Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][N:19]=1)(=[O:16])=[O:15]>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:23]=[C:22]([CH:24]([CH:1]2[CH2:3][CH2:2]2)[OH:25])[C:21]([S:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[CH:20][N:19]=1)(=[O:16])=[O:15]
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(C(O)C2CC2)c(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A solution of cyclopropylmagnesium bromide (0.5 M, 1.55 ml, 0.78 mmol) was added to a stirred solution of 2,4-dichloro-N-{4-formyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide (130 mg, 0.22 mmol) in THF (15 ml) and the mixture stirred for 2 hours. The reaction was concentrated under reduced pressure onto silica and the residue purified by flash column chromatography using ethyl acetate 1/1 hexane as eluent to afford 2,4-dichloro-N-{4-(cyclopropyl-hydroxy-methyl)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide as a green foam (74 mg, 54%). 1H NMR (CDCl3): 8.40 (1 H, s, py); 8.18 (1 H, d, Ar); 7.51 (3 H, m, py and Ar); 7.39 (1 H, s, py); 7.34 (1 H, d, Ar); 7.06 (2 H, d, Ar); 4.50 (1 H, d, CHOH); 2.89 (4 H, m, 2×CH2N pip); 1.54 (4 H, m, 2×CH2 pip); 1.34 (2 H, m, CH2 pip); 0.97 (1 H, m, CH cprop); 0.39 (4 H, m, 2×CH2 cprop).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1.[N:19]1[N:20]=[CH:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=12.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[N:19]1[N:20]=[CH:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=3)[CH2:24][C:23]=12
Reactant: c1nnc2n1CCNC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CCl)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CN2CCn3cnnc3C2)cc1

Procedure:
A solution of (S)-tert-butyl 1-(4-(chloromethyl)phenyl)ethylcarbamate (127 mg, 0.47 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (91 mg, 0.56 mmol) and DIPEA (183 mg, 1.41 mmol) in DMSO (2.3 mL) was heated at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). After separation, the aqueous phase was washed with EtOAc (2×15 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude product was used to next step without further purification.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([C:13]4[CH:18]=[C:17](Br)[CH:16]=[C:15](Br)[CH:14]=4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:21]45[CH2:38][C:25]6([CH3:39])[CH2:26][C:27]([C:30]7[CH:35]=[C:34](Br)[CH:33]=[C:32](Br)[CH:31]=7)([CH2:29][C:23]([CH3:40])([CH2:24]6)[CH2:22]4)[CH2:28]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.C1(P([C:54]2[CH:59]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:60][Si:61]([C:64]#[CH:65])([CH3:63])[CH3:62]>[Cu](I)I.C(N(CC)CC)C>[CH3:1][C:2]12[CH2:12][C:6]3([C:13]4[CH:18]=[C:17]([C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH:16]=[C:15]([C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH:14]=4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:21]45[CH2:38][C:25]6([CH3:39])[CH2:26][C:27]([C:30]7[CH:35]=[C:34]([C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH:33]=[C:32]([C:54]#[C:59][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH:31]=7)([CH2:29][C:23]([CH3:40])([CH2:24]6)[CH2:22]4)[CH2:28]5)([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC12CC3(C)CC(c4cc(Br)cc(Br)c4)(C1)CC(C14CC5(C)CC(C)(CC(c6cc(Br)cc(Br)c6)(C5)C1)C4)(C2)C3
Reactant: C#C[Si](C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC12CC3(C)CC(c4cc(C#C[Si](C)(C)C)cc(C#C[Si](C)(C)C)c4)(C1)CC(C14CC5(C)CC(C)(CC(c6cc(C#C[Si](C)(C)C)cc(C#C[Si](C)(C)C)c6)(C5)C1)C4)(C2)C3
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
Next, 50 g (62.9 mmol) of the previously obtained 3,3′,5,5′-tetramethyl-7,7′-bis(3,5-dibromophenyl)-1,1′-biadamantane, 3.53 g (5.0 mmol) of dichlorobistriphenylphosphinepalladium, 6.60 g (25.2 mmol) of triphenylphosphine, 4.79 g (25.2 mmol) of copper(II) iodide and 750 ml of triethylamine were added to a flask and stirred. The mixture was raised to 75° C., and then 37.1 g (377.7 mmol) of trimethylsilylacetylene was slowly added. After stirring at 75° C. for 7 hours, the temperature was raised to 120° C. to remove the triethylamine. After returning to room temperature, 1000 ml of dichloromethane was added to the reaction mixture and stirring was continued for 20 minutes. The precipitate was removed by filtration, and 1000 ml of a 5% hydrochloric acid aqueous solution was added to the filtrate for liquid separation. The organic layer was washed three times with 1000 ml of water, and then the solvent of the organic layer was removed under reduced pressure. The obtained compound was dissolved in 1500 ml of hexane. The insoluble portion was removed by filtration and the hexane in the filtrate was removed under reduced pressure. After introducing 1000 ml of acetone thereinto, the precipitate was washed 3 times with acetone to obtain 43 g of 3,3′,5,5′-tetramethyl-7,7′-bis[3,5-bis(trimethylsilylethynyl)phenyl]-1,1′-biadamantane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:23]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:21]([O:20][CH3:19])[CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC)c(OC)c1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (89 mg, 0.3 mmol) was treated with 3,4-dimethoxy-aniline following general procedure B to afford 4-(3,4-dimethoxy-phenylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (103 mg). Thus obtained amino-ester (38 mg, 0.1 mmol) was subjected to reaction with ethyl isocyanate (0.5 mmol) according to general procedure C to furnish 1-(3,4-dimethoxy-phenyl)-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (23 mg). LCMS: m/z 408 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.64 (s, 1H), 7.11 (m, 2H), 7.00 (s, 1H), 6.91 (m, 2H), 6.60 (s, 1H), 4.20 (q, 2H), 4.09 (s, 3H), 3.99 (s, 3H), 3.86 (s, 3H), and 1.37 (t, 3H) ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]=[CH:13][C:14]([OH:16])=O.[NH2:22][C:23]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:13]/[C:14]([NH:22][C:23]2[CH:35]=[C:34]([CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C(=O)Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h

