Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH2:25][CH2:26][CH2:27][CH:28]2[O:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])(C)C.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([CH2:25][CH2:26][CH2:27][CH:28]2[O:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:16][C:17]=1[CH3:18]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2OC(=O)NC2=O)cc1OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2OC(=O)NC2=O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
A solution of titanium tetrachloride (TiCl4) (1.1 g) in dichloromethane (5 ml) was added dropwise, at 0° C., to a solution of 5-[3-[3-isopropoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione (0.7 g) in dichloromethane (25 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was poured over 2N HCl, which was stirred for 15 minutes at room temperature. The organic layer was separated, and the aqueous layer was subjected to extraction with chloroform. The organic layer combined was and successively washed with water, 2N HCl and water, which was dried (MgSO4) and concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), was obtained 5-[3-[3-hydroxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione (0.22 g, 34%), which was recrystallized from chloroform-methanol to give colorless prisms, m.p.162-164° C.
Reaction SMILES: [OH:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[S:4][N:3]=1.[P:9](Cl)([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[S:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:11][P:9]([O:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[S:4][N:3]=1)([O:14][CH2:15][CH3:16])=[S:10])[CH3:13]
Reactant: CCOP(=S)(Cl)OCC
Reactant: CSc1nc(O)ns1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nsc(SC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.6 g of the product of Step A, 9.5 g of diethyl chlorothiophosphate and 7 g of potassium carbonate in 50 ml of acetone was stirred overnight at room temperature and the mixture was then filtered. The filtrate was concentrated by evaporation under reduced pressure and was chromatographed over silica. Elution with a 9-1 benzene-ethylacetate mixture yielded 3-(diethoxythiophosphoryloxy)-5-methylthio-1,2,4-thiadiazole with a refractive index of nD20 = 1.5534 and Rf=0.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br>ClCCl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccnc4)cc32)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cccnc3)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.1 %

Procedure:
In a 5 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-pyridin-3-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (35 mg, 0.069 mmol) was dissolved in dichloromethane (1 ml), and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (0.4 ml, 0.415 mmol) was added thereto and then stirred at room temperature for 15 hours. n-hexane solvent was added thereto and the formed solid was filtered. The resulting solid was dissolved in methanol and concentrated. After dissolving by adding water, the mixture was adjusted to pH 6 with saturated solution of sodium hydrogen carbonate, and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and n-hexane to obtain the target compound 52 as white solid (18 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:20]([C:17]2[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A 200 mL round-bottom flask was charged with 2-bromo-5-chloro-pyridin-3-ylamine (10.4 g, 50.0 mmol), 4-tert-butyl-benzenesulfonyl chloride (20.0 g, 85.0 mmol), and pyridine (38 mL). The resultant solution was heated to 70° C. and stirred overnight. The following day, the pyridine was removed by removed in vacuo and 30 mL THF (tetrahydrofuran) and 100 mL 4.0 N NaOH were added and the reaction was stirred at 60° C. overnight. The organics were subsequently removed in vacuo and the residues were diluted with 400 mL water. The small quantity of insoluble solid was removed by filtration and the pH was adjusted to 6-7 with concentrated HCl. The resultant aqueous solution was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure to afford the desired sulfonamide (13.4 g) in 66% yield: MS (ES) M+H expected 403.0, found 403.1.
Reaction SMILES: [C:1]([C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(Cc4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
Dissolve the compound obtained in Example 18 (0.7 g) in trifluoroacetic acid (1.6 ml) and then add triethylsilane (0.5 ml). Leave at ambient temperature for 2 days with magnetic stirring. Hydrolyse the reaction mixture and then extract twice with 30 ml of ether each time. Dry the organic phase over magnesium sulphate and evaporate it under reduced pressure. Carry out flash chromatography on the resulting residue using an 8/2 cyclohexane/ethyl acetate mixture as eluant.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CSc1c(Cl)nc(-c2ccc(NS(C)(=O)=O)cc2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (30 mg, 0.091 mmol.), methanesulfonyl chloride (15.5 mg, 0.136 mmol, 1.5 eq.) and CH2Cl2 was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at r.t. for 2 hrs. The reaction mixture was partitioned between CH2Cl2 and NaHCO3 (aq), the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. A white solid of 30.3 mg (82.1%) was obtained as the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:34]=[O:35]>>[CH2:1]([O:8][C:9]1[C:13]([CH:34]=[O:35])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc(OCc3ccccc3)nn2C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C=O)c(OCc3ccccc3)nn2C(C)C)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole (0.40 g) in N,N-dimethylformamide (1.5 mL) was added phosphorus oxychloride (0.23 g) at 80° C. and the mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, a sodium hydroxide aqueous solution (1 mol/L, 5 mL) was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (0.42 g).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].C1C=CC=CC=1.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH2:6]
Reactant: CC(C)c1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: CC(C)c1cccc(Br)c1N
Reaction time: 2 h

