Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=C.C[OH:27]>>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]2=[C:5]3[C:4]=1[CH2:1][CH:2]([OH:27])[N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)[C:6]3=[N:7][CH:8]=[N:9]2
Reactant: CO
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Product: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.17 g, 0.42 mmol) (from Example 17, Step E, supra) in methanol (50 mL) at −78° C. was passed a continuous stream of 03 until the color of the solution became blue. The reaction solution was then purged with argon, and methyl sulfide (5 mL) (Aldrich) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The solution was concentrated, the residue was dried in vacuo to give the desired 7,8-dimethoxy-4-(3-bromo-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol as a crude brown oil. (Yield 0.16g, 100%).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:28][NH2:29])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:29]([CH2:28][C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Reactant: NCc1cnc(OCC(F)F)c(Cl)c1
Agent: Cl
Product: CC1c2c(ccnc2Cl)C(=O)N1Cc1cnc(OCC(F)F)c(Cl)c1
Yield: 16 %

Procedure:
The title compound is prepared in 16% yield (45 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (223 mg, 0.86 mmol, Amine-12) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([O-])(=[O:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11].[Li].[H-].O>CCOCC>[CH2:1]([OH:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC=CC=C/C=C/C(=O)[O-]
Agent: [H-]
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CCCCC=CC=C/C=C/CO
Yield: 64.7 %

Procedure:
To a solution of ethyl trans, trans, trans-2,4,6-undecatrienoate (12 g) in dry ether (300 ml) was added little by little, lithium alminum hydride (1.6 g) with stirring under ice-cooling in the course of 30 minutes and then the mixture was stirred for 30 minutes at ambient temperature. To the resultant mixture was added ether containing water and then insoluble materials was removed by filtration. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give oily trans, trans, trans-2,4,6-undecatrien-1-ol (7.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.[ClH:45]>C1COCC1>[ClH:43].[ClH:45].[ClH:43].[Cl:43][C:37]1[CH:36]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)[CH:40]=[C:39]([F:41])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 65 °C
Yield: 191.5 %

Procedure:
To a solution of tert-butyl (1-(5-((3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (85 mg, 0.14 mmol) in THF (5 mL) was added water (3 mL) and HCl (6 M in water, 2 mL, 12 mmol). The reaction mixture was heated at 65° C. for 3 h, cooled to room temperature and concentrated. The resultant residue was triturated with dichloromethane to give the desired product (55 mg, 64%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.31 (s, 1H), 8.31-8.23 (m, 2H), 8.10-8.03 (m, 2H), 7.95 (dd, J=9.4, 2.4 Hz, 1H), 7.22 (dd, J=11.5, 2.3 Hz, 1H), 7.18-7.11 (m, 2H), 4.14-4.08 (m, 2H), 3.98-3.86 (m, 2H), 3.83-3.74 (m, 1H), 2.84 (s, 3H), 2.79 (s, 3H), 2.71-2.60 (m, 1H), 2.47-2.36 (m, 1H). ESI MS m/z 506 [C27H25ClFN50O2+H]+; HPLC 97.4% (AUC), tR=9.62 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[C:15]([CH2:14][O:1][C:2]3[CH:9]=[N:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=3[CH:4]=[O:5])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: COc1cncc(O)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cncc(OCc2cccnc2-c2ccnn2C(C)C)c1C=O
Temperature: 70 °C
Yield: 42.6 %

