Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:36][C:37](Cl)=[O:38].C(N(CC)CC)C.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>CC(N(C)C)=O.C(OCC)(=O)C>[C:32]([C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37](=[O:38])[CH2:36][N:51]4[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]4)[S:3][C:4]=3[C:10]=2[N+:11]([O-:13])=[O:12])[CH:16]=1)=[O:34])([CH3:30])[CH3:31])#[N:33]
Reactant: CN1CCNCC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])c2)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)c([N+](=O)[O-])c3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a solution of N-{3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.32 mmol) produced in Example 37(ii) in dimethylacetamide (2 mL) was added chloroacetyl chloride (55 μL, 0.70 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (3 mL). Triethylamine (130 μL, 0.95 mmol) and 1-methylpiperazine (105 μL, 0.95 mmol) were added to the mixture, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL), washed successively with water (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→15/85), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to give the title compound (162 mg, 84%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([CH2:18][CH2:19][CH:20]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[C:21]([O:23]C)=[O:22])[C:14]([O:16]C)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[K+].O.Cl>C(O)C>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([CH:20]([CH2:19][CH2:18][CH:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:14]([OH:16])=[O:15])[C:21]([OH:23])=[O:22])[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COC(=O)C(CCC(C(=O)OC)c1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(CCC(C(=O)O)c2cc(OC)c(OC)c(OC)c2)C(=O)O)cc(OC)c1OC
Yield: 97 %

Procedure:
A mixture of dimethyl α,α'-bis(3,4,5-trimethoxyphenyl)adipate (11.0 g, 21.7 mmoles), potassium hydroxide (13.0 g, 202 mmoles), water (163 ml), and ethanol (65 ml) was heated at 90° in a nitrogen atmosphere for 3 hours. After cooling the clear solution was added slowly to 250 ml of 1N hydrochloric acid with vigorous stirring. The slurry was stirred and warmed to 50° for several minutes. After cooling in an ice bath the solid was filtered, washed with water (4 times) and dried to give 10.07 g (97%) of α,α'-bis(3,4,5-trimethoxyphenyl)adipic acid, m.p. 226°-223°. NMR (DMSO-d6) indicates a 9:1 mixture of meso and racemic isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH:8]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccccc1CBr
Reactant: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)N(C)c3ccc(Cl)cc32)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
(Z)-7-Chloro-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (0.2 g, 0.635 mmol) was dissolved in dry THF (5 mL) under nitrogen and cooled to −78° C. Potassium tert-butoxide (86 mg, 0.762 mmol) was added as a solid in two portions with rapid stirring. The mixture instantly colored and rapidly turned deep red. After 5 min, 2-chlorobenzyl bromide (107 μL, 0.836 mmol) was added dropwise by syringe. The mixture was allowed to stir at −78° C. for 1 h under nitrogen. It turned a light brown color. TLC (1:1 hexanes:ethyl acetate) indicated no starting material remained with a major less polar product and a minor more polar product plus some residual 2-chlorobenzylbromide. The reaction was quenched cold by adding ˜2 mL 1:1 methanol:water. A yellow precipitate formed. The cold bath was removed and the mixture was allowed to warm to room temperature. Water and ethyl acetate were added. The organic layer was separated and washed one time with brine then dried over magnesium sulfate, filtered and the solvent evaporated. Chromatography on a 10 g silica gel eluting with a gradient of 30-50% ethyl acetate in hexanes gave (Z)-7-chloro-3-(2-chlorobenzyl)-5-(4-methoxyphenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one as a yellow oil (232 mg, 0.528 mmol, 83%). 1H NMR (300 MHz, CDCl3) δ 3.37 (s, 3H), 3.6-3.75 (m, 2H), 3.79-3.86 (m, 1H), 3.81 (s, 3H), 6.85 (d, J=9 Hz, 2H), 7.1-7.6 (m, 9H); ESI m/z 439.6 [M+H+].
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:24]=[CH:25][C:26]([F:27])=[C:18]([F:17])[CH:19]=2)[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(F)c(F)c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,4-difluorobenzoic acid
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH:19]([O-:21])=O.[Na+].C([O-])(=O)C.[NH4+:27]>CN(C)C=O.O>[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:27]=[CH:19][O:21][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C[O-]
Reactant: [NH4+]
Reactant: O=C(CBr)c1ccccc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccccc2-c2cocn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A mixture of 2-bromo-1-(2-benzyloxyphenyl)ethanone (J. Med. Chem., 35:3045, 1992; 10.0 g, 32.77 mmol) and sodium formate (4.46 g, 65.6 mmol) in dry dimethylformamide (100 ml) is stirred at room temperature overnight. The mixture is poured into water (400 ml) and extracted with dichloromethane (2×100 ml). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure. The residue is dissolved in acetic acid (100 ml), treated with ammonium acetate (12.62 g, 163.7 mmol), and the mixture is heated for 3 hours. After cooling, the mixture is diluted with water (400 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers are washed with saturated aqueous sodium bicarbonate solution (2×100 ml), dried over sodium sulfate, and concentrated in vacuo. 4-(2-Benzyloxyphenyl)oxazole (1.99 g, 24%) is obtained after chromatography (silica gel, dichloromethane).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.OO>>[CH:1]1([NH:7][S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1nc2ccccc2s1
Reactant: NC1CCCCC1
Agent: OO
Product: c1ccc2sc(SNC3CCCCC3)nc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Example 1 of DE-A-31 27 193 was reworked: in a 250 ml glass reactor, 59.9 g of 50% strength aqueous cyclohexylamine and 0.1 mol of 2-mercaptobenzothiazole were heated to 85° C. with vigorous stirring, with the resulting cyclohexylamine salt of 2-mercaptobenzothiazole going largely into solution. After the mixture had been cooled to 45° C., 92 g of 5% strength hydrogen peroxide (0.135 mol) were metered in over the course of 60 min with vigorous stirring. Stirring was continued for 30 min at the same temperature, and then the reaction mixture was cooled to room temperature, and the precipitate was filtered off, washed with 10% strength cyclohexylamine solution and water, and dried. Cyclohexylbenzothiazolylsulphenamide was obtained in a yield of 75.6% of theory (melting point 99°-100° C.; purity (Lichty titration) 97.6%).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH:22]=[C:21]([C:30]([OH:32])=O)[CH:20]=2)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[CH3:50][C@H:51]([NH2:59])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:50][C@@H:51]([NH:59][C:30]([C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=1)=[O:32])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: C[C@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3nccs3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3nccs3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion at 0° C. to a solution of 4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (63 mg, 0.214 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.0 mmol) in CH2Cl2 (3 mL). After the reaction stirred at 0° C. for 1 hour, (S)-1-Methyl-2-morpholin-4-yl-ethylamine (50.0 mg, 0.230 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to afford (R)-4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)-amide as a white solid (72 mg, 81%). MS (M+H)=422.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:28][CH2:27][C:26]([N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:30])[CH3:29]
Reactant: COCCNC(C)(C)CO
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)CO

