Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C1(S([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C:14]([CH3:27])=[CH:13]2)(=O)=O)C=CC=CC=1.[C:28]([CH2:35][C:36]([NH2:47])([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-].C([O-])(O)=O.[Na+]>CO>[C:28]([CH2:35][C:36]([NH2:47])([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:37]([N:24]1[CH2:23][CH2:22][N:21]([C:20]2[C:15]3[C:14]([CH3:27])=[CH:13][NH:12][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:26][CH2:25]1)=[O:38])([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)CC(N)(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)C(N)(CC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-benzenesulfonyl-5-methyl-4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (35 mg. 0.081 mmol), 3-Boc-amino-2-(4-chlorophenyl)-propionic acid (27 mg, 0.089 mmol), and TEA (0.11 mL, 0.81 mmol) 1.2 mL DCM was added HBTU (34 mg, 0.089 mmol). The reaction mixture was stirred at room temperature 2 hours, after which 0.15 mL 3M LiOH and 1.0 mL MeOH were added. The reaction mixture was stirred at 35° C. for 3.5 hours, after which saturated NaHCO3 was added. The mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (flushed with 1:1 DCM:EtOAc, then gradient to 1:4 DCM:EtOAc) to give 3-Boc-amino-2-(4-chlorophenyl)-1-[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one, which was used in the next step.
Reaction SMILES: CC([CH:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([C:31]#[N:32])[CH:22]=4)[O:18][N:17]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][N:7](C([O-])=O)[CH2:6]1)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[CH3:30][CH:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([C:14]3[CH:13]=[CH:12][C:11]4[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=4[CH:15]=3)[N:20]=2)=[CH:22][C:23]=1[C:31]#[N:32])[CH3:29]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)[O-])CC4C(C)(C)C)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C#N
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl-7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 43) (735 mg, 1.55 mmol) was dissolved in 4M HCl in dioxane and the solution stirred for 1 h. The title compound was filtered off as a white solid and dried in a vacuum oven (462 mg, 1.13 mmol). δH (d6DMSO, 400 MHz): 9.24 (2H, brs), 8.51 (1H, d), 8.40 (1H, dd), 7.95 (1H, d), 7.92 (1H, dd), 7.57 (1H, d), 7.45 (1H, d), 4.98 (1H, septet), 3.28-3.18 (8H, m), 1.39 (6H, d). MS (ES): C22H22N4O2 requires 374; found 375 [M+H]+.
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[CH3:17][O:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:34][CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[C:21]([C:37]#[N:38])[CH:20]=1.C(OCC)(=O)C>C(O)(=O)C>[CH3:17][O:18][C:19]1[C:32]2[C:31](=[O:33])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:34][CH3:35])[C:24](=[O:36])[C:23]=2[CH:22]=[C:21]([C:37]2[NH:16][N:15]=[N:14][N:38]=2)[CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C#N)cc1C2=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc2c1C(=O)c1c(OC)cc(-c3nnn[nH]3)cc1C2=O
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Tri-n-butyltin azide (100 ml) was added to 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carbonitrile (5.75 g) and heated and stirred at 150° C. for 4 hours, cooled to room temperature, poured into ethyl acetate (1000 ml). Acetic acid (10 cm3) was added and the solution allowed to stand 16 hours, the resultant precipitate was filtered to give the dimethoxyetrazole, m.p. 262°-264° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH3:13])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38]1[N:46]2[C:41]([C:42]3([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[O:43][C:44]3[CH:50]=[C:49]([C:51]([O:53][CH3:54])=[O:52])[CH:48]=[CH:47][C:45]=32)=[CH:40][CH:39]=1.CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:57]2[CH2:58][CH2:59][C:42]3([O:43][C:44]4[CH:50]=[C:49]([C:51]([O:53][CH3:54])=[O:52])[CH:48]=[CH:47][C:45]=4[N:46]4[CH:38]=[CH:39][CH:40]=[C:41]34)[CH2:55][CH2:56]2)=[O:9])=[CH:5][C:4]=1[O:12][CH3:13])[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1OC
Reactant: COC(=O)c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)OC)ccc2-n2cccc23)cc1OC
Yield: 95.5 %