Procedure:
A mixture of 3-hydroxy-5-methoxyisonicotinaldehyde (30 mg, 0.20 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (54 mg, 0.20 mmol, 1 eq.), and K2CO3 (110 mg, 0.80 mmol, 4 eq.) in DMF (2.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes to give 3-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-5-methoxyisonicotinaldehyde (30 mg, 43%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.65 (dd, J=4.7, 1.1 Hz, 1H), 8.13 (s, 1H), 8.11 (dd, J=7.9, 1.1 Hz, 1H), 7.96 (s, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.37 (dd, J=7.9, 4.8 Hz, 1H), 6.29 (d, J=1.7 Hz, 1H), 5.11 (s, 2H), 4.55 (sep, J=6.6 Hz, 1H), 3.95 (s, 3H), 1.40 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 353.1.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].O1CCOCC1.[CH3:26][NH:27][CH3:28]>CO>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:27]([CH3:28])[CH3:26])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: CNC
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)c1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.4 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo [4,3-b]pyridazine was suspended in 14 ml. of a mixture of dioxan and methanol (1:1), 6.7 ml. 30percent methanolic dimethylamine solution were added thereto, the reaction mixture was stirred for 1 hour at 60° C., then cooled in an ice bath, the product was filtered off with suction, washed with a mixture of dioxan and methanol (1:1) and then with ether and the product thus obtained (0.66 g.) recrystallized from 15 ml. dioxan-dimethylformamide (9:1), with the addition of charcoal, 0.35 g. of intense yellow crystals of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-dimethylamino-s-triazolo [4,3-b]pyridazine thereby being obtained. It has a melting point of 233° -236° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1.[CH2:46]([C:48]1[CH:49]=[C:50]([CH2:56][CH:57]([NH:61][C:62]([N:64]2[CH2:69][CH2:68][CH:67]([N:70]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[NH:72][C:71]3=[O:80])[CH2:66][CH2:65]2)=[O:63])[C:58](O)=[O:59])[CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH3:47]>C1COCC1.C(N(CC)CC)C>[CH2:46]([C:48]1[CH:49]=[C:50]([CH:51]=[CH:52][C:53]=1[CH2:54][CH3:55])[CH2:56][CH:57]([NH:61][C:62]([N:64]1[CH2:69][CH2:68][CH:67]([N:70]2[CH2:79][C:78]3[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=3)[NH:72][C:71]2=[O:80])[CH2:66][CH2:65]1)=[O:63])[C:58]([N:43]1[CH2:44][CH2:45][N:40]([CH:37]2[CH2:36][CH2:35][N:34]([CH3:33])[CH2:39][CH2:38]2)[CH2:41][CH2:42]1)=[O:59])[CH3:47]
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 40 °C
Reaction time: 2 h

Procedure:
336 mg (1.05 mmol) of TBTU, 161 mg (1.05 mmol) of HOBt, 1.02 mL triethylamine and 326 mg (1.05 mmol) of 1-(1-methyl-piperidin-4-yl)-piperazine (used as the tris-hydrochloride) were added to a solution of 500 mg (1.05 mmol) of 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid in 100 mL of THF, stirred for 4 h at RT and 2 h at 40° C. The solvent was removed in vacuo, the residue was stirred with 40 mL of saturated NaHCO3 solution, the precipitated product was suction filtered, taken up in MeOH and purified by chromatography over silica gel (MeOH). The product fractions were evaporated down, the residue triturated with diethyl ether, suction filtered, washed twice with diethyl ether and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:16][O:17][C:18]1[CH:42]=[CH:41][C:21]([CH2:22][O:23][C:24]2[C:25](B(O)O)=[CH:26][C:27]3[C:28]([CH3:37])([CH3:36])[CH2:29][CH2:30][C:31]([CH3:35])([CH3:34])[C:32]=3[CH:33]=2)=[CH:20][CH:19]=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:6]=1[C:25]1[C:24]([O:23][CH2:22][C:21]2[CH:41]=[CH:42][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:33][C:32]2[C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29][C:28]([CH3:37])([CH3:36])[C:27]=2[CH:26]=1
Reactant: COc1ccc(COc2cc3c(cc2B(O)O)C(C)(C)CCC3(C)C)cc1
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Product: COc1ccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2O)C(C)(C)CCC3(C)C)cc1
Yield: 51.7 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 2.0 g (5.5 mmol) of 3-(4-methoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained above, 930 mg (49%) of the expected compound were obtained in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][O-:38].[Na+]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[N:11]=[C:12]([O:38][CH3:37])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)c2ccccc12