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-(2-methoxyethylamino)-2-methylpropan-1-ol (CAN 1156380-97-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=414.4 [MH+].
Reaction SMILES: C(SC=C)=C.C1C(I)=[C:10]([OH:13])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.FC1C=CC(S[C:49]2([C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([O:68][C:69](=[O:74])[C:70]([CH3:73])([CH3:72])[CH3:71])[CH:63]=3)[C:52]3([CH:59]4[CH2:60][CH:55]5[CH2:56][CH:57]([CH2:61][CH:53]3[CH2:54]5)[CH2:58]4)[O:51][O:50]2)=CC=1.O1CCO1>CO>[CH3:10][O:13][C:49]1([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([O:68][C:69](=[O:74])[C:70]([CH3:73])([CH3:71])[CH3:72])[CH:63]=2)[C:52]2([CH:53]3[CH2:54][CH:55]4[CH2:56][CH:57]([CH2:58][CH:59]2[CH2:60]4)[CH2:61]3)[O:51][O:50]1
Reactant: CC(C)(C)C(=O)Oc1cccc(C2(Sc3ccc(F)cc3)OOC23C2CC4CC(C2)CC3C4)c1
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: C1COO1
Agent: C=CSC=C
Agent: O=O
Solvent: CO
Product: COC1(c2cccc(OC(=O)C(C)(C)C)c2)OOC12C1CC3CC(C1)CC2C3
Temperature: 25 °C

