Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:25]2[CH2:26][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CC2)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OCc2ccccc2)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopropylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[C:35]2[CH2:36][CH2:37][C@H:38]([OH:43])[C:39]=2[CH:40]=[CH:41][CH:42]=1)=[NH:33]>CN(C=O)C.O>[OH:43][C@@H:38]1[C:39]2[C:35](=[C:34]([C:32]3[N:31]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:33]=3)[CH:42]=[CH:41][CH:40]=2)[CH2:36][CH2:37]1
Reactant: N=C(NO)c1cccc2c1CC[C@@H]2O
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4O)no2)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
Prepared using General Procedure 1. To 3-cyano-4-isopropoxybenzoic acid (93.2 mg, 0.45 mmol) in DMF (3 mL) was added HOBt (104.3 mg, 0.68 mmol) and EDC (130.6 mg, 0.68 mmol). The reaction was stirred at room temperature for 16 h until the acid was fully activated. (S)—N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-2 (97 mg, 0.5 mmol) was added in one portion and the reaction was stirred at room temperature for 2 h. The crude material was heated to 85° C. for 18 h. The reaction mixture was cooled to room temperature. Water (15 mL) was added and the mixture was allowed to stand and the dark brown precipitate was filtered. The precipitate was purified by silica gel chromatography (EA/hexane) to give 73 mg (40%) of (S)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 6 as a white solid. LCMS-ESI (m/z) calculated for C21H19N3O3: 361.1; found 362.1 [M+H]+, tR=3.63 min. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.1, 1H), 8.36 (dd, J=8.9, 2.2, 1H), 8.16 (dd, J=7.7, 0.5, 1H), 7.63 (d, J=7.5, 1H), 7.46 (t, J=7.6, 1H), 7.15 (d, J=9.0, 1H), 5.36 (dd, J=12.6, 6.8, 1H), 4.82 (hept, J=6.1, 1H), 3.54 (ddd, J=17.5, 8.7, 4.6, 1H), 3.31-3.18 (m, 1H), 2.63 (dddd, J=13.2, 8.4, 7.1, 4.7, 1H), 2.07 (dddd, J=14.1, 8.7, 6.6, 5.5, 1H), 1.84 (d, J=7.1, 1H), 1.50 (d, J=6.1, 6H). 13C NMR (101 MHz, DMSO) δ 173.07, 168.30, 162.46, 148.27, 142.29, 134.57, 133.77, 127.53, 127.28, 127.05, 122.26, 116.00, 115.25, 114.87, 102.43, 74.05, 72.49, 35.03, 30.80, 21.46. Chiral HPLC: (S)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile was eluted with 20% IPA in hexane: >99.9% ee, tR=25.07 min. (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 and racemic material were obtained in an analogous fashion from (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile and racemic 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile respectively using General Procedure 1. tR for (R)-enantiomer=17.60 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.[C:21](OCC)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1COCC1>[O:28]=[C:21]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CC(=O)c2ccncc2)ccn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
Tert-butyl 4-methyl-2-pyridinylcarbamate (Ihle, N. C.; Krause, A. E.; J. Org. Chem., 1996, 61(14):4810-4811; 10 g, 48.0 mmol) was dissolved in 100 mL THF and cooled to −78° C. under argon and was treated with n-butyllithium (2.5-M in hexanes, 48.0 mL, 120 mmol) such that the internal temperature did not exceed −50° C. The reaction was warmed to 20° C. for 20 min. then was recooled to −78° C. and ethyl isonicotinate (10.79 mL, 72.0 mmol) was added neat and the reaction again was warmed to 20° C. and stirred 45 minutes. The reaction was quenched with sat. NaHCO3 and extracted with ethyl acetate. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a red-orange oil which was purified by silica gel chromatography, eluting from 50% ethyl acetate in hexanes to 100% ethyl acetate to afford 7.56 g (50%) of the titled compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[O:6][CH2:5]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.[C:24](=[O:27])([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:8][CH2:9][N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:10]3[CH2:11][CH2:12][C:7]4([C:13]5[C:14](=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=5)[CH2:24][O:27]4)[CH2:8][CH2:9]3)[CH2:11][CH2:12]1)[O:6][CH2:5]2
Reactant: Cc1ccc2c(c1)COC21CCNCC1
Reactant: O=C([O-])[O-]
Reactant: BrCCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cc1ccc2c(c1)COC21CCN(CCCCCCN2CCC3(CC2)OCc2cc(C)ccc23)CC1

