=[O:40])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: Cn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)c1cn(C)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. LCMS m/z=573 (M+1); 1H NMR (CDCl3) δ: 11 (s, 1H), 8.61 (s, 1H), 8.54 (d, 1H, J=9 Hz), 8.49 (d, 1H, J=5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 4H), 6.81 (dd, 1H, J=3, 9 Hz), 6.74 (d, 1H, J=3 Hz), 6.5 (d, 1H, J=5 Hz), 4.05 (s, 6H), 3.84 (s, 3H), 3.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]([Cl:23])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=C(Nc1c(F)cncc1F)c1c(Cl)cc(I)cc1Cl
Reactant: O=S(Cl)Cl
Product: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzamide (21.3 g, 49.7 mmol) in thionyl chloride (118 mL) was heated under reflux for 20 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was azeotroped with toluene (×3) and dried under vacuum to afford the title compound as a brown solid (22.4 g, quantitative). LCMS (Method E): RT=4.69 min, m/z: 448 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (6.43 g, 35.9 mmol) and Et3N (5.50 ml, 39.5 mmol) in THF (70 ml) was added phenyl isocyanate (3.90 ml, 35.9 mmol), and the reaction mixture was stirred at room temperature for 4 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-(N′-phenylureido)phenylacetate (9.64 g, 90%) as a white crystalline powder. mp 153-155° C.; 1H-NMR (CDCl3) δ1.26 (t, J=7.1 Hz, 3 H), 3.52 (s, 2 H), 4.15 (q, J=7.1 Hz, 2 H), 6.98-7.04 (m, 1 H), 7.07-7.11 (m, 4 H), 7.18-7.25 (m, 5 H), 7.42 (s, 1 H); MS (FAB) m/z 299 (M++1); Anal. Calcd. for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.22; H, 6.10; N, 9.36.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[N-:27]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].[ClH:34]>CN(C=O)C.C(O)C.[Pd]>[NH2:27][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3.[ClH:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: NCC1COc2ccc3c(c2O1)CC(=O)N3
Temperature: 45 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (3.0 g, 8.0 mmole) and sodium azide (1.6 g, 24.0 mmole) were placed in 300 ml of DMF and the reaction mixture was heated at 45° C. for 15 hours. Most of the DMF was removed and the residue was partitioned between dichloromethane and water. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was pure enough without further purification and was identified as the desired product, (S)-2-azidomethyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one. An aliquot amount of the azide (0.8 g, 3.2 mmole) in ethanol (50 ml) was hydrogenated with 10% palladium on carbon (100 mg) for 15 hours. The resulting mixture was acidified with 4 N isopropanolic HCl until pH<3. The catalyst was then filtered off and the filtrate was concentrated. The residue was dissolved in 90% aqueous ethanol and precipitated with diethyl ether to give the (S) enantiomer of the title compound as a white solid hydrochloride, 1.25 hydrate, (0.7 g, 85%), m.p. 278-280° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[C:23]([C:25]1[S:26][C:27]([Cl:32])=[C:28]([Cl:31])[C:29]=1[Cl:30])#[N:24].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:24]=[C:23]([C:25]2[S:26][C:27]([Cl:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1sc(Cl)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Cl)c(Cl)c1Cl
Temperature: 145 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
To a mixture of N-methyl-N-benzenesulfonyl-2-chloro-6-fluorobenzhydrazonoyl chloride (47.5 g, 0.131 mol) and 2-cyano-3,4,5-trichlorothiophene (26.5 g 0.125 mol in o-dichlorobenzene (18 mL),was added aluminum chloride (11.1 g, 0.083 mol). The mixture was lowered into a preheated oil bath maintained at 140-150° C. The mixture was allowed to remain in the hot oil bath 40 min and was then removed from the bath and stirred for 2 hr as it gradually cooled. The reaction mixture was poured into 2N sodium hydroxide (300 mL-enough to dissolve the aluminum salts) and extracted with methylene chloride (3×250 mL). The organic phases were combined, washed with brine, dried (MgSO4), and the solvent removed in vacuo to give the crude product. The residue was placed on silica gel (150 g) and then chromatographed using ethyl acetate/hexanes as eluant to obtain 39.7 g (55.3% yield) of the title compound; 99.4% pure by GC analysis; mp 129-130° C.; 1H NMR (CDCl3) δ 7.3 (m, 2H), 7.1 (m, 1H), 4.0 (s, 3H); Anal. for C13H6Cl4FN3S: Calcd. C, 39.32; H, 1.52; N, 10.58. Found C, 39.08; H, 1.30; N, 10.34.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])=[CH:51][CH:50]=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:55][CH2:56][C:57](=[O:59])[CH3:58])=[CH:53][CH:54]=2)[N:10]=[CH:9]1
