Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1)([O-:21])=[O:20]
Reactant: c1ccc(-n2cccn2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Reaction time: 4 h
Yield: 36.58 %

Procedure:
1-Phenyl-1H-pyrazole (500 mg, 3.4 mmol) was added to a cold mixture (−10° C.) of acetic anhydride (2.6 mL) and conc. HNO3 (0.3 mL) and stirring was continued at ambient temperature for 4 hrs. The reaction mixture quenched with cold water and filtered. Isolation of the filter cake afforded 240 mg (36.58% Yield) of 4-nitro-1-phenyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][CH:34]=3)[CH2:20][CH2:21]2)=[O:33])=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NS(C)(=O)=O)cc1
Yield: 48.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (50.0 mg, 0.11 mmol) and methanesulfonyl chloride (0.025 ml, 0.316 mmol), the procedure of Inventive Example 94 was repeated to obtain 29.5 mg (50.7%) of the title compound in a colorless amorphous form.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1)C1C=CC=CC=1.COCCOC>CO.[C].[Pd]>[OH:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(N2CCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1nc(N2CCCC2)ccc1O
Yield: 100 %

Procedure:
6.10 g (19.5 mmol) of methyl 3-benzyloxy-6-(1-pyrrolidinyl)picolinate was catalytically reduced in 50 ml of methanol and 100 ml of 1,2-dimethoxyethane in the presence of 1.5 g of 10% palladium carbon. The catalyst was filtered off, and the solvent was distilled off, and the residue was crystallized from diisopropyl ether-n-hexane to obtain the desired product.
Reaction SMILES: [CH3:1][C@@H:2]([OH:115])[C@@H:3]1[NH:51][C:49](=[O:50])[C@H:48]([CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])[NH:47][C:45](=[O:46])[C@H:44]([CH2:57][C:58]2[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[NH:60][CH:59]=2)[NH:43]C(=O)[C@H](CC2C=CC=CC=2)NC(=O)[C@H](CC2C=CC=CC=2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(CNC([C@@H](N)C)=O)=O)CSSC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@H](O)C)[NH:10][C:8](=[O:9])[C@H:7]([CH2:108][C:109]2C=CC=C[CH:114]=2)[NH:6][C:4]1=[O:5].[CH:116]1[CH:121]=[C:120]2[C:122]([C:124](O)(O)[C:125](=O)[C:119]2=[CH:118][CH:117]=1)=[O:123].C1(OC)C=CC=CC=1>>[N:6]12[CH2:114][CH2:109][CH2:108][C@H:7]1[C:8]([NH:10][C@H:124]([C:122]([NH:43][C@@H:44]([C:45]([NH:47][C@H:48]([C:49]([NH:51][C@H:3]([C:4]2=[O:5])[C@@H:2]([CH3:1])[OH:115])=[O:50])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:46])[CH2:57][C:58]1[C:62]2[C:61](=[CH:66][CH:65]=[CH:64][CH:63]=2)[NH:60][CH:59]=1)=[O:123])[CH2:125][C:119]1[CH:118]=[CH:117][CH:116]=[CH:121][CH:120]=1)=[O:9]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: C[C@H](N)C(=O)NCC(=O)N[C@H]1CSSC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC1=O
Solvent: COc1ccccc1
Product: C[C@@H](O)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]2CCCN2C1=O

Procedure:
After conventional solid-phase assembly beginning with 1 mmole of Boc-Phe-Merrifield resin (1% cross-linked), the protected peptide hydrazide, H-D-Trp-Lys(Cl-Z)-Thr(Bzl)-Pro-Phe-NHNH2, is cleaved from the support by treatment with hydrazine in methanol and isolated by a procedure described by D. F. Veber et al., Proceedings of the National Academy of Science, U.S.A., 75: 2636-2640, (1978). Without further purification, the hydrazide is converted to the azide, neutralized with triethylamine, and cyclized in DMF solution to yield the protected ninhydrin negative material, cyclo[Pro-Phe-D-Trp-Lys-(Cl-Z)-Thr(Bzl)]. When this protected ninhydrin negative material is hydrogenated at atmospheric pressure and room temperature over 10% Pd on charcoal, the compound, cyclo[Pro-Phe-D-Trp-Lys-Thr(Bzl)], is formed and found to be a very effective somatostatin antagonist. When, however, the protected crude ninhydrin negative material is deprotected by treatment with HF-anisole under standard conditions, as described by G. T. Engberg et al., Nature, 293: 222-223, (1981), and purified by preparative HPLC eluting with 10-55% gradient of CH3CN in 20% AcOH, the reaction yields the pure peptide, cyclo(Pro-Phe-D-Trp-Lys-Thr), which has somatostatin antagonist activity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:19][CH3:20].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:17][C:16]([C:15]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:19][CH3:20])[CH:4]=1)=[O:18]
Reactant: COc1cc(-c2nc3sccn3c2C(C)=O)ccc1F
Reactant: COC(OC)N(C)C
Product: COc1cc(-c2nc3sccn3c2C(=O)C=CN(C)C)ccc1F
Temperature: 25 °C
Yield: 85 %