Procedure:
To o-isopropylaniline in 4 l. benzene (0.74 mol, 100 g) was added 131.7 g (0.74 mol) NBS all at once. There was an exotherm to 35° C. Material was stirred two hours, then let stand overnight. The volume was reduced by three-quarters, and solid removed by filtration. Benzene was then removed from the filtrate, pentane added with ice, followed by 40 ml acetic anhydride. After ca. 15 minutes, solid was filtered off, pentane solution separated from filtrate, washed with ammonia water. After evaporation of pentane, oil was distilled 83° C. (0.25 mm) to give 64.5 g of 2-bromo-6-isopropylaniline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: C[C@H](N)c1cccc(F)c1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(F)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-chloro-3-fluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 504 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[N+:2]=[N-:3].[OH-].[Na+]>CO>[N:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: COC(=O)CCCN=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NCCCC(=O)O

Procedure:
Methyl 4-azidobutanoate was suspended in 1N NaOH (1.2 eq) and the minimum of MeOH was added to make the reaction mixture homogenous. After 1 h at RT temperature, MeOH was removed in vacuo. The aqueous solution
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH:23]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:3](=[O:4])[C:2](=[O:1])[C:6]4[N:14]5[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]5)=[CH:8][C:7]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)[CH:23]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
Oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 40 g, 0.14 mol) was added portion-wise to a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94, 18 g, 63.8 mmol) in pyridine (150 mL). The reaction mass was stirred for 1 hour then quenched slowly into cold water (3 L). The precipitated solid was filtered and washed with water (3×50 mL). The solid was dissolved in chloroform (200 mL) and washed successively with bicarbonate solution (3×200 mL) and brine (200 mL). The chloroform layer was separated, diluted with chloroform (800 mL), and to this was added neutral alumina (150 g) and charcoal (5 g). The mixture was stirred for 2 hours at room temperature then filtered through celite. The treatment was repeated with another 75 g of neutral alumina with over night stirring. Filtration and concentration gave a solid which was dissolved in toluene (500 mL) and extracted with 25% aqueous acetic acid solution (3×500 mL). The combined aqueous layers were basified with 25% ammonium hydroxide solution (2 L) to pH ˜7 and extracted with diethyl ether (2×300 mL). The combined ether extracts were washed with bicarbonate solution (2×200 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give a solid. This was further purified by passing through a short silica pad (60-120 silica gel) eluting with 30% ethyl acetate in chloroform. After concentration, the solid was dissolved at reflux in ethanol (300 mL). The solution was cooled to 0° C., and stirred for 15 minutes, whereupon the precipitated solid was filtered and dried on the sinter. Further drying at 60° C. under high vacuum afforded the title compound N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (10.4 g, 30.5%) as a yellow powder.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=4)[CH:16]=[C:11]3[C:10]([CH3:28])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:28][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(c2)c(C)nn3Cc2ccc(OC)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a stirred solution of N-(3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acrylamide (154) (70 mg) in CHCl3 (20 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture heated at 50° C. for 12. After completion of the reaction the solvents were removed, diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform twice. The organic layer was washed with brine solution and dried over sodium sulphate and the solvent completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound in 60% EtOAc/hexane gave pale yellow solid compound N-(3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)acrylamide 155. 1H NMR (400 MHz, CDCl3) δ: 10.29 (s, H), 8.75 (d, J=2.07, 1H), 8.40 (d, J=1.95, 1H), 8.03 (s, 1H), 7.69 (s, 1H), 7.43 (m, 1H), 6.50 (m, 1H), 6.46 (m, 1H), 6.26 (m, 1H), 2.55 (bs, 3H); MS m/z 277.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Br)ccc1N1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
Dissolve 1-(4-bromo-2-methoxy-phenyl)-piperazine (7.0 g, 25.8 mmol) and acetic acid (5.9 mL, 103.2 mmol) in methanol (500 mL) and add aqueous formaldehyde (37%, 5.3 mL). After 5 min, add sodium cyanoborohydride (4.05 g, 64.5 mmol) and stir the mixture at room temperature overnight. Concentrate the reaction mixture in vacuo and partition between dichloromethane (200 mL) and 1 N sodium hydroxide (200 mL). Separate the organic portion and extract the aqueous portion with dichloromethane (2×100 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo to afford 7.1 g (96%) of the title compound. MS/ES m/z (79Br) 285.0 [M+H]−.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][CH:3]=1.[CH2:10]([O:17][CH2:18][CH:19]=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[Cl-]>C1COCC1>[CH2:10]([O:17][CH2:18][CH:19]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCOCc1ccccc1
Reactant: Clc1nc(Br)ccc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)c1ccc(Br)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
6-Bromo-2-chloro-3-iodopyridine (1.50 g, 4.71 mmol) was dissolved in THF (15 mL) and cooled to −78° C., followed by addition of isopropylmagnesium chloride-lithium chloride complex (3.99 mL, 5.18 mmol). The mixture was stirred at −78° C. for 1 h. 2-(benzyloxy)acetaldehyde (0.849 g, 5.65 mmol) was added and the resulting mixture warmed to 0° C. and stirred for 2 h. The mixture was treated with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to gave 2-(benzyloxy)-1-(6-bromo-2-chloropyridin-3-yl)ethanol (1.54 g, yield: 95%). MS (M+H)+: 344.
Reaction SMILES: [C:1]([O:20]CC(CO)O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.[S:26]([O-])([O:29]CCCCCCCCCCCC)(=[O:28])=[O:27].[Na+:43]>>[S:26]([O-:29])([O:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:28])=[O:27].[Na+:43]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCOS(=O)(=O)[O-]