Procedure:
A solution of 5-methyl-spiro[isobenzofuran-1(3H),4'-piperidine] (4 g), 1,6-dibromo-hexane (2.2 g), finely powdered potassium carbonate (2.7 g) and a crystal of potassium iodide in MIBK (150 ml) was refluxed for 4 h. Inorganic salts were filtered off and MIBK evaporated. Column chromatography on silica gel (eluted with ethyl acetate/ethanol/triethylamine 75:25:4) gave the pure title compound 11a. Yield 1.0 g. Mp 113-116° C. (recrystallized from 2-propyl ether). 1H NMR (CDCl3) δ 1.30-1.45 (m,4H), 1.50-1.65 (m,4H), 1.80 (d,4H), 2.00 (dt,4H), 2.35 (s,6H), 2.45-2.50 (m,8H), 2.85 (broad d,4H), 5.05 (s, 4H), 6.95-7.10 (m,6H).
Reaction SMILES: [CH:1]([C:9]1[C:17]2[C:12](=[CH:13][C:14](N)=[CH:15][CH:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[I:31]I>CC(O)=O.O.Cl>[I:31][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([CH:1]=[CH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:10][N:11]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1
Reactant: II
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(N)cc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 113.7 %

Procedure:
To a solution of 3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-ylamine (1.58 g, 4 mmol) in AcOH (14 mL), water (3 mL) and concentrated HCl (1.67 mL) cooled to 2° C. was added a solution of NaNO2 (304 mg, 4.4 mmol) in water (0.5 mL) over 5 min. The resulting dark red solution was stirred at 2° C. for 0.5 h, then a solution of KI (797 mg, 4.8 mmol) and I2 (610 mg, 2.4 mmol) in water (1 mL) was added drop-wise so as to keep the internal temperature below 5° C. After 2 h at 2° C. the reaction was allowed to stir at 23° C. for 17 h. The reaction was quenched with 3 N NaOH (aq), diluted with EtOAc (50 mL) and H2O (15 mL), the phases were separated and the aqueous was extracted 2×15 mL EtOAc. The pooled organic phase was washed 3×20 mL 5% NaHSO3, brine (15 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (eluting with 1:1 hexane:EtOAc) to give 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a white solid (1.3 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.30-7.60 (m, 8H), 5.73 (s, 2H), 3.63 (t, 2H, J=6.0 Hz), 0.96 (t, 2H, J=6.0 Hz), 0.0 (s, 9); 13C NMR (75 MHz, CDCl3) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129.0, 128.3, 126.8, 122.5, 122.4, 119.6, 119.5,92.9, 78.1,66.9, 18.0, −1.2. Anal. Calc'd: C, 52.94; H, 5.29; N, 5.88. Found: C, 52.66; H, 5.29; N, 5.74.
Reaction SMILES: Cl.[NH2:2][OH:3].CO.C[O-].[Na+].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][CH:13]=1)([O-])=[O:10].[OH2:21]>CS(C)=O>[OH:3][N:2]=[C:19]([NH2:20])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:10])=[O:21])=[CH:17][CH:16]=1
Reactant: O
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: NC(Cc1ccc([N+](=O)[O-])cc1)=NO
Temperature: 100 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of hydroxylamine hydrochloride (21.5 g) and dimethyl sulfoxide (50 mL) was added dropwise 28% sodium methoxide methanol solution (59.6 g) at room temperature. A solution (50 mL) of (4-nitrophenyl)acetonitrile (10.0 g) in dimethyl sulfoxide was further added dropwise to the reaction mixture. The reaction mixture was stirred at 100° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give N′-hydroxy-2-(4-nitrophenyl)ethanimidamide as brown crystals (7.10 g, yield 59%). Recrystallization thereof from ethyl acetate-diisopropyl ether gave brown prism crystals. melting point: 170-171° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][N:14]2[CH2:13][CH2:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=4[CH2:7][C:8]4[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=4[C@@H:10]3[CH2:15]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: Fc1ccc2c(c1)Cc1ccccc1[C@@H]1CNCCN21
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccc(F)cc3Cc3ccccc3[C@@H]2C1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-8-fluoro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8](O)=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C(C1NC=CN=1)([C:27]1[NH:28]C=CN=1)=O.[Sn](Cl)Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:27]([NH2:28])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[O:16][CH3:15])[CH2:8]2
Reactant: COc1ccccc1CN
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: Cl[Sn]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CN(Cc1ccccc1OC)C(N)=N2