Procedure:
A 100 ml round bottom flask was charged with the 1-[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone (1.12 g, 3.86 mmol) and dimethylformamide dimethylacetal (25 ml). The mixture was refluxed for 20 hours and then cooled to room temperature. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (ethyl acetate), giving a pale yellow solid (1.138 g, 85%). 400 MHz 1H NMR (DMSO-d6) δ: 8.39 (d, J=4.7 Hz, 1H), 7.62 (d, J=12.5 Hz, 1H), 7.45-7.40 (m, 2H), 7.31 (dd, J=11.3, 8.2 Hz, 1H), 7.20 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 5.10 (d, J=12.5 Hz, 1H), 3.87 (s, 3H), 3.06 (br. s, 3H), 2.49 (br. s, 3H). LCMS: 346 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][NH:6][C:7]([NH:9][C:10](=[O:26])[CH:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:8])C.[OH-].[K+]>C(O)C.O>[CH:13]1([CH2:12][CH:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][C:4]([OH:27])=[O:3])=[O:26])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A solution of {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid ethyl ester (prepared in Example 12B-d, 77 mg, 0.19 mmol) in ethanol (5 mL) at 25° C. was treated with a solution of potassium hydroxide (36 mg, 0.65 mmol) in water (1 mL). The reaction mixture was stirred at 25° C. for 2 h. At this time, the reaction was diluted with water (5 mL) and the ethanol was removed in vacuo. The aqueous layer was then acidified to pH=2 with a 1N aqueous hydrochloric acid solution and extracted with methylene chloride (3×15 mL). The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 88/12 chloroform/methanol plus 1% acetic acid) afforded {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid (43 mg, 60%) as a white solid: mp 204.2-206.8° C.; EI-HRMS m/e calcd for C17H20Cl2N2O4 (M+) 386.0800, found 386.0795.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([C:31]([F:34])([F:33])[F:32])=[N:12]1)[C:5]([NH2:7])=[O:6].[NH2:35]C1C=C(C=CC=1N1C2=NC=CC(I)=C2C(C(F)(F)F)=N1)C(N)=O>>[NH2:35][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([C:31]([F:33])([F:34])[F:32])=[N:12]1)[C:5]([NH2:7])=[O:6]
Reactant: Cc1cc(C(N)=O)ccc1-n1nc(C(F)(F)F)c2c(-n3cnc(-c4cnn(C)c4)c3)ccnc21
Reactant: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Product: Cn1cc(-c2cn(-c3ccnc4c3c(C(F)(F)F)nn4-c3ccc(C(N)=O)cc3N)cn2)cn1

Procedure:
According to Example 99(2), compound (155) (0.040 g, 36%) was prepared using compound (158b) (0.090 g) instead of compound (99a).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([F:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=3)[C:6]2=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][CH2:30][CH2:31]Br>CN(C=O)C.CO>[Br:20][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[C:7](=[N:8][C:3]([NH2:2])=[N:4][CH:5]=3)[N:9]([CH3:21])[N:10]=2)[CH:17]=[C:16]([F:18])[C:15]=1[O:19][CH2:31][CH2:30][O:29][CH3:28]
Reactant: Cn1nc(-c2cc(F)c(O)c(Br)c2)c2cnc(N)nc21
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COCCOc1c(F)cc(-c2nn(C)c3nc(N)ncc23)cc1Br
Temperature: 120 °C

