Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1.[C:34]1([CH2:40][CH2:41][SH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]3[CH2:12][S:42][CH2:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: SCCc1ccccc1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: COc1ccc(F)cc1-c1ccc2c(c1)C(CSCCc1ccccc1)=CC(C)(C)N2

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 5-fluoro-2-methoxyphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 20 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:38]Br>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([Br:38])=[CH:19][C:18]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a −78° C. solution of [(2-Benzyloxy-phenyl)-tert-butoxycarbonylmethyl-amino]-acetic acid tert-butyl ester (6.3 g, 14.7 mmol) in CH2Cl2 (100 mL) was added pyridine (1.8 mL, 22.1 mmol) followed by bromine (0.91 mL, 17.6 mmol) under an Ar atmosphere. After 30 min, the mixture was allowed to warm to room temperature and then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:4:0.2 to yield 5.9 g (79%) of 13 as a white solid. Rf=0.43 (in CH2Cl2/hexane/EtOAc=1:4:0.2); 1H NMR (300 MHz, CDCl3) δ 7.45-7.26 (m, 5H), 6.99 (m, 2H), 6.73 (m, 1H), 5.09 (s, 2H), 4.04 (s, 4H), 1.41 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.1, 151.1, 138.7, 136.6, 128.6, 127.9, 127.4, 124.1, 120.5, 117.6, 113.7, 81.2, 71.2, 54.5, 28.0; mass spectrum, calculated for C25H32BrNO5 (MH+) 506.2, Found 505.8.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][O:5][C:6]=1[CH:7]=C.I([O-])(=O)(=O)=[O:15].[Na+]>C1COCC1.O.[Os]>[CH:7]([C:6]1[O:5][N:4]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]=1[CH3:1])=[O:15]
Reactant: C=Cc1onc(C(=O)OCC)c1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Os]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1noc(C=O)c1C
Temperature: 25 °C

Procedure:
To ethyl 4-methyl-5-vinylisoxazole-3-carboxylate (3 g, 16.56 mmol) in THF (40 mL) and water (20 mL) at room temperature, was added sodium periodate (10.62 g, 49.7 mmol) and Osmium ENCAT 40 (828 mg, 0.248 mmol). The reaction mixture was stirred at room temperature over the weekend. The resulting mixture was filtered over Celite® (5 g), washing with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude material was suspended in DCM, sonicated and passed through a phase separating cartridge. The eluent was collected and the solvent removed under reduced pressure to afford the title compound;
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11](OCC)C>>[CH3:11][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][O:1]2
Reactant: CCOCC
Reactant: c1cc2c(cn1)CCCO2
Product: Cc1nccc2c1CCCO2

Procedure:
To 2.45 g (18.15 mmol) of 6-azachroman (prepared as described in Sliwa, et al., J. Het. Chem. 12:809 (1975)) in 25 ml of ethyl ether is added 61 ml of 1.5 M methyllithium-lithium bromide complex. The mixture is heated at reflux for 17 hours and worked up as described above to yield 0.800 g of the titled compound. High resolution mass spectrum: Calcd. for C9H11NO: 149.0841; Found: 149.0834.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:11][C:10]=1[C@@H:26]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:27][CH2:28][N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:57]Br)=[CH:52][C:51]=1[NH:67][S:68]([CH3:71])(=[O:70])=[O:69])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)(=O)C.O>CS(C)=O>[NH3:25].[CH2:42]([O:49][C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]([O:59][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:62])[CH3:61])[CH2:57][NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C@@H:26]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:27][CH2:28][N:29]([CH:30]([CH3:32])[CH3:31])[CH:33]([CH3:34])[CH3:35])[CH:11]=2)=[CH:52][C:51]=1[NH:67][S:68]([CH3:71])(=[O:69])=[O:70])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CCCCCCCCCN)ccc1OCc1ccccc1)C(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=CCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)ccc1OCc1ccccc1)C(C)C
Product: N

Procedure:
10-{4-(Benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}dec-9-en-1-amine (Preparation 3, 170 mg, 0.33 mmol) and N-{2-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanesulfonamide (Prepared according to WO2005/080324, 180 mg, 0.33 mmol) were heated at 90° C. in dimethylsulfoxide (0.5 ml) for 12 hours. Ethyl acetate (20 ml) and water (10 ml) were added and the organics separated, washed with water (10 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (80/20/2.0 by volume) to furnish the title compound as a glass, 90 mg.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:19])=O)C1C=CC=CC=1.[N:26]1[C:35]2[C:30](=[N:31][C:32]([CH:36]=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.N1CCCCC1>CC(O)C>[N:31]1[C:30]2[C:35](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:34]=[CH:33][C:32]=1[CH:36]=[C:15]1[NH:11][C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:19])=[N:13][C:14]1=[O:16]
Reactant: Cc1ccsc1C(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: Cc1ccsc1C(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To a mixture of 2-[(3-methyl-thiophene-2-carbonyl)-amino]-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (42.0 mg, 0.12 mmol), 1,5-naphthyridine-6-carboxaldehyde (18.6 mg, 0.12 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 3-methyl-thiophene-2-carboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light yellow solid (13.3 mg, 30.5%). HR-ES (+) m/e calcd. for C18H13N5O2S: (M+H)+ 364.0863. Found: 364.0862.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:28]=[C:25]([CH3:26])[N:27]=[CH:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.6 g (0.005 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol was stirred at room temperature, under argon, and treated with 0.8 g (0.015 mol) of sodium methylate in one portion. After stirring for 10 min, 30 ml of methylene chloride was added and stirring was continued. Another 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.015 mol of sodium methylate and 0.0075 mol of acetamidine hydrochloride was repeated after another 2 hr and stirring at room temperature was continued overnight. After diluting with 50 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization occurred when the residue was dissolved in 20 ml of warm hexane and cooled. Evaporation of the solvent gave a second crop of product. Recrystallization from hexane (charcoal) gave off-white crystals: mp 120°-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>O.CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:43]
Reactant: CS(=O)(=O)NCCc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.3 %