Procedure:
A solution of 4-ethyl-3-methoxy-benzoic acid (450 mg, 2.5 mmol), HATU (940 mg, 2.5 mmol), methyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylate (830 mg, 2.5 mmol), and Et3N (1.7 mL, 9.9 mmol) in DMF (8 mL) was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude mixture that was purified by silica gel chromatography eluting with 0-30% EtOAc in hexanes to yield methyl 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylate (1.1 g, quant). ESI-MS m/z calc. 460.5, found 461.5 (M+1)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:32])=[O:38])=[CH:27][CH:26]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CN(C(=O)Cc1ccc(OCc2ccccc2)cc1)c1ccc(SC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)Cc1ccc(OCc2ccccc2)cc1)c1ccc(S(C)=O)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 1.34 g (2.98 mmols) of ethyl N-(2-(4-benzyloxyphenyl)acetyl)-N-(4-methylthiophenyl)glycinate (VIIq) in 25 mL dry dichloromethane (CH2Cl2) was added 1.05 equivalents of m-chloroperoxybenzoic acid at 0° C. After stirring for 30 min., the solution was poured into 200 mL of saturated NaHCO3 solution containing 10 mL of 10% NaHCO3 solution and was extracted with two 100 mL portions of CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated to give 1.40 g (ca. 100% yield) of the sulfoxide (VIIt) was an oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=2[N:13]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:5]3[CH:10]=[N:9][C:8]([C:11]#[N:12])=[N:7][C:6]=3[N:13]=2)=[CH:24][CH:23]=1)=[O:21]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 95 °C

Procedure:
A mixture of 7-chloro-6-phenylpyrido[2,3-d]pyrimidine-2-carbonitrile (2-4) (0.350 g, 1.31 mmol), 4-formylphenyl boronic acid (0.492 g, 3.28 mmol), cesium carbonate (1.28 g, 3.94 mmol), and Pd(PtBu3)2 (0.067 g, 0.131 mmol) in anhydrous dioxane (8 mL) was degassed (3× vacuum pump/refilled with N2) and heated to 95° C. for 18 hr. The mixture was cooled, diluted with water, and extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. Purified by silica gel chromatography (10-30% EtOAc in Hexanes). 1H-NMR (500 MHz, CDCl3) δ 10.05 (s, 1H), 9.61 (s, 1H), 8.44 (s, 1H), 7.84 (d, 2H, J=8.3 Hz), 7.72 (d, 2H, J=8.3 Hz), 7.46-7.36 (m, 3H), 7.29-7.25 (m, 2H); LRMS, calc'd: 337.0, found: 337.0.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17]([OH:21])(=[O:20])[CH2:18][CH3:19]>O>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17]([O-:21])(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)O
Agent: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: O
Product: CCC(=O)[O-]
Temperature: 25 °C

Procedure:
100 g of ethoxyquin and 34 g of 100% propionic acid were mixed with stirring at room temperature. The resulting salt was liquid and had a viscosity of 100 cps at 20° C. With 5% of water added the viscosity was reduced to 60 cps at 20° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[N:3]1[C:7]2([CH2:12][CH2:11][N:10]([N:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]2)[C:6](=[O:16])[CH:5]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[C:4]1=[O:26].C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1>[CH2:39]([O:38][C:36](=[O:37])[O:16][C:6]1[C:7]2([CH2:12][CH2:11][N:10]([N:13]([CH3:14])[CH3:15])[CH2:9][CH2:8]2)[N:3]([N:2]([CH3:1])[CH3:27])[C:4](=[O:26])[C:5]=1[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH3:40]
Reactant: Cc1cc(C)c(C2C(=O)N(N(C)C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(N(C)C)C12CCN(N(C)C)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
150 mg 1,8-Bis-dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (PREPARATION EXAMPLE 1) is dissolved in 3 ml tetrahydrofuran, 75 mg triethylamine is added, and the mixture is cooled to 0° C. 44 mg ethyl chloroformate is added and the resulting suspension stirred for 3 hours, thereby warming to room temperature. Then the mixture is partitioned between water and ethyl acetate, the organic layer separated and washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/heptane (1:1) as a solvent. Thus, 145 mg Carbonic acid 1,8-bis-dimethylamino-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester is obtained as a solid, mp 105° C. 1H-NMR (CDCl3): 6.83 ppm (s, 2H), 4.02 ppm (q, 2H), 3.05 ppm (m, 2H), 2.94 ppm (s, 6H), 2.80 ppm (m, 2H), 2.43 ppm (s, 6H), 2.40 ppm (m, 2H), 2.23 ppm (s, 3H), 2.17 ppm (s, 6H), 1.86 ppm (m, 2H), 1.08 ppm (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])[NH:27][C:26](=[O:37])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])[NH:27][C:26](=[O:37])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 67.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (48 mg, 67.9%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:15])[CH2:30][CH2:31]3)[S:23][N:22]=2)=[CH:17]1
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)co1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Yield: 30.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (207 mg, 0.770 mmol), 1-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.846 mmol) and diisopropylethylamine (0.134 ml, 0.846 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 84.5 mg (30.8%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:16][C:17](=O)[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH2:9][CH2:10]OS(C)(=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:17]1[S:36][CH2:10][CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:16]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)OCCC(NC(=O)c1c(F)cccc1F)c1ccccc1Br
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1C1=NC(c2ccccc2Br)CCS1
Yield: 48.7 %

