Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@H:7]([OH:20])[CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[OH:20][C@H:7]([CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:6][NH:5][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1CN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)C(=O)N1
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
Acetic acid (0.14 mL, 2.38 mmol) was added dropwise into a mixture of 4-{[(2S)-3-amino-2-hydroxypropyl]oxy}-1,3-dihydro-2H-benzimidazol-2-one (265 mg, 1.19 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidinedione (400 mg, 1.19 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (303 mg, 1.43 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 3/1) to produce a brown solid (256 mg, 40% yield): mp 230° C. (decomposed); 1H NMR (400 MHz, DMSO-d6): δ 1.52-1.63 (m, 2H), 2.04-2.15 (m, 2H), 2.48 (m, 2H), 2.9-3.0 (m, 2H), 3.13-3.15 (m, 1H), 3.2-3.4 (m, 3H), 4.0-4.1 (m, 5H), 4.42 (s, 2H), 6.6-6.63 (m, 2H), 6.8-6.85 (m, 1H), 7.03-7.05 (m, 2H), 7.78-7.8 (m, 2H), 10.6 (s, 1H), 10.7 (s, 1H); MS m/e 543 (M−H)+; Analysis for: C24H28N6O7S Calc'd: C, 45.24; H, 5.38; N, 12.88 Found: C, 45.88; H, 5.36; N, 13.88.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.OCCOC1C=CC([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])=CC=1.CO.C(N(C(C)C)CC)(C)C>C1COCC1>[ClH:10].[CH2:31]([NH:32][C:14]([NH:13][C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])=[NH:17])[CH2:30][CH2:29][CH3:28]
Reactant: NCCCCc1ccc(OCCO)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCNC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Product: Cl
Temperature: 25 °C
Yield: 194 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.32 g, 0.8 mmol) was added to a solution of amine 115 (0.25 g, 1.2 mmol) in a mixture of THF (15 mL), methanol (5 mL) and diisopropylethylamine (1 mL). The reaction mixture was stirred at reflux for 3.5 h and then cooled to room temperature. The formed precipitate was isolated, washed with ethyl acetate (2×5 mL) and treated with 5% HCl (10 mL). The resulting solid was isolated by filtration, washed with water and dried under vacuum to give compound 116 (0.25 g, 73%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.56 (m, 4H), 2.57 (m, 2H), 3.32 (m, 2H), 3.70 (m, 2H), 3.93 (m, 2H), 4.90 (t, 1H), 6.84 (d, 2H), 7.12 (d, 2H), 7.45 (s, 2H), 8.70 (br s, 1H), 8.88 (br s, 1H), 9.12 (br s, 1H) 10.45 (s, 1H). APCI MS m/z=422 [C18H24ClN7O3+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([S:31][CH3:32])[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[CH:7][CH:6]=1.[NH2:33][C:34]1([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([S:31][CH3:32])[O:23]2)=[CH:18][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([NH:33][C:34]2([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:14])=[CH:16][CH:17]=1
Reactant: NC(=O)C1(N)CCCC1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCC(=O)O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCC(=O)NC4(C(N)=O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)butanoic acid (39, 46 mg, 0.10 mmol), 1-aminocyclopentanecarboxamide (26 mg, 0.20 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (0.5 mL) and stirred overnight at room temperature. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The material was purified by prep HPLC (C18 30×100 mm column, 20-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) and lyophilized to give 35 mg (61% yield) of amide 41 as a white solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10-7.19 (m, 3 H), 7.04 (d, J=8.6 Hz, 2 H), 6.81 (m, J=8.6 Hz, 2 H), 4.39 (d, J=9.3 Hz, 1 H), 4.12 (d, J=9.1 Hz, 1 H), 3.96 (t, J=6.2 Hz, 2 H), 3.92 (s, 2 H), 3.34-3.50 (m, 3 H), 2.41 (t, J=7.5 Hz, 2 H), 2.12-2.22 (m, 8 H), 2.04 (quin, J=6.9 Hz, 2 H), 1.93 (dt, J=12.8, 5.1 Hz, 2 H), 1.64-1.75 (m, 4H); MS (ES+) [M+H]+=573.