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)CCc1ccc(OCCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol, 6 mmol of triphenylphosphine and 5 mmol of 4-(4-hydroxyphenyl)-2-butanone are dissolved under nitrogen in the cold. 6 mmol of diethyl azodicarboxylate, dissolved in 4 ml of THF, are added and the reaction mixture is stirred at room temperature for 48 hours. After evacuation of the solvent under reduced pressure and column chromatography (eluent: ethyl acetate), the residue is dissolved in 10 ml THF and 30 ml of 2N HCl and heated to 70° C. for 2 hours. The solvent is evaporated off under reduced pressure and triphenylmethanol is extracted using diethyl ether. The aqueous phase is neutralized with potassium carbonate and the product extracted with diethyl ether. The ethereal solution is dried and evaporated to obtain an oil, which is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[N:4]=[N:3]1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>ClCCl>[CH3:9][O:10][C:11](=[O:12])/[CH:13]=[CH:7]/[C:5]1[N:4]=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc(C=O)nn1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1cn(C)nn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 212.7 %

Procedure:
1-Methyl-1,2,3-triazol-4-carboxaldehyde (1 g, 9 mmol) was added to a solution of methoxycarbonylmethylene triphenylphosphorane (4.5 g, 13.5 mmol) in dichloromethane (50 ml) and stirred at room temperature for 3.5 hours. The solvent was removed and the residue purified by silica gel chromatography to afford the title compound, (3.2 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@@H:4]1[OH:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(Cl)Cl>[OH:8][C@H:4]1[CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C:3]1([CH3:9])[CH3:2]
Reactant: CC1(C)CNC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a mixture of (3R)-4,4-dimethyl-3-pyrrolidinol hydrochloride (0.9920 g, 6.630 mmol) in 1:1 DCM-1 N aq. NaOH (33 mL) was added benzyl chloroformate (0.994 mL, 6.963 mmol). The mixture was vigorously stirred overnight and then diluted with DCM (100 mL). The phases were partitioned, and the organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was then purified by silica gel chromatography (40% EtOAc in hexanes) to afford phenylmethyl (4R)-4-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate (1.4654 g, 89% yield) as a colorless oil. LCMS: (M+H)+: 250.1.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH:8]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[O:7]1[CH:8]=[C:4]([CH2:3][CH2:1][NH2:2])[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]1=2
Reactant: N#CCc1coc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCc1coc2ccccc12
Yield: 79.4 %

Procedure:
A solution of 3.97 g (0.025 mole) of 3-cyanomethylbenzo[b]furan in 200 mL of diethyl ether was slowly added to a refluxing suspension of 3.84 g (0.1 mole) of lithium aluminum hydride in 400 mL of ether. The reaction was heated 3 hrs., cooled and water was slowly added. The suspension was filtered through a pad of filter aid and the filtrate was evaporated to give 3.2 g of oily product. The hydrochloride salt has m.p. 183°-185° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:20]([O-])(=[O:22])C.[Na+]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([CH2:20][OH:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nccn1Cc1ccccc1Cl
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Reaction time: 4 h
Yield: 41.1 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole (95.5 g, 0.384 mol), 37% formaldehyde (500 mL), sodium acetate (80 g) and acetic acid (60 mL) was heated to reflux for 40 hours under argon. The reaction was concentrated in vacuo, and the residue was stirred with 500 mL of 20% sodium hydroxide solution for 4 hours, diluted with water and extracted with methylene chloride. The extract was washed, dried, and concentrated. The crude product (117 g) was flash chromatographed over 600 g of silica gel with a gradient of ethyl acetate to 10% of methanol in ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixture of starting material and product, and 44 g (41%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86°-88° C. (from ethyl acetate). Further elution provided the bis (4,5-hydroxymethyl) derivative; mp 138°-140° C. (from ethyl acetate).