Procedure:
To a solution of 1.0 g of N-[1-(2-bromophenyl)-3-(methylsulfonyloxy) propyl]-2,6-difluorobenzamide in 15 ml of toluene at room temperature, was added 1.1 g of Lawesson's Reagent. The reaction mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.4 g of 2-(2,6-difluorophenyl)-4-(2-bromophenyl)-5,6-dihydro-4H-1,3-thiazine. m.p. 136°-138° C.
Reaction SMILES: C[Sn](C)(C)C.[Cl-].[Li+].[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:28]1[CH:29]=[CH:30][C:31]2[C:32](=[O:70])[N:33]3[CH2:54][CH:53]=[CH:52][CH2:51][CH2:50][C@@H:49]4[CH2:55][CH2:56][CH2:57][C@H:48]4[O:47][C:46](=[O:58])[NH:45][C@@H:44]([CH:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)[C:43](=[O:64])[N:42]4[CH2:65][C@@H:39]([CH2:40][C@H:41]4[C:66]([O:68][CH3:69])=[O:67])[O:38][C:34]3=[N:35][C:36]=2[CH:37]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:69][O:68][C:66]([C@@H:41]1[CH2:40][C@@H:39]2[CH2:65][N:42]1[C:43](=[O:64])[C@H:44]([CH:59]1[CH2:60][CH2:61][CH2:62][CH2:63]1)[NH:45][C:46](=[O:58])[O:47][C@@H:48]1[CH2:57][CH2:56][CH2:55][C@H:49]1[CH2:50][CH2:51][CH:52]=[CH:53][CH2:54][N:33]1[C:32](=[O:70])[C:31]3[CH:30]=[CH:29][C:28]([CH3:8])=[CH:37][C:36]=3[N:35]=[C:34]1[O:38]2)=[O:67]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCn1c(nc3cc(Br)ccc3c1=O)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cn1c(nc3cc(Br)ccc3c1=O)O2
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cn1c(nc3cc(C)ccc3c1=O)O2
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCn1c(nc3cc(C)ccc3c1=O)O2
Temperature: 90 °C

Procedure:
Tetramethyltin (0.041 ml, 0.298 mmol), lithium chloride (50.5 mg, 1.191 mmol), triphenylphosphine (15.62 mg, 0.060 mmol) and bis(triphenylphosphine)palladium(II) chloride (15.68 mg, 0.022 mmol) were added to a nitrogen purged solution of methyl (3aR,7S,10S,12R,22E,25aS)-16-bromo-7-cyclopentyl-5,8,19-trioxo-1,2,3,3a,5,6,7,8,11,12,21,24,25,25a-tetradecahydro-10H,19H-9,12-methanocyclopenta[18,19][1,10,3,6,12]dioxatriazacyclononadecino[11,12-b]quinazoline-10-carboxylate, Example 59 Step 1 (100 mg, 0.149 mmol) in DMF (2 ml). The mixture was heated to 90° C. for 3 hr. The reaction was diluted with aqueous. KHSO4 and product extracted into ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, concentrated and chromatographed on silica using 20-50% ethyl acetate/hexane to give the title compound as a foam, (74 mg, 82%). LCMS (ES+) m/z 607.3 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH:24]C(=O)OC(C)(C)C)=[CH:19][C:20]=3[NH:21]2)=[CH:13][CH:12]=1.Cl>O1CCOCC1>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH2:24])=[CH:19][C:20]=3[NH:21]2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.3 %

Procedure:
To tert-butyl 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ylcarbamate (130 mg, 0.3 mmol) was added 10 mL of a 4 M HCl in dioxane solution. The mixture was stirred at rt for 5 h and concentrated under reduced pressure. The residue was washed with ether (15 mL) and suspended in EtOAc (50 mL). To this suspension was added 10 mL of a NaHCO3 (sat.) and the mixture was stirred for 5 min. The organic layer was dried over MgSO4 and concentrated to afford 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-amine as a brown solid (95 mg, 95%). MS (ESI) m/z 333 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([O:18]C)=[O:17])[NH:4]1.[OH-].[Na+]>CO>[OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[NH:4]1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Yield: 65 %