Procedure:
1.0 mL of Methylene chloride, 0.010 mL of N,N-dimethylformamide and 0.064 mL of oxalyl chloride were added to 0.13 g of 3,4-dimethoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 1.5 mL of methylene chloride and 0.14 mL of triethylamine containing 0.15 g or tert-butyl 2-amino-4-phenethylbenzoate while ice-cooled and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and ethyl acetate and 10% critic acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed, with 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=4:1] to obtain 0.12 g of tert-butyl 2-((E)-3-(3,4-dimethoxyphenyl)acrylamido)-4-phenethylbenzoate as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
3.04 g (9.9 mmol) of the compound of Example 4A were dissolved in 100 ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a small spatula tip of potassium iodide were added. The reaction mixture was heated at reflux for 1 h, allowed to cool to RT and filtered. The filtrate was freed from the volatile components on a rotary evaporator and the residue was dried under high vacuum. This gave 3.70 g of the title compound in a purity of about 90% (89% of theory).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH3:19][O-].[Na+].C(OC(=O)[CH:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27])C>C1(C)C=CC=CC=1>[CH2:29]([N:28]([CH2:26][CH3:27])[CH2:31][CH2:32][C:19]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1)[CH3:30]
Reactant: C[O-]
Reactant: CCOC(=O)C(C)N(CC)CC
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 87 %

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 6.4 g. of diethylamino propionic acid ethyl ester and 100 cm3 of toluene are reacted according to Example a. 6.3 g. (87% yield) of 7-[{5-(2-diethylamino-ethan-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline are obtained. M.p.: 69°-70° C. (cyclohexane).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[CH3:20][S:21][CH2:22]Cl>CN(C=O)C>[F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5](=[O:8])[N:6]([CH2:20][S:21][CH3:22])[CH:7]=1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CSCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCn1cc(F)c(N=CN(C)C)nc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.7 %

Procedure:
A 250 mL round bottom flask was charged with N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (1.00 g, 5.43 mmol) and DMF (55 mL) to give a white suspension. Solid potassium tert-butoxide (1.07 g, 9.53 mmol) was added, and the resulting pale yellow suspension was allowed to stir under nitrogen at room temperature for 20 min. Chloromethyl methyl sulfide (682 microliters (μL), 8.14 mmol) was then added, and the mixture was heated at 60° C. for 21 h. The crude reaction mixture was concentrated in vacuo at 55° C. to give an off-white residue which was purified by reverse phase column chromatography yielding N′-(5-fluoro-1-methylsulfanylmethyl-2-oxo-1,2-dihydropyrimidin-4-yl)-N,N-dimethylformamidine (36 mg, 25%) as a pale yellow solid: mp 132-136° C.; 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.20 (d, J=3.2 Hz, 1H), 5.40 (s, 2H), 3.19 (s, 3H), 3.07 (s, 3H), 2.20 (s, 3H); IR 2960 (w), 2926 (w), 1640 (s), 1582 (s), 1447 (s), 1382 (m), 1319 (m), 1269 (m), 1108 (m), 1051 (m) cm−1; ESIMS m/z 267 ([M+Na]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14]CC)=O)=[C:7](O)[CH2:6][CH2:5]2.[NH2:18][C:19]([NH2:21])=[NH:20]>>[NH2:20][C:19]1[NH:21][C:12](=[O:14])[C:8]2[C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[CH2:5][CH2:6][C:7]=2[N:18]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1=C(O)CCc2cc(Br)ccc21
Product: Nc1nc2c(c(=O)[nH]1)-c1ccc(Br)cc1CC2