Procedure:
4-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-bromo-6-fluoro-phenol hydrochloride (Example 42b) (30 mg, 0.08 mmol) is dissolved in DMF (1 ml) then treated with K2CO3 (24 mg, 0.18 mmol) and 2-bromoethyl methyl ether (7.5 μL, 0.08 mmol). The reaction mixture is heated at 120° C. for 3 hours then cooled to room temperature, diluted with MeOH and concentrated in vacuo. The crude residue is dry loaded onto silica and purification by flash chromatography on silica eluting with iso-hexanes:EtOAc (50% EtOAc to 100% EtOAc) affords the title compound as an off-white soild.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:29][C:28](=[O:30])[NH:27][N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[CH:33]=[CH:34][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:39])[N:26]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:31]=[C:32]([C:35]([F:37])([F:36])[F:38])[CH:33]=[CH:34][C:16]=3[CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc3c(c2)N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)Cc2ccc(C(F)(F)F)nc2N3)oc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]-1,3,4-oxadiazol-2(3H)-one (Example 441, 10 mg, 0.0183 mmol) in DMF (0.10 mL) was added cesium carbonate (6 mg, 0.0183 mmol) and iodomethane (0.0011 mL, 0.0183 mmol). After stirring at rt for 1.5 h, the reaction mixture was quenched with water, and the product was extracted with EtOAc (3×). The combined extracts were washed with water and brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 chromatography, to provide the title compound. LC/MS: m/e 560.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.09 (1H, d, J=2.0 Hz), 7,69 (1H, dd, J=8.5, 2.1 Hz), 7.61 (1H, d, J=7.5 Hz), 7.10-7.20 (3H, m), 6.94-6.98 (3H, m), 6.83 (1H, d, J=8.7 Hz), 4.65-4.95 (2H, br), 3.53 (3H, s), 1.25 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[CH:13]([CH:15]=O)=O.O>C(O)(C)C>[N:10]1[C:7]2[C:6](=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:9][CH:8]=2)[N:11]=[CH:15][CH:13]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=CC=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc2nccnc2c1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a stirred solution of 3,4-diamino-benzoic acid methyl ester (236, 2 g, 12.03 mmol) in isopropanol (50 mL) was added oxaldehyde as a 40% solution in water (13.23 mmol, 1.52 mL). The reaction mixture was heated at 80° C. for 2 hours, the solvent was removed under reduced pressure and the residue was dried under vacuum to yield 237a as a yellow solid (2.09 g, 93% yield). 1H NMR: (DMSO) δ 9.01 (s, 2H), 8.54 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.6, 2.0 Hz, 1H), 8.14 (dd, J=8.6, 0.6 Hz, 1H), 3.35 (s, 3H).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([C:18]3[N:27]=[C:26]4[C:21]([C:22](=[O:41])[C:23]([C:36]([O:38]CC)=[O:37])=[CH:24][N:25]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])=[CH:20][C:19]=3[F:42])[CH2:14][CH2:13]2)[CH2:10]1)=O)(C)(C)C.[ClH:43]>>[ClH:43].[NH2:8][CH:9]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([C:18]3[N:27]=[C:26]4[C:21]([C:22](=[O:41])[C:23]([C:36]([OH:38])=[O:37])=[CH:24][N:25]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])=[CH:20][C:19]=3[F:42])[CH2:14][CH2:13]2)[CH2:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC4(CC3)CC(NC(=O)OC(C)(C)C)C4)c(F)cc2c1=O
Agent: Cl
Product: NC1CC2(CCN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC2)C1
Yield: 58 %

