Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S:11]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[N:13]=[C:12]1[NH2:20]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:12]2[S:11][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1nc2c(s1)CCCC2
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2c(s1)CCCC2)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
4-Bromobenzoyl chloride (1.5 g, 6.83 mmol) and 4,5,6,7-Tetrahydro-1,3-benzothiazol-2-amine (1.054 g, 6.83 mmol) were dissolved in Pyridine (15 ml) and stirred at 50° C. for 1.5 h. The reaction mixture was cooled to room temperature and poured in water. The solid formed was filtered, washed with water. The solids were co-evaporated with toluene twice to afford 1.8 g of 4-bromo-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide (78%) as a yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[Cl:18])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:17][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([Cl:18])[C:9]=1[OH:8])[CH2:13][OH:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(CO)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a solution of 1.83 g (5.96 mmol) of the product of Step B dissolved in 6 mL of THF was added 5.96 mL (5.96 mmol) of a 1M solution of tetra-n-butylammonium fluoride in THF and the reaction mixture was stirred at room temperature 30 minutes. The solution was then evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 4% methanol/chloroform to afford 0.733 g (64%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:34][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:36])[CH2:23][O:24][P:25]([O:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])([OH:27])=[O:26])=[O:19].CCCCCCCC/C=C/CCCCCCCCOCCOP(OC[CH2:81][N+:82](C)([CH3:84])[CH3:83])([O-])=O>C(Cl)(Cl)Cl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:34][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:36])[CH2:23][O:24][P:25]([O:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])([OH:27])=[O:26])=[O:19].[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C@@H:22]([O:34][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:36])[CH2:23][O:24][P:25]([O:28][CH2:29][CH2:30][N+:82]([CH3:84])([CH3:83])[CH3:81])([O-:27])=[O:26])=[O:19]
Reactant: CCCCCCCC/C=C/CCCCCCCCOCCOP(=O)([O-])OCC[N+](C)(C)C
Agent: CCCCCCCCC=CCCCCCCCC(=O)OCC(COP(=O)(O)OCC(O)CO)OC(=O)CCCCCCCC=CCCCCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
DOPG/DOPC SUV's were prepared by dissolving 40 mg DOPG and 60 mg OOPC in chloroform and drying off the solvent under a stream of nitrogen gas. This dried film was placed under vacuum overnight to remove traces of solvent. The film was then suspended in 2 ml water with vigorous shaking and sonicated in a bath type sonicator for 30 minutes until clear, producing DOPG/DOPC SUV's at a concentration of 50 mg/ml.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14](OC)(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][CH2:9][C:10]1[O:11][CH:14]=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)COCc1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1ccc(COCc2nnco2)cc1
Yield: 49 %

Procedure:
To a mixture of 71, (2.7 g, 15 mmol) and trimethyl orthoformate (5 mL) was added p-TSA, (anhydrous, 255 mg, 1.5 mmol). The mixture was refluxed for 3 h and the excess trimethyl orthoformate evaporated under reduced pressure. The crude product was purified over a column of silica gel, eluting with 30% acetone-petroleum ether to give 72 as a colorless liquid (1.4 g), in 49% yield (two steps). 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.39-7.31 (m, 5H), 4.77 (s, 2H), 4.64 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[F:31])[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:39][CH:40]([F:42])[F:41])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[F:31])[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2cccc(F)c2C1)c1cc2cn[nH]c2cc1C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2cccc(F)c2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 70.2 %

Procedure:
Using the compound (909 mg, 2.07 mmol) of step A and 2,2-difluoroethyl trifluoromethanesulfonate (612 mg, 2.86 mmol), and according to the method of Example 241, step C, the title compound (732 mg, yield 70%) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Product: COc1ccc(C2CC(OC(C)=O)CCC2[N+](=O)[O-])cc1OC
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
6.0 g of (±)-(1SR,3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanol (compound E5) are dissolved in 40 ml of acetic anhydride and stirred for 1.5 h at 100° C. The reaction mixture is concentrated and the residual title compound of melting point 108-110° C. is used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[CH3:28])=[O:15])[CH:5]=[CH:4][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:48]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[CH2:28][Br:48])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(CBr)c1

Procedure:
A solution of methyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)methyloxy]-3-methylbenzoate (3.73 g, 9.5 mmol), benzoyl peroxide (0.02 g) and N-bromosuccinimide (1.74 g, 9.8 mmol) in carbon tetrachloride (200 ml) was heated to reflux and irradiated with a 1000 W lamp for fifteen minutes. 300 ml of water and 150 ml of dichloromethane were added. After separation of the phases once settling had taken place, the organic phase was washed twice, with 250 ml of water, and dried over magnesium sulfate. After concentration on a rotary evaporator at 40° C. under vacuum, the product obtained was purified by flash chromatography (10% CH2Cl2, 90% heptane). Its properties were as follows:
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])(C)C)[CH2:6][CH2:5][C:4](=[O:16])[O:3]1.[CH3:17][CH2:18]OC(C)=O>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH2:14][CH2:17][CH3:18])[CH2:6][CH2:5][C:4](=[O:16])[O:3]1
Reactant: CCOC(C)=O
Reactant: C[C@H]1OC(=O)CC[C@H]1NC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@@H]1CCC(=O)O[C@@H]1C