Reaction SMILES: [ClH:1].C([O-])(O)=O.[Na+].O[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1>C(O)(=O)C>[Cl:1][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: Oc1nc(-c2ccccc2)cc2ccncc12
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1nc(-c2ccccc2)cc2ccncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl gas was bubbled through a warmed solution of Intermediate 1 (3.49 g, 14.0 mmol) in glacial acetic acid (35 ml) for about 2 min. The reaction flask was stoppered and the reaction mixture was stirred at 40° for 6 h and at room temperature for 18 h. The volatiles were removed in vacuo to afford a yellow solid which was treated with saturated aqueous NaHCO3 (50 ml). The obtained light yellow powder was collected by filtration, washed with water and dried to afford a mixture of 1-hydroxy-3-phenyl-2,7-naphthyridine and the title compound (2.58 g, 2:1 ratio). This mixture was treated with phosphorus oxychloride (30 ml) at 130° for 7 h. The volatiles were removed in vacuo and the obtained yellow solid partitioned (with CARE) between EtOAC (150 ml) and ice-cold saturated aqueous NaHCO3 (50 ml+5 g solid NaHCO3). The phases were separated and the aqueous layer re-extracted with EtOAc (2×50 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dull yellow solid (2.5 g). Chromatography (silica: 1:1:2-2:1:1 EtOAc/DCM/Hexane) afforded the title compound as a pale yellow solid (2.21 g, 51% over two steps). δH (CDCl3) 9.74 (1H, s), 8.81 (1H, d, J 5.7 Hz), 8.17 (1H, d, J 8.0 Hz), 7.99 (1H, s), 7.70 (1H, d, J 5.7 Hz), 7.60-7.49 (3H, m); m/z (ES+, 70V) 241 and 243 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][C:17]#[N:18])=[CH:13][C:12]=2[CH:19]=1>CO>[OH:3][N:2]=[C:17]([NH2:18])[CH2:16][C:14]1[S:15][C:11]2[CH:10]=[CH:9][C:8]([Br:7])=[CH:19][C:12]=2[CH:13]=1
Reactant: NO
Reactant: N#CCc1cc2cc(Br)ccc2s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1cc2cc(Br)ccc2s1)=NO
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (3.86 g, 0.056 mol) in MeOH (100 mL) was added sodium methoxide (25 wt % in MeOH, 10.33 g, 0.056 mol). Stirring was continued for 15 minutes and 5-bromo-2-benzthiophenylacetonitrile (7.0 g, 0.028 mol) was added. The resulting mixture was refluxed for 2 days, cooled, and concentrated. The residue was diluted with H2O. The solid was collected by filtration, purified by column chromatography (eluant: EtOAc/hexane, 2:3) to give 4.0 g (50%) of product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH2:3]1.I[CH2:15][CH:16]([CH3:18])[CH3:17]>>[O:13]=[C:4]1[N:5]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:2](=[O:1])[CH2:3]1
Reactant: CC(C)CI
Reactant: O=C1CC(=O)Nc2ccccc2N1
Product: CC(C)CN1C(=O)CC(=O)N(CC(C)C)c2ccccc21

Procedure:
2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A and 1-iodo-2-methylpropane (Aldrich). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to 1:1), then recrystallization from EtOAc/hexanes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH3:17])\[CH3:7])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH3:17])\[CH2:7][Br:19])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1ccccc1O/C(C)=C/C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1ccccc1O/C(=C/C(=O)OCC)CBr
Yield: 49.7 %

Procedure:
To a stirred mixture of (E)-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (3.10 g, 0.012 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (3.30 g, 0.019 mol) and benzoyl peroxide (300 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (1.95 g, 48%) as a yellow oil.