Procedure:
6-Methoxy-3-(2-methoxybenzyl)-3,4-dihydroquinazolin-2-amine was synthesized from 5-methoxy-2-nitrobenzoic acid and 2-methoxybenzylamine by analogy with EXAMPLE 89. The peptide coupling was performed with carbonyl diimidazole and triethylamine in dimethylformamide. The nitro group was reduced with tin(II) chloride instead of iron(III) chloride to form the corresponding aniline. Subsequent cyclization to the dihydroquinazoline with cyanogen bromide was performed using a mixture of dichloromethane and ethanol.
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:35])[CH3:34])[C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1>>[CH:1]1([C:7]2[N:16]3[C:10]([C:11](=[CH:46][C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[NH:37][CH:38]=4)[C:12](=[O:36])[N:13]([CH2:21][C:22]([N:24]([CH:33]([CH3:34])[CH3:35])[C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Yield: 64 %

Procedure:
Following the procedure described for Example 1(A), Step A, 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 8(A)) (90 mg, 0.184 mmol) was condensed with 1H-indole-3-carbaldehyde (32 mg, 0.221 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) yielded 72.5 mg of 2-[1-cyclohexyl-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.63 (s, 1H), 8.16 (m, 1H), 7.88-7.96 (m, 1H), 7.45-7.76 (m, 2H), 7.12-7.44 (m, 1H) 6.83 (m, 1H), 5.10 (m, 1H), 4.11-4.35 (m, 1H), 3.94 (t, 2H), 3.84 (dd, 1H), 2.94 (m, 1H), 2.25 (m, 1H), 1.99 (m, 2H), 1.70 (m, 6H), 1.35 (m, 3H), 1.15 (m, 6H); MS 616.4 (M+1), 614.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:17])=[CH:6][C:7]=1[C:8]([C:10]1[N:11]=[C:12]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(=O)c3cc(Br)cnc3N)n2)CC1
Temperature: 95 °C
Yield: 36.7 %

Procedure:
A mixture of (2-amino-5-bromopyridin-3-yl)(6-bromopyridin-2-yl)methanone (6.0 g, 16.8 mmol), 1-Boc-homopiperazine (3.64 ml, 18.48 mmol) and K2CO3 (8.13 g, 58.8 mmol) in DMF (50 ml) was heated at 95° C. for 17 hours. Additional 1-Boc-homopiperazine (0.3 ml, 0.1 eq) was added and the mixture heated at 95° C. for a further 4 hours for reaction to go to completion. Reaction mixture was then allowed to cool to room temperature and solvent removed in vacuo. The resulting solid was slurried in EtOAc and filtered through a short pad of silica, washing through with EtOAc and the resulting filtrate was then concentrated to dryness in vacuo. The crude product was purified by flash chromatography on silica (5 to 25% EtOAc/Petrol) to give pure title compound as a yellow solid (2.94 g, 37%). 1H NMR (DMSO-d6) (quoted as a mixture of rotamers) 1.25 (9H, d), 1.91-1.77 (2H, m), 3.34 (2H, masked signal), 3.57-3.50 (2H, m), 3.65-3.62 (2H, m), 3.77-3.70 (2H, m), 6.95 (1H, dd), 7.12 (1H, dd), 7.75-7.69 (1H, m), 7.80 (2H, br s), 8.32 (1H, d), 8.60 (1H, dd). ES+ 477.98.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32](O)=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](N1C=CN=C1)([N:37]1[CH:41]=CN=C1)=O.C[NH:48][S:49](NC)(=[O:51])=[O:50].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([NH:48][S:49]([N:37]([CH3:41])[CH3:35])(=[O:51])=[O:50])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNS(=O)(=O)NC
Reactant: COc1ccc2c(c1)C=C(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.2 %

Procedure:
13-Cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (63 mg, 0.14 mMol) was dissolved in 1.7 mL of THF and carbonyldiimidazole (31 mg, 0.19 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr then heated to reflux for 1 hr. The reaction was cooled under nitrogen atmosphere and dimethylsulfamide (91 mg, 0.73 mMol) added followed by DBU (23 uL, 0.15 mMol). The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, cooled under nitrogen and stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase washed with brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 103 mg of a crude product as an amorphous yellow film. The crude product was dissolved in methanol and purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=25 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=12.16 min to 12.96 min. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23 (1 H, br. s.), 1.36-1.45 (2 H, m), 1.56 (1 H, br. s.), 1.78 (2 H, d, J=10.07 Hz), 2.00 (2 H, br. s.), 2.07 (2 H, br. s.), 2.78-2.91 (1 H, m), 3.09 (6 H, s), 3.94 (3 H, s), 4.43 (1 H, br. s.), 5.91 (1 H, br. s.), 7.03 (1 H, d, J=2.44 Hz), 7.10 (1 H, dd, J=8.55, 2.75 Hz), 7.50 (1 H, d, J=1.53 Hz), 7.55 (1H, d, J=8.55 Hz), 7.65 (1 H, s), 7.69 (1 H, s), 7.89 (1 H, d, J=8.55 Hz), 8.24 (1 H, s), 8.81 (1 H, br. s.). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.65 min, purity 93%; Flow injection Mass Spectrometry: MS m/z 561(MH+), m/z 559(M-H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)C.OC1N(C)N=CC=1.CS(C1C=CC(C(O)=O)=C(C)C=1C(OC)=O)(=O)=O.[CH:34]([O:37][C:38]([C:40]1[C:41]([CH3:53])=[C:42]([CH:46]=[CH:47][C:48]=1[S:49]([CH3:52])(=[O:51])=[O:50])[C:43](O)=[O:44])=[O:39])([CH3:36])[CH3:35]>>[OH:8][C:7]1[N:3]([CH3:1])[N:4]=[C:5]([C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:48]([S:49]([CH3:52])(=[O:51])=[O:50])=[C:40]([C:38]([O:37][CH:34]([CH3:35])[CH3:36])=[O:39])[C:41]=2[CH3:53])[CH:6]=1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C(=O)OC(C)C
Reactant: CCn1nccc1O
Agent: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: Cn1nccc1O
Product: Cc1c(C(=O)c2cc(O)n(C)n2)ccc(S(C)(=O)=O)c1C(=O)OC(C)C
Yield: 45 %