Procedure:
The vinyl sulfide of Example 4(a) (0.051 g) was irradiated in 20 mL of CH3OH containing ca. 1 mg of Rose Bengal with continuous oxygen bubbling at -78° C. using a 1000 W Na lamp. When the alkene was shown by TLC to be completely consumed, iodine (0.096 g) and 1 mL of 30% H2O2 were added and the mixture warmed to room temperature. Progress of the reaction was monitored by the disappearance of dioxetane 4 by TLC (20% ethyl acetate in hexane) and the appearance of new bands which emitted blue light when the plate was heated and by observing the color of chemiluminescence from an aliquot of the reaction solution reacted with 0.1 M TBAF in DMSO. The yellow emission of dioxetane 4 was gradually replaced by the blue emission of dioxetane 20 over a period of two hours. The solution was concentrated to 1-2 mL and separated on preparative TLC with 5% ethyl acetate in hexane. The band containing dioxetane 20 was collected and desorbed and evaporated to yield the product as a slightly yellow oil: 1H NMR (CDCl3) δ1.02 (m, 1H), 1.28 (m, 1H), 1.375 (s, 9H), 1.45-1.94 (m, 10H), 2.17 (br s, 1H), 3.04 (br s, 1H), 3.232 (s, 3H), 7.07-7.49 (m, 4H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[C:10]([C:13]#[N:14])=[N:11][CH:12]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=2)[C:10]([C:13]#[N:14])=[N:11][CH:12]=1
Reactant: COc1ccc(CNc2cnc(C#N)c(Nc3cc(C)cc(C)n3)c2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(Nc2cc(N)cnc2C#N)c1
Reaction time: 0.17 h

Procedure:
To a suspension of 5-[(2,4-dimethoxybenzyl)amino]-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (240 mg, 0.62 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.96 mL, 12.5 mmol) dropwise, and the reaction mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-65% ethyl acetate/hexanes, linear gradient) to afford 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile. MS ESI calc'd for C13H14N5 [M+H]+ 240. found 240. 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 6.25 (s, 2H), 2.28 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl>[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
To a solution of 10 (1.06 g, 2.46 mmol) in 30 mL of CH2Cl2 was added triethylamine (0.62 mL, 4.45 mmol). 4-Toluenesulfonyl chloride (TsCl, 567 mg, 2.97 mmol) was added to this solution in one portion at 0° C., and the mixture was stirred at under Ar for 24 h allowing it to warm to room temperature slowly. The reaction was quenched by pouring into a mixture of water (100 mL) and chloroform (70 mL), separated organic layer, and the aqueous layer was further extracted with chloroform (100 mL). The combined organic layers were dried over sodium sulfate (Na2SO4) and concentrated. The crude product was chromatographed (SiO2, gradient, hexane/EtOAc 5:1 to 2:1) to give 1.08 g (1.85 mmol, 75%) of 11 as a clear colorless oil. Rf 0.65 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.79 (d, 2H, J=8.3 Hz, H-2 of tosyl), 7.68 (m, 4H, H-2 of phenyl), 7.44-7.35 (m, 6H, H-3 and H-4 of phenyl), 7.32 (d, 2H, J=8.7 Hz, H-3 of tosyl), 4.14 (t, 2H, J=4.9 Hz, TsOCH2CH2), 3.80 (t, 2H, J=5.3 Hz, CH2OSi), 3.66 (t, 2H, J=4.9 Hz, TsOCH2CH2), 3.64-3.54 (m, 10H, (OCH2CH2)2OCH2CH2OSi), 2.43 (s, 3H, CH3 of tosyl), 1.04 (s, 9H, C(CH3)3); MS (ESI) Calcd for C31H42O7SSiNa (M+Na+): 609.2. Found: 609.2.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:23])[CH3:22])[CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Cl
Reactant: Fc1nccnc1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nccnc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-fluoro-3-(piperidin-4-yl)pyrazine (0.311 g, 1.716 mmol) dissolved in DCM (5 mL) was added triethylamine (0.286 mL, 2.06 mmol), then acetyl chloride, reagent grade (0.134 mL, 1.89 mmol). The reaction mixture was stirred at RT for 1 h then partitioned between DCM and water. The aqueous layer was extracted with DCM (3×) and the combined organic layer was washed with brine, dried (Na2SO4) and concentrated to give 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone as a yellow oil. MS (ESI, pos. ion) m/z: 224.0 (M-56).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:38])=[C:16]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][C:25]=2[NH:33][CH2:34][C:35](O)=[O:36])(=[O:20])=[O:19])[CH:17]=1)#[N:11].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.C(N(CC)CC)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:38])=[C:16]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][C:25]=2[NH:33][CH2:34][C:35]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])(=[O:19])=[O:20])[CH:17]=1)#[N:11]
Reactant: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(NCC(=O)O)c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)CNc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
To a stirred solution of 0.11 g of ethyl 3-aminopropionate hydrochloride in 10 mL of N,N-dimethylformamide were added 0.072 ml of triethylamine, 0.30 g of [[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]amino]acetic acid, and 0.121 g of 1-hydroxybenzotriazole monohydrate under ice-cooling, and the mixture was stirred at 5minutes. To the mixture was added 0.140 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride under the same condition, and the mixture was stirred at room temperature for 7 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.278 g of ethyl 3-[2-[[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]amino]acetylamino]propionate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1
Reactant: Oc1ccccc1Br
Reactant: CN1CCC(OS(C)(=O)=O)C1
Product: CN1CCC(Oc2ccccc2Br)C1