Procedure:
Data for tert-butyl (2R,3R)-2-methyl-6-oxo-tetrahydro-2H-pyran-3-ylcarbamate: m.p.=98.2-99.5° C.; Rf=0.27 (50% EtOAc in hexanes); IR (neat): 3337, 2979, 2935, 1709 (C═O), 1697 (C═O), 1527, 1250, 1171, 1059 cm−1; [α]D25+38.8 (c 1.0, CHCl3); 1H NMR (300 MHz, 293 K, CDCl3) δ 4.74 (br, 1H), 4.52 (ddd, 1H, J=12.9, 6.3, 2.4 Hz), 3.99 (m br, 1H), 2.55 (dd, 2H, J=8.1, 6.9 Hz), 2.24-2.12 (m, 1H), 1.99-1.88 (m, 1H), 1.43 (s, 9H), 1.33 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, 293K, CDCl3) δ 171.2, 155.5, 79.8, 77.4, 46.6, 28.2, 26.0, 25.5, 16.8; HRMS (EI+) calcd. for C11H19NO4 (M)+ 229.1314. found 229.1306.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11](O)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B#B>O1CCCC1>[C:1]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(Oc1ccc(C(C)(C)C)cc1)C(=O)O
Agent: B#B
Solvent: C1CCOC1
Product: CC(CO)Oc1ccc(C(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A solution of 6.6 g of 2-(p-tert-butylphenoxy)propionic acid in 25 ml of tetrahydrofuran is added dropwise to a chilled (5° C.) solution of 60 ml of 1M diborane in tetrahydrofuran. The mixture is stirred for 1 hr at 5° C. and at room temperature overnight. The mixture is poured onto 300 g of ice-water and extracted with ether. The ether extracts are dried (MgSO4) and concentrated under vacuum to give 5.5 g of product as a colorless liquid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: CN1CCN(Cc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Yield: 10 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 1-methyl-piperazine as starting materials, 25 mg (10%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.00 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.50 (s, 2 H), 2.50 (m, 4 H), 2.30 (s, 4 H), 2.10 (s, 3 H); ES-MS m/z 529.05 [M+H]+, HPLC RT (min) 2.27.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:22])=[C:15]([CH2:20][NH2:21])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:22])=[C:15]([CH2:20][NH:21][C:29]([C:28]3[N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:26]=[N:25][C:24]=3[Cl:23])=[O:30])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
To a solution of ({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (105 mg, 0.307 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (85 mg, 0.307 mmol) and HATU (117 mg, 0.307 mmol) in DMF (3 ml) was added diisopropylethyl amine (0.107 ml, 0.614 mmol) and the reaction mixture was stirred at rt for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (151 mg, 0.251 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (t, 1H), 7.95 (s, 1H), 7.39-7.46 (m, 1H), 7.34 (t, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.66 (s, 1H), 5.47 (s, 2H), 4.45 (d, 2H), 3.36 (t, 2H), 2.50 (t, 2H), 1.46 (t, 2H), 1.16-1.28 (m, 2H), 0.82 (t, 3 H), 0.73 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:37])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:56])C=1.C(OCC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)=[O:37])=[O:56])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3SCCCCCC(=O)N3CCN(C)CC3)cc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3S(=O)CCCCCC(=O)N3CCN(C)CC3)cc2)cc1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-ylthio]phenyl]benzamide (500 mg) and m-chloroperbenzoic acid (133 mg) in dichloromethane (20 ml) was stirred in an ice bath for 2 hours and the solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a syrup. The crude product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-ylsulfinyl]phenyl]benzamide (423 mg) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CCO>[CH:19]1([NH:22][CH2:2][C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CNC2CC2)c1
Reaction time: 24 h
Yield: 86.7 %

Procedure:
23.7 g of tert-butyl 3-(bromomethyl)-4-nitrobenzoate are suspended in 400 ml of EtOH and treated at 0° C. with 9.0 g of cyclopropylamine. The mixture is stirred for 24 h, concentrated, and the residue is crystallized from petroleum ether. The mother liquor is chromatographed and crystallized. 19 g of the title compound are obtained. MS (DCI) 293 (M+H).
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=CC=1>>[C:1]1([C:7]([CH:16]2[CH2:17][CH2:18][CH2:13][CH2:19]2)([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: Cc1ccccc1
Product: COC(=O)C(O)(c1ccccc1)C1CCCC1
Yield: 76.9 %