Procedure:
A solution of 7- (2-tert-butoxycarbonylamino-7-azaspiro[3.5 ]non-7-yl) 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester (399 mg, 0.68 mmol) was hydrolyzed with hydrochloric acid to provide the title product, mp 270° C. (decomp.), 223 mg (0.45 mmol, 58% yield for two steps).
Reaction SMILES: I[CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:12]=3)([CH2:7][CH2:8]1)[O:5][CH2:4]2.[C-:24]#[N:25].[Na+]>CN(C=O)C.CCOC(C)=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][C:13]1[CH:12]=[C:11]([C:6]23[CH2:9][CH2:10][C:3]([CH2:2][C:24]#[N:25])([CH2:8][CH2:7]2)[CH2:4][O:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 4-(iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane (1.5 g, 3.50 mmol) and NaCN (0.687 g, 14.01 mmol) in DMF (8 mL) was stirred at 80° C. for 18 h. The reaction was diluted with EtOAc (10 mL), washed with water (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetonitrile (1.15 g, 3.50 mmol, 100% yield) as light brown oil. The above nitrile (1.15 g, 3.50 mmol) was taken up in ethylene glycol (20 mL) and treated with 40% KOH (5.00 mL, 35.0 mmol). The reaction was stirred at 165° C. for 18 h and concentrated in vacuo. The residue was dissolved in water (15 mL), acidified to pH 2 with 1 N aqueous HCl, and extracted with EtOAc (5×5 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.91 g, 99% yield) as a light brown solid. LCMS, [M−H]+=261.3.
Reaction SMILES: [CH2:1]1[C:30]2[C:5](=[CH:6][C:7]3[C:8](=O)[C:9]4[C:26]([CH2:27][C:28]=3[CH:29]=2)=[CH:25][C:24]2[C:23](=O)[C:22]3[C:13](=[CH:14][C:15]5[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=5[CH:21]=3)[CH2:12][C:11]=2[CH:10]=4)[CH2:4][CH2:3][CH2:2]1.C1C2C(=CC3C(=O)C4C(CC=3C=2)=CC2CC3C(=CC5CCCCC=5C=3)C(=O)C=2C=4)CCC1>COCCOCCOC>[CH2:16]1[C:15]2[C:20](=[CH:21][C:22]3[C:13]([CH:14]=2)=[CH:12][C:11]2[C:24](=[CH:25][C:26]4[C:9]([CH:10]=2)=[CH:8][C:7]2[C:28](=[CH:29][C:30]5[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=5[CH:6]=2)[CH:27]=4)[CH:23]=3)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1c2cc3c(cc2Cc2cc4c(cc21)Cc1cc2c(cc1C4=O)CCCC2)CCCC3
Agent: O=C1c2cc3c(cc2Cc2cc4c(cc21)C(=O)c1cc2c(cc1C4)CCCC2)CCCC3
Solvent: COCCOCCOC
Product: c1c2c(cc3cc4cc5cc6cc7c(cc6cc5cc4cc13)CCCC7)CCCC2
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.0 gram of 1,2,3,4,8,10,11,12,13,17-decahydroheptacen-6,15-dione and 1,2,3,4,10,11,12,13-octahydroheptacen-6,8(15H,17H)-dione and 20 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 0.766 grams of sodium borohydride. The resulting mixture was stirred overnight at room temperature. To the mixture was added 7.2 mL of methanol and stirring was continued for 30 minutes. To the resulting mixture was added 0.2 grams of sodium borohydride, and stirring was continued at room temperature for 5 hours. The resulting mixture was heated to 60° C. for one hour. To the mixture was added 11.4 mL of glacial acetic acid and 7.3 mL of concentrated hydrochloric acid. The resulting mixture was heated at 60° C. for one hour. To this mixture was added 20 mL of water and the resulting solid was collected by filtration. The solid was washed with water followed by acetone followed by tetrahydrofuran and dried to give 1,2,3,4,10,11,12,13-octahydroheptacene.
Reaction SMILES: [CH2:1]([S:5]([N:8]([CH2:22][CH:23]=C)[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])[CH2:2][CH:3]=C>C(Cl)Cl.C1(P([Ru-2](Cl)(Cl)(P(C2CCCCC2)(C2CCCCC2)C2CCCCC2)=CC2C=CC=CC=2)(C2CCCCC2)C2CCCCC2)CCCCC1>[O:6]=[S:5]1(=[O:7])[CH2:1][CH2:2][CH:3]=[CH:23][CH2:22][N:8]1[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: C=CCCS(=O)(=O)N(CC=C)c1cc(CCC)cc(C(=O)OC)c1
Agent: Cl[Ru-2](Cl)(=Cc1ccccc1)([PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CCCc1cc(C(=O)OC)cc(N2CC=CCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.3 %

