Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[N:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[H][H]>[Ni].C(O)C>[CH3:1][N:2]1[CH2:9][NH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: Cn1cnc(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CN1CNC(=O)NC1=O
Temperature: 90 °C
Yield: 59 %

Procedure:
A hydrogenation mixture consisting of 203.5 gm. (1.6 moles) of the 1-methyl-5-azauracil prepared in Part B, above, 7 teaspoons of Raney Nickel, and 8 liter ethanol in a five-gallon autoclave is subjected to 750 p.s.i. hydrogen pressure at 125° C. for an interval of 12 hours. The hydrogen is flushed out of the chamber with nitrogen gas and the reaction mixture is siphoned out of the chamber into a five-gallon carboy. The walls of the chamber are washed down with water and these washings are siphoned into the carboy. The carboy is then flushed with nitrogen (<20 p.s.i.) so as to force the medium through a filter stick onto a filter bed of Dicalite 4200 (diatomaceous earth). The solids are retained in the carboy substantially undisturbed. The medium is then sucked through the dicalite filter under reduced pressure until 1 inch of liquid remains. The solids retained in the bottom of the carboy are now mixed with two (2) liters water and 500 ml. Dicalite 4200 and this mixture is added to the filter cake. The filter cake is then washed with water. The filtrate and washings are combined and the water is removed to a volume of 1200 ml. by evaporation under reduced pressure, 20 mm mercury, and 50° C. temperature. The concentrate thus obtained is heated to 90° C., and 95% aqueous ethanol is added to a volume of two liters. Upon cooling, crystallization occurs. The crystals are collected on a filter and dried. There is thus obtained 120 gm. (59% yield) of 5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione having a melting point of 252° C. to 254° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[N:23]=[C:24]4[C:29](=[C:30]5[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]5)[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12][C@:11]2([C:38]([NH:40][S:41]([CH:44]3[CH2:46][CH2:45]3)(=[O:43])=[O:42])=[O:39])[CH2:37][C@H:10]2[CH2:9][C:8]([F:48])([F:47])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH3:50][N:51]1[C:55]([CH3:56])=[CH:54][C:53]([C:57](O)=[O:58])=[N:52]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH:44]1([S:41]([NH:40][C:38]([C@@:11]23[CH2:37][C@H:10]2[CH2:9][C:8]([F:47])([F:48])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:57]([C:53]2[CH:54]=[C:55]([CH3:56])[N:51]([CH3:50])[N:52]=2)=[O:58])[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]4[N:23]=[C:24]5[C:29](=[C:30]6[C:35]=4[CH:34]=[CH:33][CH:32]=[CH:31]6)[CH:28]=[CH:27][CH:26]=[CH:25]5)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12]3)=[O:39])(=[O:43])=[O:42])[CH2:46][CH2:45]1
Reactant: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Reactant: Cc1cc(C(=O)O)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a mixture of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 20a, 12 mg, 0.017 mmol), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2.57 mg, 0.018 mmol) and 2-(3H-[1,2,3]triazolo [4,5-b]pyridin-3-yl)-1,1,3 ,3-tetramethylisouronium hexafluorophosphate(V) (7.0 mg, 0.018 mmol)in dichloromethane (167 μl) was added N-ethyl-N-isopropylpropan-2-amine (10.18 μl, 0.058 mmol) and the mixture was stirred for 3 h at room temperature. 0.1 N HCl was added and organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The residue after solvent evaporation under reduced pressure was eluted through silica gel with 10% acetone/dichloromethane. The fractions containing the title compound were combined and the resulting crude material was purified by preparative thin layer chromatography on silica gel (20:1 dichloromethane/methanol) to provide the title compound (2R,6S,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide (8 mg 60% yield) as a white solid. MS (ESI): m/z=806.1 [M+H]. Example 21 provided a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of <1.0 nM in a replicon cell line assay in a 1b-con1 background.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]C(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][Br:30])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)cnc1Cl
Yield: 72.5 %

Procedure:
2,3-Dichloro-5-(hydroxymethyl)pyridine (275 mg) was dissolved in dichloromethane (10 ml) and stirred in the presence of triphenylphosphine (444 mg) and tetrabromometliane (641 mg) overnight. The solution was concentrated in vacuo and the residue purified by column chromatography using isohexane: 2.5% ethyl acetate as eluent to yield the product as a white solid (270 mg, 73%). NMR: δ 4.75 (s, 2H), 8.25 (m, 1H), 8.5 (m, 1H); m/z 242 (M+H+).