Reaction SMILES: [CH2:1]([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:30])[C:24](=[CH:28][CH:29]=1)[C:25](O)=[O:26].C1N=CN(C(N2C=NC=C2)=O)C=1.O>C1COCC1>[CH2:1]([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]2[C:25](=[O:26])[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:29][CH:28]=3)[NH:30][C:18]2=[O:19])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CCOC(=O)Cc1cccc(S(=O)(=O)N=C=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)Cc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Following the Synthesis Method (A), 3.27 g (11.6 mmol) of 3-allyloxycarbonylmethylbenzenesulfonyl isocyanate was dissolved in 100 ml of anhydrous THF, then 1.98 g. (11.5 mmol) of 4-chloroanthranilic acid was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled with ice water, then 1.87 g (11.5 mmol) of CDI was added and the resultant mixture was stirred under ice cooling for 30 minutes. An excess amount of water was poured into the reaction solution, then the mixture was extracted with ethyl acetate. The organic layer was washed, dried, and concentrated to obtain a crude product. This was crystallized with a small amount of ethyl acetate to obtain 2.0 g (yield 40%) of 3-(3allyloxycarbonylmethylbenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione. The allyl product thus obtained was dissolved in 100 ml of a formic acid-THF (1:9) mixture and 700 mg of triphenylphosphine was added. The reactor was shaded from light and under nitrogen atmosphere, then 700 mg of tetrakis(triphenylphosphine)palladium (0) was added and the resultant mixture was stirred while shaded at room temperature overnight. The reaction solution was concentrated in vacuo and the solid obtained was washed with methylene chloride to obtain 1.47 g (yield 81%) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.76 (2H, s), 7.13 (1H, s), 7.24 (1H, d), 7.61-7.69 (2H, m), 7.86 (1H, d), 8.05 (1H, s), 12.50 (1H, br).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=[C:54]1[C:62](O)=[O:63].C(N(CC)CC)C>CN(C)C=O.O>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[C:7]1[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3](=[O:25])[CH:2]([NH:1][C:62]([C:54]2[NH:53][C:61]3[C:56]([CH:55]=2)=[CH:57][CH:58]=[CH:59][CH:60]=3)=[O:63])[N:8]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)c2cc3ccccc3[nH]2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 0.38 g of the laevorotatory enantiomer of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one in 10 ml of dimethylformamide, cooled to 50° C., are added 0.52 g of BOP and 0.19 g of indole-2-carboxylic acid, followed by 0.23 ml of triethylamine. The reaction mixture is stirred overnight at room temperature and is then poured into water and extracted with ethyl acetate, dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on a column of silica gel (eluent: dichlormethane/methanol: 95/5). The fractions of pure product are evaporated to dryness and the residue is crystallized from isopropyl ether. White crystals of (-)-N-[2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-1H-indol-2-carboxamide are obtained, melting at 135° C.; Yield=81%; [α]D20 =-408 (c=0.35 in 1N HCl/CH3OH-50/50).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:18][C:2]1[N:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=[N:19][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1
Reactant: Nc1ccccn1
Reactant: CCC1Oc2ccc(C(=O)C(C)Br)cc2NC1=O
Product: CCC1Oc2ccc(-c3nc4ccccn4c3C)cc2NC1=O
Yield: 47.7 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.07 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.28 g) and 2-aminopyridine (2.0 g).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:5])([CH3:4])[CH3:3].CC[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])C.CN(C([O:30]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>ClCCl>[NH:16]1[CH2:17][CH2:19][CH2:22][C@H:20]1[C:21]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:13])=[O:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of L-proline-tert-butyl ester hydrogen chloride salt 75 (0.5 g, 2.9 mmol) in dichloromethane (50 mL) was added 76 (0.98 g, 2.99 mmol), DIPEA (756 mg, 4.35 mmol) and HATU (1.3 g, 3.5 mmol). The reaction mixture was allowed to stir at an ambient temperature for 16 h. The mixture was poured into ethyl acetate (100 mL) and was washed with 0.2 N HCl (50 mL), water (50 mL), brine (50 mL) and dried over MgSO4. Chromatography was conducted on a 2 mm radial chromatotron plate eluting with 10% ethyl acetate in hexanes. Product-containing fractions were concentrated under reduced pressure, dissolved in dichloromethane (8 mL) and treated with piperidine (2 mL). The mixture was stirred for 1 h, concentrated under reduced pressure and purified on a 2 mm radial chromatotron plate eluting with 5% methanol/dichloromethane. This gave 200 mg (26%) of the dipeptide 74: 1H-NMR (400 MHz, CDCl3) δ 4.41 (m, 1H), 4.17 (m, 1H), 3.82 (m, 1H), 3.57 (m, 4H), 3.2 (m, 1H), 2.82 (m, 1H), 2.83-1.65 (m, 5H), 1.44 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C-:13]#[N:14].[K+]>>[C:13]([C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([OH:4])[C:2]([F:11])([F:12])[F:1])#[N:14]