Procedure:
Glyceryl monostearate containing sodium lauryl sulphate
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:18][C:19]1([CH3:33])[CH2:23][O:22][C:21]([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)=[N:20]1.C(N(CC)CC)C>CN(C)C=O>[O:15]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:26]3[CH:25]=[C:24]([C:21]4[O:22][CH2:23][C:19]([CH3:33])([CH3:18])[N:20]=4)[CH:29]=[CH:28][CH:27]=3)[C:12]=2[CH:13]=[CH:14]1
Reactant: O=S(=O)(Oc1cccc2occc12)C(F)(F)F
Reactant: CC1(C)COC(c2cccc(B(O)O)c2)=N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2cccc(-c3cccc4occc34)c2)=N1
Temperature: 85 °C
Yield: 69.4 %

Procedure:
A mixture of 4-trifluoromethylsulfonyloxy-benzofuran (2 g), 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyldihydroxyborane (2.14 g), tetrakis(triphenyl-phosphine)palladium(0) (0.26 g) and triethylamine (2.28 g) in N,N-dimethylformamide (40 ml) was heated at 85° C. for 3 hours under nitrogen atmosphere. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% sodium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired products were collected and evaporated in vacuo to afford 2-[3-(benzofuran-4-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.52 g).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:36][CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)[CH3:28])=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(NC3CCCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine by method L. This resulted in the product with the molecular weight of 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1)C>O1CCCC1.C(OCC)(=O)C>[C:24]([O:23][C:21](=[O:22])[N:16]([CH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][CH2:6][OH:5])[CH:9]=1)[CH2:17][CH2:18][O:19][CH3:20])([CH3:25])([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cc1cccc(CCN(CCOC)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCN(CCc1cccc(CCO)c1)C(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
2M Lithium borohydride in tetrahydrofuran solution (0.7 mL) was added to a solution of (3-{2-[tert-butoxycarbonyl-(2-methoxy-ethyl)-amino]-ethyl}-phenyl)-acetic acid ethyl ester (230 mg) in tetrahydrofuran (10 mL) and heated to reflux for 1 hour. On cooling, the reaction was diluted with ethyl acetate and extracted sequentially, twice with saturated aqueous sodium bicarbonate solution, once with brine, dried over magnesium sulfate and evaporated, to give the subtitle compound as an oil (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:10]=3[NH:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[N:14]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:10]=3[NH:11][C:12](=[S:32])[C:13]([CH3:16])([CH3:15])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)C(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)C(=S)N2

Procedure:
A round bottomed flask was charged with 5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one (324 mg, 0.973 mmol) and a stir bar. Toluene (20 mL, 0.05 M) was added, followed by Lawesson's Reagent (217 mg, 0.535 mmol, 0.55 equiv), and the solution stirred at reflux 4 h. The solution was concentrated and purified by column chromatography (eluting with hexanes/ethyl acetate) to yield 5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-thione as a yellow amorphous solid (m/z=349) that was used in the subsequent reaction.