Procedure:
Ethyl 6-bromo-3,4-dihydro-2-hydroxy-1-naphthoate (6.0 g, 20.2 mmoles) was reacted with guanidine (6.9 g of hydrochloride salt, 72.2 mmoles) in the same manner as in example 1. The product was precipitated from aqueous sodium hydroxide with acetic acid, filtered, washed with water and dried to give 3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one as an off-white solid. (2.75 g, 46%) 1H NMR (DMSO-d6, 300 MHz) δ: 2.55 (t, J=7.5 Hz, 2H, CH2); 2.79 (t, J=7.4 Hz, 2H, CH2); 6.75 (br s, 2H, NH2); 7.32 (dd, J=8.4, 2.3 Hz, 1H, Ar); 7.34 (s, 1H, Ar); 8.40 (d, J=8.4 Hz, 1H, Ar); 11.00 (br s, 1H, NH).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[CH3:16]O>[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(O)/C=C/c1ccc2ccccc2n1
Reactant: CO
Agent: [Pd]
Product: COC(=O)CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of methyl (E)-3-(2-quinolinyl)-2-propenoate (2) (0.26 g 1.22 mmol) in methanol (5 ml), 5% palladium on activated carbon (0.05 g) was added and the resulting suspension was hydrogenated by vigorous stirring for 2 hours at room temperature. The reaction mixture was filtered through a short column of silica gel (ca. 2 g), the column was washed with methanol (3 ml), and the filtrate was evaporated in vacuo. The residue (0.270 g) was chromatographed on silica gel (10 g) with chloroform-ethyl acetate (9:1) as eluent to afford the title compound (0.111 g, 43%) as an oil. 1H NMR (CDCl3, HMDSO), δ: 2.93 (2H, t, J=7.2 Hz); 3.29 (2H, t, J=7.2 Hz); 3.67 (3H, s); 7.29-7.85 (4H, m); 7.89-8.11 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:39])[NH:29][C:30]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:32][CH2:31]3)[CH:25]=[CH:24][C:23]=2[CH3:40])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)CCl.CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([NH:1][S:48]([CH3:47])(=[O:50])=[O:49])[C:21]([C:22]4[CH:27]=[C:26]([C:28](=[O:39])[NH:29][C:30]5([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)[CH2:32][CH2:31]5)[CH:25]=[CH:24][C:23]=4[CH3:40])=[CH:20][C:5]=3[C:6]=2[C:16]([NH:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Solvent: ClCCCl
Solvent: CO
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Reaction time: 22 h

Procedure:
To a mixture of 6-amino-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide (53.3 mg, 0.100 mmol) (crude) in C1CH2CH2Cl (1 ml) at r.t. under N2 was added pyridine (0.024 mL, 0.300 mmol). The mixture was then added a solution of methanesulfonyl chloride (22.88 mg, 0.200 mmol) in C1CH2CH2Cl (0.3 ml), and stirred for about 22 hours. The mixture was diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.75-7.37 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, J=8.85, 5.19, 2H), 7.85 (dd, J=8.09, 1.98, 1H), 7.79 (s, 1H), 7.75 (d, J=1.53, 1H), 7.51 (s, 1H), 7.47 (d, J=7.93, 1H), 7.17 (m, 1H), 7.30-7.26 (overlapping m, 5H), 7.29 (s, 1H), 2.93 (s, 3H), 2.88 (s, 3H), 2.23 (s, 3H), 1.35 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=612.34, HPLC Rt=1.583 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=7.48 min; Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=6.24 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl, Rt=11.46 min.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[CH2:16]([N:15]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Ethyl bromoacetate (19.52 mL, 176 mol) was added in a single portion to a chilled (0° C.) solution of dibenzylamine (33.84 mL, 176 mmol) and triethylamine (27 mL, 193.6 mmol) in THF. The reaction mixture was stirred overnight at ambient temperature. Additional triethylamine (30 mL) and THF (100 mL) were added and the reaction mixture was heated at 50° C. for 1.5 hours. Additional ethyl bromoacetate (13 mL) was added and the reaction mixture was heated for 1 hour and then stirred at ambient temperature overnight. About half of the THF was removed under reduced pressure. The mixture was diluted with water (300 mL) and then extracted with ethyl acetate (2×400 mL). The combined extracts were washed sequentially with water and with brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (700 g of silica gel, eluting with 20% ethyl acetate in hexanes) to provide 37.12 g of ethyl dibenzylaminoacetate as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:1]([N:3]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:2]
Reactant: CCNc1cccc2ccccc12
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(CC)c1cccc2ccccc12
Temperature: 25 °C
Yield: 32.1 %