Procedure:
The title compound was prepared from 2-bromophenol and 1-methylpyrrolidin-3-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].[C:8](OCC)(=[O:13])[CH2:9][C:10]([CH3:12])=O.[OH-].[K+]>C(O)C.Cl.CO>[CH2:1]([N:4]1[C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[NH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(N)=O
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: C=CCn1c(=O)cc(C)[nH]c1=O
Reaction time: 288 h

Procedure:
To allylurea (25 g, 0.25 mol) in ethanol (10 mL) was added ethyl acetoacetate (31.86 mL, 0.25 mol) and 10 drops conc. HCl. After 12 days at room temperature, concentration gave an oil which was dissolved in MeOH. KOH (22.5 g, 0.34 mol) was added and the solution refluxed for 1 hour. After neutralization, the resulting solid 1 was collected. Yield 2.7 g (7%). NMR (CDCl3) δ: 2.16 (3H, s), 4.52 (2H, d), 5.18 (1H, d), 5.23 (1H, d), 5.60 (1H, s), 5.82-5.93 (1H, m), 10.3 (1H, s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:18]([NH:26][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 100 °C

Procedure:
To a stirred solution of 1-fluoro-2-nitrobenzene (14.1 g, 0.1 mol) and triethylamine (14 ml, 0.1 mol) in DMF (150 ml) was added phenethylamine (12.1 g, 0.1 mol). The mixture was now heated to 100° C., and the reaction was monitored by TLC. After the reaction was completed (2 h) the solvent was removed by evaporation in vacuo. The residue was partitioned between 0.5N aqueous HCl (100 ml) and ether (100 ml). The organic phase was washed with water, dried and evaporated to give the title compound as a yellow oil.
Reaction SMILES: C(O[CH:5]1[CH:9]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH:7]([O:19][CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[O:6]1)(=O)C.[CH3:29][O:30][C:31]([C:33]1[N:37]=[CH:36][NH:35][N:34]=1)=[O:32].[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>>[CH3:29][O:30][C:31]([C:33]1[N:37]=[CH:36][N:35]([CH:5]2[CH:9]([O:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:8][CH:7]([O:19][CH2:20][P:21]([O:23][CH2:24][CH3:25])([O:26][CH2:27][CH3:28])=[O:22])[O:6]2)[N:34]=1)=[O:32]
Reactant: CCOP(=O)(COC1CC(OC(=O)c2ccccc2)C(OC(C)=O)O1)OCC
Reactant: COC(=O)c1nc[nH]n1
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Product: CCOP(=O)(COC1CC(OC(=O)c2ccccc2)C(n2cnc(C(=O)OC)n2)O1)OCC
Yield: 65 %

Procedure:
Benzoic acid 2-acetoxy-5-(diethoxy-phosphorylmethoxy)-tetrahydro-furan-3-yl ester (170 mg, 0.4 mmol), 1H-[1,2,4]Triazole-3-carboxylic acid methyl ester (51 mg, 0.4 mmol) and Bis-(p-nitrophenyl)phosphate were reacted according to literature procedure (J. Med. Chem. 2000, 43, 1019-1028). The desired product was isolated in 65% yield (150 mg). 1H NMR (CDCl3, 300 MHz) δ 8.60 (s, 1H), 8.00 (d, 2H, J=7.8 Hz), 7.60 (t, 1H, J=7.2 Hz), 7.45 (app t, 2H, J=7.7 Hz), 6.29 (d, 1H, J=1.5 Hz), 5.91-5.98 (m, 1H), 5.67-5.71 (m, 1H), 4.11-4.23 (m, 4H), 3.96-4.04 (m, 4H), 3.85-3.92 (m, 1H), 2.55-2.72 (m, 2H), 1.29-1.37 (m, 6H). 31P NMR (121.4 MHz, CDCl3) δ 19.8. LRMS (ESI) MH+ C20H27N3O9P requires 484.1 Found 483.8.