Reaction SMILES: [OH-].[NH4+].[SH:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:6].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=O.[Na+].[Na+]>O1CCCC1>[NH4+:7].[SH:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[O:12])=[O:6]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
An aqueous solution of 3N ammonium hydroxide (7.2 ml., 0.0216 mole) is slowly added to a suspension of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole) in 40 ml. of tetrahydrofuran with 5 mg. of disodium edetate. The resulting solution is diluted with 300 ml. of tetrahydrofuran and after cooling in a dry ice-ethanol bath to promote crystallization is stirred overnight. The precipitated solid is collected, washed with tetrahydrofuran and air dried to afford 4.6 g., (79.3% yield) of N-[3-(mercaptoacetylamino)benzoyl]glycine ammonium salt susquihydrate, m.p. 56°-119° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Cl[C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[CH:10][N:9]=1.[OH2:17]>COCCOCCOC.CN(C)C>[NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[NH:9]1[C:10](=[O:17])[C:11]2[NH:12][CH:13]=[N:14][C:15]=2[N:16]=[C:8]1[NH2:1]
Reactant: O
Reactant: Clc1ncc2[nH]cnc2n1
Agent: CN(C)C
Agent: O=C1CCCN1
Solvent: COCCOCCOC
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The chloropurine pyrrolidone (1 mmol) from the previous paragraph is dissolved in diglyme (10 ml) and 25% aqueous trimethylamine (2 ml). The solution is stirred at rt for 5 h, water (10 ml) is added, and the mixture concentrated to 10 ml under reduced pressure. Acetic acid (2 ml) is added, and the mixture was evaporated under reduced pressure to an oil. The residue which contains trimethylammonium acetate is used directly for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH2:29]C)=[O:27]>CC(C)=O>[CH3:29][O:28][C:26]([CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)=[O:27]
Reactant: CCOC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
4.5 g (0.02 mol) of benzyl p-hydroxybenzoate were suspended in about 60 ml of acetone together with 9.7 g (0.03 mol) of cesium carbonate and treated with 2.3 ml (0.025 mol) of ethyl bromoacetate. The mixture was then refluxed until reaction was complete. For working-up, the reaction solution was filtered through a clarifying layer and the filtrate was concentrated to dryness. The residue was taken up in ethyl acetate and the mixture was washed three times each with 10% strength citric acid solution and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was recrystallized from diisopropyl ether/heptane. Yield: 5.5 g.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:14][CH:11]1OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:43]([OH:46])(=[O:45])[CH3:44].N1C=CC=CC=1.S(=O)(=O)(O)O>O>[C:43]([O:46][CH:11]1[O:14][C@@H:15]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:10]1[O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:45])[CH3:44]
Reactant: COC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
59.40 g out of 62.69 g of the crude 2,3,5-tri-O-benzoyl-1-O-methyl-L-ribofuranose synthesized in (2) above was added to a 1-L flask. Thereafter, acetic anhydride (31.2 ml; 2.65 equivalents), acetic acid (26.7 ml; 3.73 equivalents), and pyridine (7.1 ml; 0.8 equivalents) were added to the flask. The obtained mixture was cooled to an ice-cooled temperature, and thereafter, concentrated sulfuric acid (13.5 ml; 2.03 equivalents) was slowly added dropwise thereto. After completion of the reaction for 30 minutes, cold water (200 ml) was slowly added dropwise to the reaction product, and crystals were then filtrated. The obtained solid was dried. Thus, 69.83 g of crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was obtained in the form of a light yellow solid. The obtained compound was analyzed by HPLC. As a result, the ratio of α-/β-anomers in the 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was 4/96, and the reaction yield of the β-anomer from the total 3 steps was 84%. 69.83 g of the crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was suspended in isopropyl alcohol (92 ml), and the suspension was then heated to reflux for 1 hour. Thereafter, the reaction solution, in which the aforementioned compound had been completely dissolved, was cooled to an ice-cooled temperature, and it was then stirred for 30 minutes. Thereafter, the resultant mixture was filtrated, and the obtained crystals were then dried under reduced pressure. Thus, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose was obtained from L-ribofuranose in the form of white crystals with a purity of 99% or more at a total yield of 75%.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:19]=[CH:18][N:17]=2)[CH2:21][C:22]([C:33]([F:38])([F:39])[C:34]([F:36])([F:37])[F:35])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccn2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[4-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-pyridin-2-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 6.0 mmol) prepared in Example 176 was added to a saturated solution of hydrochloric acid in ethyl acetate (20.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 380.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH:19]1([CH2:22][O:23][C:24]2[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)[CH2:21][CH2:20]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH2:22][CH:19]4[CH2:21][CH2:20]4)=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1cnc(OCC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC4CC4)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (example 36) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=436.2 [M+H]+.