Reactant: [C-]#N
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [K+]
Product: N#CC(O)(c1ccccc1)C(F)(F)F

Procedure:
1-Cyano-1-phenyl-2,2,2-trifluoroethanol was prepared from α,α,α-trifluoroacetophenone by a cyanohydrin reaction with potassium cyanide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Nc1ccccn1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
2-aminopyridine (5.0 g) was dissolved in chloroform (40 mL) and acetic acid (10 mL), and n-butyraldehyde (4.2 g) was added, then stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (16.9 g) was added and stirred at room temperature for three hours. Ethyl acetate (300 mL) was added to the reaction solution, and the organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate (200 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration, and vacuum concentration, the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to give the above-identified compound (2.7 g, yield 34%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>CN(C=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][O:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1
Reactant: BrCc1ccccn1
Reactant: O=C(N1CCc2ccc(CCn3ccc(O)cc3=O)cc2CC1)C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 200 mg (0.53 mmol) 4-hydroxy-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 21b) in DMF is added 145 mg (1.05 mmol) potassium carbonate and the mixture is stirred 10 min at RT before 133 mg (0.53 mmol) 2-(bromomethyl)-pyridine hydro-bromide is added. The reaction mixture is stirred 5 h at RT and is directly purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 5:95).
Reaction SMILES: [Cl:1][C:2]1[C:18]([N+:19]([O-])=O)=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5].CC/C=C/C=C\CCCCCCCCOC(C)=O.[H][H]>CO>[Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([F:22])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][S:7]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])(=[O:9])=[O:8])=[O:5]
Reactant: [H][H]
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c([N+](=O)[O-])c1Cl
Agent: CC/C=C/C=C\CCCCCCCCOC(C)=O
Solvent: CO
Product: CC(C)N(C)S(=O)(=O)NC(=O)c1ccc(F)c(N)c1Cl
Reaction time: 6 h

Procedure:
182.4 g (0.500 mol) of N-(2-chloro-4-fluoro-3-nitrobenzoyl)-N′-isopropyl-N′-methylsulfamide in 391 g of methanol were admixed with 1.33 g (0.005 mol %) of 1% Pt-2% V/C and hydrogenated with 5 bar of hydrogen with stirring at 60° C. After 6 h the solution was depressurized, the reaction mixture was filtered and the solvent was removed by distillation. This gave 157.1 g (97%) of the title compound in the form of a solid (m.p.: 147-149° C.).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C([N:25]([C:33]1[S:42][CH2:41][C@H:40]2[C@:35]([C:43]3[CH:48]=[C:47](Br)[CH:46]=[CH:45][C:44]=3[F:50])([CH2:36][O:37][CH2:38][CH2:39]2)[N:34]=1)C(OC(C)(C)C)=O)(=O)C1C=CC=CC=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:50][C:44]1[CH:45]=[CH:46][C:47]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:48][C:43]=1[C@@:35]12[N:34]=[C:33]([NH2:25])[S:42][CH2:41][C@@H:40]1[CH2:39][CH2:38][O:37][CH2:36]2
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@@]2(c3cc(Br)ccc3F)COCC[C@H]2CS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)COCC[C@H]2CS1
Temperature: 90 °C
Reaction time: 6 h
Yield: 38.6 %

Procedure:
2-Fluoropyridine-3-boronic acid (25.6 mg), tetrakis(triphenylphosphine)palladium (10.5 mg) and a 1 N sodium carbonate solution (182 μl ) were added to a solution of (±)-N-benzoyl-N-(tert-butyloxycarbonyl)-[(4aR*,8aS*)-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (50 mg) in DMF (5.0 ml). After replacement with nitrogen, the mixture was stirred at 90° C. for six hours. The reaction solution was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (12.7 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClC1C=C(C2C=CC=C(Cl)C=2)C=CC=1.Cl[C:39]1[CH:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[CH:60]=4)[CH:53]=3)[CH:46]=2)[CH:42]=[CH:43][CH:44]=1>O.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:43]1[CH:42]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[CH:60]=4)[CH:53]=3)[CH:46]=2)[CH:40]=[CH:39][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)c1