Procedure:
In the same manner as described in Reference Example 2-(1) using methyl (1RS,3SR)-trans-1-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.60 g), 10N NaOH (1.2 ml) and methanol (50 ml), there is obtained the title compound (1.60 g, 65%), m.p. 231°-233°C.
Reaction SMILES: [N:1]1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([N:5]1[CH2:44][CH2:43][CH2:42][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4]>N1CCCCC1.C(#N)C>[NH:1]1[CH2:47][CH2:46][CH2:45][C@H:2]1[C:3]([N:5]1[CH2:44][CH2:43][CH2:42][C@H:6]1[C:7]([NH:9][C@H:10]([C:36]([C:38]([CH3:39])([CH3:40])[CH3:41])=[O:37])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:35])[NH:16][S:17]([C:20]1[C:33]([CH3:34])=[C:31]([CH3:32])[C:30]2[O:29][C:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][C:23]=2[C:21]=1[CH3:22])(=[O:19])=[O:18])=[O:8])=[O:4]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Solvent: CC#N
Solvent: C1CCNCC1
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2

Procedure:
A solution of the Fmoc-Pro-Pro-Arg(Pmc)-t-Bu (4.15 g, 4.4 mmol) in 10% piperidine in acetonitrile (v/v, 50 ml) was stirred at RT for 30 min. All the volatiles were removed under reduced pressure and the residue was chromatographed on flash silica gel (360.0 g). All the fast moving impurities were removed by washing the column with 10% methanol in chloroform. Continued elution with 20% methanol in chloroform containing 0.1% TEA eluted the required amine. The fractions containing the amine were pooled and evaporated to furnish the amine as a colorless foam. Rf: 0.125 (20% methanol in chloroform). Yield: 3.0 g (98%). MS m/z 691.4 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH3:14][O:15][C@@H:16]1[CH2:24][C:20]2=[N:21][O:22][CH2:23][C@@H:19]2[CH2:18][CH2:17]1.[Cl-].[NH4+]>CCCCCC.C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1COCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C@:20]12[CH2:24][C@@H:16]([O:15][CH3:14])[CH2:17][CH2:18][C@H:19]1[CH2:23][O:22][NH:21]2
Reactant: Fc1ccccc1Br
Reactant: CO[C@H]1CC[C@H]2CON=C2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H]2CON[C@@]2(c2ccccc2F)C1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
THF (3 mL) and toluene (20 mL) were added to 2-bromofluorobenzene (1.23 mL, specific gravity: 1.614 g/cm3) under a nitrogen atmosphere, and the mixture was cooled to −78° C. A solution of n-butyllithium in hexane (3.9 mL, 2.63 M) was slowly added so that the internal temperature was maintained at −60° C. or less. After completion of the addition, the mixture was stirred for 10 minutes. After slowly adding a boron trifluoride-diethyl ether complex (1.29 mL), a solution of (±)-(3aR*,6S*)-6-methoxy-3,3a,4,5,6,7-hexahydrobenz[c]isoxazole obtained in Preparation Example 57-(4) (796 mg) in toluene (10 mL) was slowly added so that the internal temperature was maintained at −60° C. or less. After completion of the addition, the mixture was stirred for one hour and 50 minutes. A saturated ammonium chloride solution was added, followed by warming to room temperature. Ethyl acetate and water were added, followed by further stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (711 mg).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[CH2:12][C@@:11]3([CH3:16])[C@H:7]([CH2:8][N:9](C(OCC)=O)[CH2:10]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.I[Si](C)(C)C.Cl>ClCCl.CO>[ClH:1].[Cl:1][C:2]1[C:14]2[C:13](=[O:15])[CH2:12][C@@:11]3([CH3:16])[C@H:7]([CH2:8][NH:9][CH2:10]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1C[C@@H]2c3cccc(Cl)c3C(=O)C[C@]2(C)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@]12CNC[C@@H]1c1cccc(Cl)c1C(=O)C2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 10.9 %

Procedure:
cis-Ethyl 6-chloro-3a-methyl-5-oxo-3,3a,4,5-tetrahydro-1H-benzo[e]isoindole-2(9bH)-carboxylate (0.162 mmol, 50 mg) was dissolved in dichloromethane (1 ml). Iodotrimethylsilane (0.487 mmol, 0.070 ml, 98 mg) was added and the reaction mixture was heated to 100° C. for 30 minutes in the microwave. 2 N HCl in MeOH (2 ml) was added to the reaction mixture was stirred at rt for 20 minutes. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 2 N HCl and washed with ether. The acidic extract was basified using 4 N NaOH and extracted with ether. The ether extract was then dried over magnesium sulphate, filtered and concentrated in vacuo to give a crude residue that was purified by basic prep-HPLC. The purified fractions were concentrated in vacuo and then redissolved in 2 N HCl in MeOH and concentrated in vacuo to give cis-6-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H-benzo[e]isoindol-5(9bH)-one hydrochloride (2.4 mg), m/z=236.3 [M+H]+.