Procedure:
The compound obtained in Example 275 was reacted with sodium methoxide by a method similar to Example 270 to yield the title compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[N:37]([O:38][CH3:39])[CH3:36])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (24.85 g, 93.66 mmol) in dichloromethane (150 mL) was added N-methylmorpholine (10.3 mL, 93.66 mmol), followed by addition of isobutyl chloroformate (12.25 mL, 93.66 mmol) at 0° C. The reaction mixture was stirred for 20 min. then N,O-dimethylhydroxylamine hydrochloride (9.14 g, 93.66 mmol) in one portion was added. Subsequently, triethylamine (13 mL, 93.66 mmol) was added dropwise over 15 min. The reaction mixture was stirred for another hour, then it was quenched with 1N HCl (100 mL) and the organic phase was washed with saturated NaHCO3 and brine (500 mL). The organic layers were dried over (MgSO4), filtered, and concentrated in vacua to give the Weinreb amide of Formula VII(a), [(S)-1-(methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a clear sticky oil (29.3 g, 100%). 1H NMR (400 MHz, d6-DMSO): δ (ppm) 7.33-7.09 (m, 6H), 4.61-4.47 (m, 1H), 3.70 (s, 3H), 3.08 (s, 3H), 2.89-2.78 (m, 1H), 2.75-2.63 (m, 1H), 1.29 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I

Procedure:
A solution of 3-iodo-4-methylaniline (1.22 g, 5.25 mmol), 3-(trifluoromethyl)benzoic acid (0.95 g, 5 mmol), HOBt (0.68 g, 5 mmol), and EDCI (1.05 g, 5.5 mmol) in THF (20 mL) was stirred overnight at rt. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (3:1 hexane/ethyl acetate) yielding the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[S:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cccc(S)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cccc(Sc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 180 °C
Reaction time: 0.01 h
Yield: 98.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (50 mg) and commercially available 3-methoxybenzenethiol (77 mg) were mixed and stirred at 180° C. for 30 seconds. Purification was carried out in the same manner as described in Example 18 to obtain 72 mg of the title compound (yield: 100%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:35][C@@H:36]1[CH:41]2[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]2)[CH2:37]1.CO>C(Cl)Cl>[N:38]12[CH2:43][CH2:42][CH:41]([CH2:40][CH2:39]1)[C@@H:36]([NH:35][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)=[CH:15][CH:14]=1)[CH2:37]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of the acid from Step F (81 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1.0M in CH3CN, 0.2 mL, 0.2 mmol) is added and the resulting solution is shaken overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (58 mg, 85%). MS for C20H21FN2O2 (ESI) (M+H)+ m/z 341.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[O:7][N:6]=[C:5]([NH:8]C(=O)N(C)C)[CH:4]=1.Cl>>[F:1][C:2]([F:15])([F:14])[C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: CN(C)C(=O)Nc1cc(C(F)(F)F)on1
Agent: Cl
Product: Nc1cc(C(F)(F)F)on1

Procedure:
A mixture of 5-trifluormethyl-3-dimethylcarbamoylaminoisoxazole (1.15 g, 0.005 mole) and 36% hydrochloric acid (10 eq.) were reacted at 100° C. for 10 hours. The reaction mixture was worked up in the usual way to give the crude title compound. Crude yield: 0.20 g (26%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:14]([OH:16])=[O:15].[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)(Cl)Cl>[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:21]1[CH:22]=[CH:23][C:18]([C:13]([CH3:17])([CH3:12])[C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: NC(=O)N1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
Add AlCl3 (8.31 g, 62.3 mmol) to carbon tetrachloride (65 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (03.5 mL, 31.2 mmol), stir for 15 minutes and add, by dropwise addition over 15 minutes, a solution of 2-methyl-2-phenyl-propionic acid, pyrrolidineamide (5.64 g, 26.0 mmol) in carbon tetrachloride (60 mL). Stir at room temperature for 17 hours, pour into ice water (100 mL) and separate the layers. Wash the aqueous layer with methylene chloride (2×70 mL), 5% aqueous sodium hydrogen carbonate, combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (6.55 g, 78%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C:22](=[O:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4].Cl>N1C(C)=CC(C)=CC=1C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C:22](=[O:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 51.2 %