Reaction SMILES: CN(C)CCN(C)C.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC.[NH2:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>C1COCC1>[NH2:22][C:23]1[C:28]([CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1ccccc1
Reactant: Nc1cnccn1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1nccnc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a mixture of N,N,N′,N′-tetramethylethylendiamine (TMEDA, 15.00 mL, 0.10 mol) in toluene (22.00 mL, 0.21 mol) at 0° C., buthyllitium 1.6M in n-hexane (63.00 mL, 0.10 mol) was added dropwise. Then the mixture was heated at 60° C. and after 30 min was slowly added to a cooled solution of 2-aminopyrazine 11 (2.00 g, 0.02 mol) in anhydrous THF (20 mL). The reaction mixture was stirred at 0° C. for 30 min, poured into ice and extracted with ethyl acetate (3×20 mL). The organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude was purified by flash chromatography (EtOAc, dichloromethane; 65:35) to get 1.38 g (35% yield) of the title compound 12 as a yellow solid (mp 93-96° C.). 1H-NMR (CDCl3): 4.08 (s, 2H), 4.33 (br s, 2H), 7.18-7.35 (m, 5H), 7.91 (m, 2H). MS (ESI): m/z 186 (M+H−).
Reaction SMILES: [C:1](=[NH:9])([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18]([N:9]=[C:1]([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: CCCCC(=N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=NC(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of 6.5 g (50.3 mmol) of ethyl valerimidate (free base) in 90 mL of dry CH2Cl2 was treated with 7.71 mL (5.60 g, 55.3 mmol) of triethylamine. The resulting solution was stirred under N2 at -10° C. in an ice-salt bath as a solution of 4.81 mL (5.46 g, 50.3 mmol) of ethyl chloroformate in 10 mL of CH2Cl2 was added dropwise over 25 minutes. Upon completion of the addition, the cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. Next, the solvent was removed by evaporation in vacuo. The residue was taken up in hexane and filtered to remove triethylamine hydrochloride. Concentration of the filtrate yielded 7.08 g (70%) of the product as a yellow oil, suitable for use in the next step without further purification. NMR indicated a mixture of syn and anti isomers. TLC (98:2 CH2Cl2 --MeOH) showed a close pair of spots, Rf 0.48, 0.52.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(O)(=O)C.[CH3:22][C:23](=O)[CH2:24][CH3:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:23]([N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH2:13][CH2:14]1)([CH2:24][CH3:25])[CH3:22]
Reactant: CCC(C)=O
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(C)N1CCC(c2cccc(S(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(3-methanesulfonyl-phenyl)-piperidine hydrochloride (20 mg), glacial acetic acid (4.4 mg) and 2-butanone (5.1 mg) were mixed in 1,2-dichloroethane (5 mL). Sodium triacetoxyborohydride (23.5 mg) was added to the solution and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 5 h (G.L.C. analysis indicated a complete reaction). The reaction was quenched with saturated aqueous NaHCO3 and the product was extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and the solvent was evaporated to afford 1-sec-butyl-4-(3-methanesulfonyl-phenyl)-piperidine as an oily residue. The product was chromatographed on a silica column with CH2Cl2:MeOH (9:1 (v/v)) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded pure amine (15 mg, 71%); MS m/z (relative intensity, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][CH3:18])[CH2:3][CH2:2]1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21]>>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([CH3:18])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CNc1cnccc1-c1ccccc1OC1CC1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC1CC1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-cyclopropoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow foam (65%). MS (ESI): m/z=491.125 [M+H]+.