Procedure:
N-Ethyl-1-naphthylamine 8 (11.4 gm, 0.066 moles), diisopropylethylamine (11.2 gm, 0.087 moles), and ethyl 4-bromobutyrate (19 gm, 0.097 moles) were heated at 110-120° C. for 16 hours under argon at which time, HPLC indicated the reaction was complete. The mixture solidified upon cooling to room temperature. The solid was partitioned between DCM and water. The aqueous layer was extracted with two portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over MgSO4, filtered, concentrated under reduced pressure by rotary evaporation to give 22 gm of a crude solid. The solid was purified by flash chromatography, eluting with ethyl acetate and hexane, to give ethyl 4-(ethylnaphthylamino)butanoate 9 (6.04 gm, 32% yield) as an orange oil. 1H NMR (CDCl3) δ 8.3, 1H, m; 7.8, 1H, m; 7.35-7.55, 4H, m; 7.15, 1H, m; 4.05, 2H, q; 3.18, 4H, m; 2.32, 2H, t; 1.8, 2H, m; 1.20, 3H, t; 1.05, 3H, t.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[N:15]1([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O.C(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([S:2]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:26][CH:25]=2)(=[O:5])=[O:3])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1Br
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Temperature: 25 °C

Procedure:
To stirred, cold (0 C) chlorosulfonic acid was added 1-bromo-2-methoxy-benzene (1 g) dropwise. The mixture was then allowed to warm to room temp and was stirred for 1 h. The mixture was then cooled again (0 C) and ice was added carefully until no further effervescence was seen. This was further diluted with water and extracted with DCM. The dried extracts were evaporated giving a pale yellow gum. This material was then dissolved in DCM (15 ml) and was treated with 4-morpholin-4-yl-phenylamine (1.43 g) and was stirred for 18 h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with DCM then DCM:EtOH:NH3; 800:8:1 and finally 400:8:1 gave an off-white solid (1.4 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ncc(Cl)cn1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(C(F)(F)F)nc2)CC1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
0.26 mmol 5-Chloro-2-trifluoromethyl-pyrimidine was added to 0.26 mmol piperazine-1-carboxylic acid tert-butyl ester in 1.5 ml dimethylacetamide, and the reaction mixture was stirred at 150° C. for 10 min. in a microwave oven. After such time, the reaction mixture was concentrated and the residue was then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound. MS (m/e): 333.2 (M+H+, 100%)
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[S:5]1[CH:9]=[CH:8][CH:7]=C1CC(O)=O.ClCCC[Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>S1C=CC=C1C(O)=O.C(O)C>[C:2]([S:5][CH2:9][CH2:8][CH2:7][Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])(=[O:1])[CH3:3]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: O=C(O)Cc1cccs1
Reactant: CC[O-]
Agent: O=C(O)c1cccs1
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCSC(C)=O)(OCC)OCC
Temperature: 25 °C
Yield: 78 %

Procedure:
This example illustrates the preparation of a thiocarboxylate alkoxysilane from a salt of a thiolcarboxylic acid using as a solvent the alcohol corresponding to the silane alkoxy group. Into a 250 ml, three-neck round bottomed flask equipped with magnetic stir bar, temperature probe/controller, heating mantle, addition funnel, condenser, and N2 inlet was charged 63 grams of a 21 weight percent sodium ethoxide in ethanol. Fifteen grams of thiolacetic acid was added slowly, keeping the temperature below 65° C. The solution was allowed to cool to room temperature, and 48 grams of chloropropyltriethoxysilane was added via the addition funnel. After addition was complete, the solution was heated to 70° C. for 24 hours whereupon a white solid formed. Analysis of the solution by gas chromatography showed a 78 percent yield of 3-(acetylthio)-1-propyltriethoxysilane.