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C[Si](C)(C)[C:22]([F:25])([F:24])[F:23].[F-].[Cs+].Cl>C1COCC1>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3](=[O:19])[C:22]([F:25])([F:24])[F:23])=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-benzyloxy-phenyl)-acetic acid methyl ester (11.7 mmol, 3.0 g), trimethyl-trifluoromethyl-silane and cesium fluoride in THF may be stirred at room temperature for 2 h. Hydrochloride may be added upon consumption of ester as indicated by TLC. The mixture may be stirred further at room temperature until the intermediate disappears as indicated by TLC to provide 3-(4-benzyloxy-phenyl)-1,1,1-trifluoro-propan-2-one.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc(I)c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 620.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[K+].[K+].Br[C:32]1[C:37]([CH:38]=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:32]2[C:37]([CH:38]=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: O=Cc1cccnc1Br
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a 250 mL flask are added copper(I) iodide (1.91 g, 10.03 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (25 g, 66.87 mmol), potassium carbonate (19.60 g, 140.43 mmol), toluene (50 mL) and a stirring bar. The reaction mixture is degassed by 5 vacuum/refill cycles. Then, 2-bromo-3-formyl pyridine (18.66 g, 100.31 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (3.16 mL, 20.06 mmol) are added. The reaction is stirred at room temperature for 5 minutes. Then, it is immersed in a preheated oil bath at 115° C. and stirred for 15 h at that temperature. Reaction mixture is cooled to room temperature, diluted with 300 mL of ethyl acetate and filtered through celite. It is washed with ethyl acetate (100 mL) and aqueous solution of ammonium hydroxide (3%) (4×100 mL) to remove copper traces, and then, it is washed with water (50 mL) and brine (50 mL). Solution is dried over sodium sulfate. The solvent is evaporated in vacuo to give a tan solid. Solid was filtered through a pad of silica gel using as eluent 2-propanol/dichloromethane (3% to 5% of 2-propanol) to give the title compound in 69% yield. MS (m/z): 479 (M+1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[CH2:31][OH:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH:19]1[CH:31]=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Dimethyl sulfoxide (0.252 mL, 3.55 mmol) was added to a to −78° C. solution of oxalyl chloride (0.200 mL, 2.37 mmol) in methylene chloride (5.4 mL). After 10 min, a solution of tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (0.63 g, 2.0 mmol from Step 1) in methylene chloride (2.8 mL) was slowly introduced over 15 min. After stirring at −78° C. for 1 h, triethylamine (1.38 mL, 9.87 mmol) was added. The mixture was warmed to RT over 30 min and then stirred for another 30 min at that temperature. The reaction mixture was diluted with DCM, washed with water (twice) and brine (once), dried over sodium sulfate, decanted and concentrated to give product as a light yellow oil (570 mg, 95%). 1H NMR (300 MHz, CDCl3): δ 9.67 (d, 1H), 7.36-7.24 (m, 5H), 3.89 (d, 1H), 3.65 (dd, 1H), 3.57 (d, 1H), 3.57-3.45 (br m, 2H), 3.36-3.22 (br m, 1H), 3.10-2.98 (br m, 1H), 2.93 (ddd, 1H), 2.30 (ddd, 1H), 1.45 (s, 9H); LCMS (M+H)+: 305.0.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.ClCCCl.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[C:20]([C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1)(=[O:22])[CH3:21]
Reactant: O=C1Nc2ccccc2Oc2sccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5 g) was suspended to 1,2-dichloroethane (50 ml) and acetyl chloride was added (2.2 g). To this reaction system was added portionwise aluminum chloride (15 g) under ice-cooling and the mixture was stirred at room temperature for 10 minutes. The reaction system was poured into ice. Chloroform was added and the mixture was stirred for 15 minutes. The precipitated crystals were collected by filtration to give 2-acetylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (5.2 g).
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:45][O:46][CH2:47][CH:48]=[CH2:49].N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:47]([O:46][N:45]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:43][C:6]=2[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)[C:8]1=[O:23])[CH:48]=[CH2:49]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: C=CCON
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CCON=C(Cn1c(=O)c2cc(CC)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), 3-(aminooxy)prop-1-ene hydrochloride (0.045 g), pyridine (10 mL) and ethanol (1010 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.19 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1N.N([O-])=O.[Na+].[I-:14].[K+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[I:14]
Reactant: Nc1cc(Br)ccc1Br
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Brc1ccc(Br)c(I)c1
Temperature: 65 °C
Reaction time: 1.25 h

Procedure:
To a stirred mixture of 2.50 g (9.96 mmol) 2,5-dibromoaniline in 7 mL conc. sulfuric acid and 20 mL water, was added a solution of 1.00 g (14.5 mmol) sodium nitrite in 10 mL water dropwise at 0° C. and the mixture was stirred at this temperature for 1.25 h. A solution of 2.15 g (13.0 mmol) potassium iodide in 20 mL water was added dropwise under ice cooling. The ice bath was removed and the reaction mixture was heated to 65° C. for 30 min. After cooling to RT, the mixture was worked up by adding aqueous sodium thiosulfate solution, followed by extraction with PE/EtOAc. The combined organic phases were washed with aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=100→96/4).