Procedure:
A mixture of N-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (4.3 g, 20 mmol), Nal (1.2 g, 8.0 mmol), K2CO3 (6.07 g, 44 mmol), ethyl bromoacetate (3.34 g, 20 mmol), and DMF (70 mL) was stirred at room temperature for 24 h. The reaction was poured into water and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with water (1×) followed by brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (hexanes to 7:3 hexanes:EtOAc) provided the title compound (800 mg). 1H NMR (400 MHz, CDCl3) δ 7.18 (m, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.97 (m, 1H), 4.65 (s, 2H), 4.24 (q, 2H), 3.42 (m, 2H), 2.94 (t, 2H), 2.75 (s, 3H), 1.27 (t, 3H); MS 319 (M+18).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:15][S:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[N:31]=[N:32][N:33]([CH2:35][C:36]([NH:38][C@H:39]([CH2:45][S:46][CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=5)[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:37])[CH:34]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:76][C:77]#[CH:78]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:15][S:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[N:31]=[N:32][N:33]([CH2:35][C:36]([NH:38][C@H:39]([CH2:45][S:46][CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH2:78][C:77]#[CH:76])[CH:49]=5)[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:37])[CH:34]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1
Reactant: C#CCBr
Reactant: CCOC(=O)[C@@H](CSCc1cccc(O)c1)NC(=O)Cn1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cccc(CSC[C@@H](NC(=O)Cn2cc(COc3ccc4nc(S(=O)(=O)NC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)sc4c3)nn2)C(=O)OCC)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a 10 mL round bottomed flask equipped with a magnetic stir bar, rubber septum and argon inlet containing DMF (0.5 mL) was placed 134 (49 mg, 0.054 mmol). To this solution K2CO3 (22 mg, 0.162 mmol) and 3-bromoprop-1-yne (0.01 mL, 0.0702 mmol) were added and the reaction was allowed to stir at 60° C. for 12 h. The reaction was then poured into water (50 mL) and extracted into EtOAc (3×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4 and concentrated in vacuo used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[SH:9].[CH3:10][C:11]1[CH:12]=C[C:14](S(O)(=O)=O)=[CH:15][CH:16]=1.C1(C)C=CC(C)=CC=1.C=C1CC(C(Cl)=O)C1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]3[CH2:16][C:15](=[CH2:14])[CH2:12]3)[S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C1CC(C(=O)Cl)C1
Solvent: Cc1ccccc1C
Solvent: Cc1ccc(C)cc1
Solvent: CCOC(C)=O
Product: C=C1CC(c2nc3ccc(Br)cc3s2)C1
Temperature: 50 °C
Yield: 250.1 %

Procedure:
The product of Example 1A (1.0 g, 4.90 mmole) was weighed into a 100 ml round bottom flask and pyrridium p-toluenesulfonate (0.37 g, 1.47 mmole) was added. The flask was placed on high vacuum overnight. Para-xylene (50 ml) was added followed by tiethylamine (0.68 ml, 4.9 mmole). The mixture was rapidly stirred at 50° C. to give an almost clear solution. A solution of 3-methylene-cyclobutanecarbonyl chloride (0.64 g, 4.9 mmole) (prepared according to literature procedure, JACS, 1959, 81, 2723-2728) in 10 ml xylene was then added dropwise over 15 minutes. The temperature was raised to 140° C. for 7 hours. The mixture was cooled to room temperature, followed by the addition of ethyl acetate (100 ml). The resulting solution was washed with saturated sodium bicarbonate, and the organic layer was dried (Na2SO4), and concentrated to give an oil. The crude product was purified by chromatography (20% hexane in dichloromethane) to give the title compound (1.03 g, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 7.98 (d, J=2.03 Hz, 1H), 7.83 (d, J=8.82 Hz, 1H), 7.55 (dd, J=8.82, 2.03 Hz, 1H), 4.83-4.98 (m, 2H), 3.83-4.04 (m, 1H), 3.10-3.35 (m, 4H). MS: (M+H)+=279/281.
Reaction SMILES: Cl.ClC1C=C(C=CC=1Cl)CN[CH2:8][C@H:9]([OH:22])[CH2:10][P:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])[OH:12]>C(O)C>[CH2:8]1[O:22][CH:9]1[CH3:10].[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][PH:11](=[O:12])[OH:13])=[CH:20][CH:19]=1
Reactant: Cc1ccc(CP(=O)(O)C[C@@H](O)CNCc2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Solvent: CCO
Product: CC1CO1
Product: Cc1ccc(C[PH](=O)O)cc1