Procedure:
A solution of 17β-methoxycarbonyl-3β-toluene-p-sulphonyloxy-5α-androstan-11-one (1.01g.) in hot collidine (5 ml.) was refluxed for 30 minutes. The solution was cooled and poured into diluted hydrochloric acid and ice, and stirred. The product was filtered, washed with water, dried and purified by filtering it through a column of alumina, eluting with ether. The eluate was evaporated to a residue and crystallisation from ether and hexane gave title compound (340 mg.) as colourless rods; m.p. 169°-175°; [α]D + 139°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:21])[CH2:19][CH3:20].O1CCCC1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](=[O:13])[NH:21][CH2:18][CH2:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
2-tert-Butoxycarbonylamino-benzoic acid (1.00 g, 0.00421 mol) and 1-Propanamine (0.249 g, 0.00421 mol) were dissolved in Tetrahydrofuran (10.0 mL, 0.123 mol) and the mixture was treated with N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.808 g, 0.00421 mol) and 1-Hydroxybenzotriazole (0.570 g, 0.00421 mol). The reaction was then allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 1.17 grams (49%) of (2-Propylcarbamoyl-phenyl)-carbamic acid tert-butyl ester.
Reaction SMILES: C(C1C=CC(S([N:13]=[N+:14]=[N-])(=O)=O)=CC=1)(O)=O.[CH:16]1([C@@H:19]([NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1>CC#N.CCOC(C)=O>[CH:16]1([C@@H:19]([NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[CH2:20][C:21](=[O:27])[C:22](=[N+:13]=[N-:14])[C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)CC(=O)C[C@H](N[S@](=O)C(C)(C)C)C1CC1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C(=[N+]=[N-])C(=O)C[C@H](N[S@](=O)C(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Carboxybenzenesulfonyl azide (28) (8.79 g, 38.7 mmol) was added to a solution of (5S)-methyl 5-cyclopropyl-5-[(R)-1,1-dimethylethylsulfinamido]-3-oxopentanoate (27) (10.2 g, 35.2 mmol) in CH3CN (230 mL) and the resulting solution was stirred at rt for 5 h. The resulting solution was diluted with EtOAc (200 mL) and washed with sat. brine (100 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-methyl 5-cyclopropyl-2-diazo-5-[(R)-1,1-dimethylethylsulfinamido]-3-oxopentanoate (29). Retention time (min)=1.634 method [1], MS (m/z) 316.2 (M+H)+.
Reaction SMILES: N#N.N[C@H](C(N[C@@H](CC1C=CC=CC=1)[C@H](O)C[C@@]1(C(N)=O)CCCN1C(C)(C)C)=O)CC(=O)N.C(O[C:43]([NH:45][C:46]1[C:47](C(O)=O)=[CH:48][C:49]2[C:54]([CH:55]=1)=CC=CC=2)=O)C1C=CC=CC=1.O[C:60]1[C:68]2N=N[NH:65][C:64]=2[CH:63]=[CH:62][CH:61]=1.C(N1CCOCC1)C>>[CH:64]1([N:65]=[C:43]=[N:45][CH:46]2[CH2:55][CH2:54][CH2:49][CH2:48][CH2:47]2)[CH2:68][CH2:60][CH2:61][CH2:62][CH2:63]1
Reactant: O=C(Nc1cc2ccccc2cc1C(=O)O)OCc1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O)C(N)=O
Agent: CCN1CCOCC1
Agent: N#N
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
In a manner analogous to that described in Example 27, from 295 mg of N2 -[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide, 214 mg of 3-(benzyloxyformamido)-2-naphthoic acid, 90 mg of hydroxybenzotriazole, 77 mg of N-ethylmorpholine and 151 mgof dicyclohexylcarbodiimide there were obtained, after chromatography on silica gel using System G for the elution, 380 mg of N2 -[3(S)-[[N-[3-(benzyloxyformamido)-2-naphthoyl]-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid from methanol: MS: m/e 751 [M+H]+.