Procedure:
To a solution of methyl 3-[(3-buten-1-ylsulfonyl)(2-propen-1-yl)amino]-5-propylbenzoate (D135) (1 g, 2.8 mmol, 1 equiv) in CH2Cl2 (200 ml) was added bis(tricyclohexylphosphino)benzylidene ruthenium (IV) dichloride (117 mg, 0.14 mmol, 0.05 equiv) and the resulting solution was stirred at room temperature for 48 h then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 9:1) gave methyl 3-(1,1-dioxido-6,7-dihydro-1,2-thiazepin-2 (3H)-yl)-5-propylbenzoate (B117) (700 mg, 76%) as a pale purple oil. [M+H]+=324.4, RT=3.10 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:25]=[CH:24][C:19]=1[O:20][CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:23][CH2:22][CH2:21][O:20][C:19]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:27][C:18]=2[CH3:17])[C:7]=1[CH3:8]
Reactant: CCCCCc1ccc(OCCN)c(C)c1
Reactant: Cc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(OCCNc2ncnc(Cl)c2C)c(C)c1
Reaction time: 5 h

Procedure:
To a solution of 3.2 g (0.02 mol) of 4,6-dichloro-5-methylpyrimidine in 50 ml of toluene were added 2.0 g (0.02 mol) of triethylamine and 4.4 g (0.02 mol) of 2-(2-methyl-4-n-pentylphenoxy)ethylamine. The mixture was then refluxed with stirring for 5 hours.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[F:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:46])=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(F)cc3)CN2C1=O
Yield: 9 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.176 mmol) and 4-fluorobenzoyl chloride (42 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 11 mg (9.1%) of 18-(4-fluorobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 95.0% pure (HPLC), MS m/z 689 (M−H)−, HRMS: calcd. 691.2813 and found 691.2827 (M+H)+, mp 154-156° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH:21]([C:20]1[O:24][C:3](=[O:4])[C:5]2=[CH:9][CH:8]=[CH:7][N:6]2[CH:19]=1)([CH3:23])[CH3:22]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1cn2cccc2c(=O)o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a slurry of 2-(trichloroacetyl)pyrrole (5.3 g, 25 mmol) and K2CO3 (11 g, 76 mmol) in 100 mL acetone was added a solution of 1-bromo-3-methylbutan-2-one (4.5 g, 27 mmol) in 30 mL acetone. The mixture was stirred for 1 hour at 50° C. before filtering and concentrating under reduced pressure to obtain 3-isopropyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (4.1 g, 93%), which was used in the following step without purification.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1ccncc1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccncc1
Yield: 12 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and H, alkylating with 4-chloromethylpyridine, in 12% yield and isolated as a beige solid, mp 153°-154° C.; IR (KBr) 3204, 1679, 1505, 1407, 1283, 1256, 1077, 1065, 750 cm-1 ; 1H NMR (CDCl3) δ 2.18-2.38 (m, 3H), 3.93 (br q, J=3.9 Hz, 2H), 4.88 (dd, J=7.7, 5.4 Hz, 1H), 5.15 (s, 2H), 6.73 (d, J=7.6 Hz, 1H), 6.92 (td, J=6.7, 3.2 Hz, 1H), 6.98-7.06 (m, 2H), 7.15 (d, J=5.9 Hz, 2H), 8.56 (dd, J=4.5, 1.5 Hz, 2H); MH+ at m/z=285; Anal. Calc'd for C16 H16N2O3 : C, 67.59; H, 5.67; N, 9.85. Found: C, 67.67; H, 5.78; N, 9.79.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:3]1=2.S(=O)(=O)(O)O.[CH2:27]([OH:29])[CH3:28]>>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([O:29][CH2:27][CH3:28])=[O:19])=[CH:16][C:3]1=2
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1ccccc1S2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc2c(c1)C(=O)Cc1ccccc1S2
Reaction time: 1 h

Procedure:
To 200 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]thiepin-2-yl)-propionamide in 4 ml of ethanol was added 0.4 ml of conc. sulfuric acid and the mixture was refluxed with stirring for 1 hour. The solvent was distilled off to obtain the residue, to which was added pieces of ice, and the mixture was extracted with ethyl acetate and the extract was washed with saturated sodium hydrogen carbonate, then saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, and eluted with benzene-chloroform. There was obtained 141 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]-thiepin-2-yl)-propionate as pale yellow oil.