Procedure:
In a manner analogous to that described in Preparation Example 3-(3,4-dichlorobenzylamino)-2(S)-hydroxy-propyl(p-methylbenzyl)phosphinic acid hydrochloride can be manufactured. Dissolution in ethanol and treatment with propylenoxide yields 3-(3,4-dichlorobenzylamino)-2(S)-hydroxy-propyl(p-methylbenzyl phosphinic acid of m.p. 222,5°-224°.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][C:8]=1[O:25][CH3:26])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][C:8]=1[O:25][CH3:26]
Reactant: CCCCCCCCC(=O)NCc1ccc(Oc2ccccc2[N+](=O)[O-])c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC(=O)NCc1ccc(Oc2ccccc2N)c(OC)c1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
N-(4-(2-nitrophenoxy)-3-methoxyphenylmethyl)nonanamide (1.23 g) is dissolved in methanol (50 mL). To this is added 10% palladium on charcoal (100.1 mg). The mixture is placed on a Paar shaker for 60 minutes at room temperature and 42 psi hydrogen. The mixture is filtered through celite, evaporated to dryness on a rotary evaporator, then dried overnight at room temperature and reduced pressure (0.5 mm Hg) to yield N-(4-(2-aminophenoxy)-3-methoxyphenylmethyl)nonanamide (1.11 g, 97%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([N:23]([C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH2:24][CH2:25][NH2:26])[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH2:24][CH2:25][NH:26][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCN(CCN)c1cccc(C)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(CCNC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1)c1cccc(C)c1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and N1-ethyl-N1-m-tolyl-ethane-1,2-diamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H30N2O5 [M+H]+: 414.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[NH:5][C:6](=[O:32])[C@@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[N:8]([C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[CH3:9].O.[OH-].[Li+].O>CO.O1CCCC1>[CH3:18][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([CH3:17])[CH:14]=1)[C:10]([N:8]([CH3:9])[C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:43])=[O:2])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:32])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)=[O:19]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(-c3ccno3)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Reaction time: 2 h

Procedure:
[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane methyl ester (50 mg) is treated with lithiumhydroxide monohydrate (3.8 mg) in methanol (1 ml), tetrahydrofurane (0.5 ml), and water (0.5 ml), at 0° C. for 1 hour, and at room temperature for 2 hours. The mixture is then partitioned between water and ether, the water phase acidified with 1N hydrochloric acid, and subsequently extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, and evaporated to give [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][O:10][C:11](=[O:27])[CH2:12]P(OCC(F)(F)F)(OCC(F)(F)F)=O>>[CH3:9][O:10][C:11](=[O:27])[CH:12]=[CH:7][C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1cc(Br)cs1
Product: COC(=O)C=Cc1cc(Br)cs1
Yield: 78 %

Procedure:
4-Bromo-thiophene-2-carbaldehyde (44 g, 0.23 mol) and [Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic methyl ester (80.6 g, 0.253 mol) were treated by the method outlined in Example 34, step a) to afford the subtitle compound that was purified by column chromatography (SiO2) using a 0-60% ethylacetate-hexane gradient (46.22 g, yield: 78%). MS calculated for C8H7BrO2S+H: 247, observed: 247 249.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (0.056 g) and 2-(dimethylamino) ethylamine (0.080 mL) in dry pyridine (0.50 mL) is heated at 80° C. The dark solution obtained is held at this temperature for 1 hour, then it is left at room temperature overnight. The dark precipitate obtained is separated by suction and purified by column chromatography (SiO2 ; eluant ethyl acetate and then methylene chloride/methanol 9/0.5 v/v) to give 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.024 g) as a red-orange solid.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1cccc(N)c1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)C23CC4CC(CC(C4)C2)C3)c1

Procedure:
Subject 6.5 g. of adamantane carboxylic acid chloride, 4.0 g. of m-anisidine and 10.0 ml. of triethylamine to the process of Example 14 and obtain thereby the title product, m.p. 172°-174° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[C:8]([C:25]#[N:26])=[N:7]1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:27]=[CH:28][C:29]([C:31]([F:33])([F:34])[F:32])=[CH:30][C:3]=3[C:2]([F:1])([F:35])[F:36])[N:7]=[C:8]4[C:25]#[N:26])[C:17](=[O:24])[N:18]=2)[CH2:46][C@H:45]1[CH2:50][OH:51])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)C[C@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(S)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.