Procedure:
Using the same method as described for (1) of example 3, raw materials at equal weight were added successively. The difference was using a reaction temperature of -10-6° C. during dropuise addition of the toluene solution of 82 g of methyl phenylglyoxylate to cyclopentadiene Grignard reagent. 90 g of methyl 2-phenyl-2-cyclopentyl-2-hydroxy-acetate was obtained in 76.9% yield, nD25 1.5203, boiling point 82-5° C./0.03 mmHg. Silicagel GF 254 thin layer plate; developer: 1,2-dichloroethane, ultraviolet 254 nm fluorescence localization, main spot: Rf=0.72, without impurity spot.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:33])([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:33][C:13]([CH3:12])([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl 2,2-dimethylpropanoate (631 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 47 (23 mg, 3% yield) as an off-white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.81-0.94 (br. m, 8H), 1.12 (s, 9H), 1.17-1.38 (m, 3H), 1.64-1.72 (br. m, 2H), 1.82-2.00 (br. m, 3H), 2.09 (tt, J=12.4, 3.2 Hz, 1H), 2.72-2.89 (br. m, 2H), 6.40 (d, J=4.8 Hz, 1H), 7.41 (t, J=5.6 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 380.23 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH3:2].O[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1.C(OC(=O)C(OCC)CC1C=CC(OC(=O)CC2N=C(C3C=CC=CC=3)OC=2C)=C(CC2C=CC=CC=2)C=1)C1C=CC=CC=1>>[CH3:35][S:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])=[O:16])=[CH:7][CH:8]=2)=[CH:26][CH:27]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Oc1ccc(CO)cc1
Reactant: CCOC(Cc1ccc(C(=O)O)cc1)C(=O)OCC(Cl)(Cl)Cl
Agent: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Product: CCOC(Cc1ccc(C(=O)OCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OCC(Cl)(Cl)Cl
Yield: 47 %

Procedure:
The title compound was prepared from 4-[2-ethoxy-2-(2,2,2-trichloro-ethoxy carbonyl)-ethyl]-benzoic acid (0.032 g, 0.087 mmol) and methanesulfonic acid 4-hydroxymethyl-phenyl ester (0.018 g, 0.09 mmol) in the same manner as described for 3-{3-benzyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester. The crude product was purified by column chromatography using n-heptane/EtOAc (2:3) as the eluent to afford the title compound as a solid (0.023, 47%). 1H NMR (400 MHz, CDCl3): δ 7.96-7.98 (d, 2H), 7.47-7.49 (d, 2H), 7.33-7.35 (d, 2H), 7.27-7.29 (d, 2H), 5.33 (s, 2H), 4.68-4.81 (q, 2H), 4.15 (m, 1H), 3.65 (m, 1H), 3.32 (m, 1H), 3.08-3.15 (m, 2H), 3.13 (s, 3H), 1.13 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>C(O)(C)(C)C>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: Cc1cc(Nc2cc(-c3ccccc3)nc(Cl)n2)[nH]n1
Reactant: CC(=O)Nc1ccc(S)cc1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
The above prepared (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60 mg, 0.21 mmol) is combined with 4-acetamidothiophenol (176 mg, 1.05 mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer is washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue is purified by flash chromatography (SiO2, DCM/MeOH gradient) to afford [2-(4-acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (74 mg, 85%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[O:12][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14]
Reactant: CN(C)CCCl
Reactant: CC(=O)Nc1ccc(Cl)c(O)c1
Agent: Cl
Product: CC(=O)Nc1ccc(Cl)c(OCCN(C)C)c1
Yield: 80 %

Procedure:
The compound 24a was prepared starting from 17a and 2-dimethylamino ethyl chloride hydrochloride, following the general procedure H, as given in Example 9, in 80% yield.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:49])[CH2:21][NH:22][C:23](=[O:48])[C@H:24]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:25][C:26](=[O:43])[C@H:27]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:28]C(OC(C)(C)C)=O)=[O:15])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:50]>ClCCl>[ClH:50].[C:1]1([CH2:7][O:8][C:9]([N:11]([CH2:13][C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:49])[CH2:21][NH:22][C:23](=[O:48])[C@H:24]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH:25][C:26](=[O:43])[C@H:27]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:28])=[O:15])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCCNC(=O)CN(C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)NCC(=O)NCCNC(=O)CN(C)C(=O)OCc1ccccc1
Yield: 95 %

Procedure:
N-(N-Phenylalanylleucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)-sarcosylamino)ethyl)amidehydrochlorlde. N-(N-(N-(1,1-Dimethylethoxycarbonyl)phenylalanyl)leucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide (1.94 g, 2.8 mmol) was treated with excess hydrogen chloride in dichloromethane (25 mL) for 1 h. The solvent and excess reagent were evaporated under reduced pressure. The residue was dissolved in methanol. Evaporation of the solvent under reduced pressure gave N-(N-phenylalanylleucyl)glycine N-(2-(N-(phenylmethoxycarbonyl)sarcosylamino)ethyl)amide hydrochloride (1.67 g, 95%).