Procedure:
The operation and treatment were conducted in the same manner as in Example 1 except that 1.12 g of 1-ethyl-5-hydroxypyrazole was changed to 0.98 g of 5-hydroxy-1-methylpyrazole, and 2.72 g of 4-methanesulfonyl-3-methoxycarbonyl-2-methylbenzoic acid was changed to 3.00 g of 3-isopropoxycarbonyl-4-methanesulfonyl-2-methylbenzoic acid, to obtain 1.71 g of the desired product. (Yield: 45%, melting point: 192°-194° C.)
Reaction SMILES: [F:1][C@:2]12[CH:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:30])[C@:15]3([O:25][C:26](=[O:29])[CH2:27][CH3:28])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH:4]=[CH:5][C:6](=[O:31])[CH:7]=1.[CH:33]([NH:35][C@H:36]([C:41](O)=[O:42])[CH2:37][CH2:38][S:39][CH3:40])=[O:34]>>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:30])[C@:15]3([O:25][C:26](=[O:29])[CH2:27][CH3:28])[C:16](=[O:19])[CH2:17][S:18][C:41](=[O:42])[CH:36]([NH:35][CH:33]=[O:34])[CH2:37][CH2:38][S:39][CH3:40])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH:4]=[CH:5][C:6](=[O:31])[CH:7]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: CCC(=O)O[C@]1(C(=O)CS)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@@]21C
Product: CCC(=O)O[C@]1(C(=O)CSC(=O)C(CCSC)NC=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 43.8 %

Procedure:
The title compound (0.47 gm) was prepared from 9-fluoro-11 hydroxy-16β-methyl-17-(1-oxopropyloxy)-pregna-1,4-diene-3,20-dione-21-thiol (0.80 gm) and N-formyl-L-methionine (0.99 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:26][S:27]([O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:26][S:27]([OH:30])(=[O:29])=[O:28].[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=2)[CH:32]=1)=[O:6]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: Cc1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: Cc1cccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)c1
Reaction time: 24 h
Yield: 32.5 %

Procedure:
To a solution of 2.3 g of m-methylbenzoic acid in 30 ml of anhydrous pyridine, was added 4.4 g of DCC. To the stirred mixture, while being cooled in ice, was added 5 g of 6-amidino-2-naphthol methanesulfonate. After stirring for 24 hours, the insolubles were removed by filtration and ethylether was added to the filtrate. On separation of the resulting oily substance by decantation, it crystallized. The crystals were recrystallized from a methanol-ether mixture to obtain 2.2 g of 6-amidino-2-naphthyl 3-methylbenzoate methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:34][CH2:35]2)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1nccc2c(-c3cc(C=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nccc2c(-c3cc(CN4CCC(NC(=O)OC(C)(C)C)CC4)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 426.9 %

Procedure:
A solution of Example 105B (125 mg, 0.317 mmol), tert-butyl piperidin-4-ylcarbamate (190 mg, 0.951 mmol) and acetic acid (0.181 mL, 3.17 mmol) in dichloromethane (3 mL) was heated at 50° C. for 1 hour. The reaction mixture was cooled in an ice bath and the sodium triacetoxyborohydride (134 mg, 0.634 mmol) was added portionwise over a few minutes. The reaction mixture was stirred 2 hours while warming to ambient temperature. The reaction mixture was quenched with 1 M sodium hydroxide (2 mL) and partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (783 mg, 100% yield).