Reactant: Oc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Agent: Clc1cccc(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2cccc(Oc3cccc(Oc4cccc(-c5cccc(Oc6cccc(Oc7cccc(Oc8ccccc8)c7)c6)c5)c4)c3)c2)cc1
Yield: 80 %

Procedure:
A 250 ml. four-necked flask, equipped with stirrer, dropping funnel, thermometer, and Dean-Stark trap surmounted by a Friedrichs condenser was charged with 59.8 g. (0.215 mole) of m-(m-phenoxyphenoxy)phenol to which 13.0 g. 0.208 mole) of potassium hydroxide was added at 90°C. followed by addition of 50 ml. of toluene. The stirred reaction mixture was heated to azeotrope water, followed by distillation of toluene until the temperature of the reaction mixture reached 230°C. To this mixture after cooling was added 50 ml. of diglyme, 2.5 g. of cuprous chloride, 0.5 g. of copper powder, and 20 g. (0.09 mole) of 3,3'-dichlorobiphenyl over a 30 min. period at 175 C. Diglyme was distilled from the reaction mixture which was then heated at 230°-260°C. for 18 hr. The cooled very thick semi-solid mass resulting was dissolved in 500 ml. of ethyl ether and the suspended salts removed by centrifugation. The resulting ethereal solution was washed thoroughly with 10% potassium hydroxide solution and with water until neutral, and finally dried over anhydrous magnesium sulfate. After concentrating this solution, it was distilled using a 25 ml. still pot attached to a Claisen head and fraction cutter. Distillation using a Wood's metal bath on the still pot gave 10 g. of viscous red-orange liquid, bp 348°-352°C/0.09 mm. at a pot temperature of 428°C. Elemental analysis showed this cut to be about 80% of the desired product and 20% 3-chloro-3'-[m-(m-phenoxyphenoxy)phenoxy]biphenyl. The pot residue was dissolved in 300 ml. of ethyl ether, treated with 1 g. of activated charcoal and filtered through filter aid. The ether was removed under vacuum to yield a light orange product, bp 380°-390°C/0.05 mm., nD25 1.658.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:15][CH2:14]1
Reactant: N#Cc1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
The crude 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carbonitrile (Intermediate 9) (0.222 g, 0.493 mmol) was suspended in dichloromethane (5 mL) and treated with diisopropylethyl amine (0.257 mL, 1.48 mmols), and ethane sulfonyl chloride (0.070 mL, 0.74 mmols) at ambient temperature. After 2 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (25 mL), and extracted with dichloromethane (100 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified by combiflash (column 10 g, eluting with 100% dichloromethane, 5% ethyl acetate/dichloromethane, 30% ethyl acetate/dichloromethane) to give the title compound (0.083 g, 24%).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccccc1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccccc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
1,3-dipropyl-5,6-diaminouracil (0.01 mol) was dissolved in 30 ml methanol, followed by 0.01 mol of benzoic acid and then 0.01 mol of DICD. The solution was stirred for 30 min at room temperature, filtered, and washed with a small amount of methanol. The solid was boiled for ten minutes in 2.5N KOH, filtered hot, and the liquid neutralized with concentrated HCl. The solid was collcted by filtration, washed with water, redissolved in 100 ml with a minimum amount of KOH, precipitated by neutralization with HCl, filtered, washed with water, and dried. The product was identified by chemical ionization mass spectrometry and elemental Analysis. Yield 77%.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[C:5](=[O:8])[NH:4][C:3]2[S:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[N+:12]([C:10]1[S:9][C:3]2[NH:4][C:5](=[O:8])[C:6](=[O:7])[NH:1][C:2]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccsc2[nH]c1=O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc([N+](=O)[O-])sc2[nH]c1=O
Yield: 25.6 %

Procedure:
Thieno[2,3-b]pyrazine-2,3(1H,4H)-dione (1.00 g, 5.95 mmol) was reacted with fuming nitric acid (0.374 ml, 8.9 mmol) in acetic anhydride following the procedure outlined in example 4 (Method F). The crude product (655 mg) was recrystallized from acetic acid to afford 325 mg (26%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 7.58 (s, 1H), 12.1 (s, 1H), 12.62 (s, 1H).