Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:7][C:8]=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.C(=O)([O-])[O-].[Na+].[Na+].S(O)(=O)(C1C=CC=C(N)C=1)=O>O>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Fc1nnnc(F)c1F
Agent: Nc1cccc(S(=O)(=O)O)c1
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
31.9 g of 2-amino-5-hydroxynaphthalene-1,7-disulphonic acid are dissolved in 400 ml of water under neutral conditions. 300 g of ice are then added, and 8.8 ml of trifluorotriazine are run in while maintaining a pH of 4.0 to 4.5 with 15% strength sodium carbonate solution. Stirring is continued for 5 minutes, and a neutral solution of 17.3 g of m-sulphanilic acid is then added while maintaining a pH of 5.0 to 5.5 with 15% strength sodium carbonate solution. During acylation, the temperature is allowed to rise to 15° to 20°. A diazo compound obtained in the usual manner by diazotisation of 30.3 g of 2-aminonaphthalene-1,5-disulphonic acid is added to the resulting solution of the reaction product of the formula ##STR15## at 5° to 10°, while simultaneously maintaining the pH at 7.0 to 7.5 by sprinkling in sodium bicarbonate. After coupling is complete, the dyestuff of the formula ##STR16## is salted out, filtered off with suction, dried and milled.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([S:37]([CH3:39])=[O:38])[CH:34]=[C:33]([F:40])[C:32]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].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>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:32]4[C:33]([F:40])=[CH:34][C:35]([S:37]([CH3:39])=[O:38])=[CH:36][C:31]=4[F:30])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)=O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (10.0 mg, 0.025 mmol), 6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylic acid (9.4 mg, 0.03 mmol), HATU (23.5 mg, 0.062 mmol) in DMF (0.06 mL) and DIPEA (9.6 mg, 0.074 mmol) was stirred at room temperature for 16 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (3.0 mg, 17%). LCMS calc. for C34H39F3N5O6S (M+H)+: m/z=702.3. Found: 702.2.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[N:1]1([CH2:6][C:7]2([C:34](=[O:35])[CH2:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:37])([F:25])[F:38])=[CH:32][CH:31]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)CNC(CN2CCCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1(C)CNC(CN2CCCC2)(C(=O)Cc2ccc(C(F)(F)F)cc2)c2ccccc21

Procedure:
Prepared as Ex. No. 1, from 2.44 g (10.0 mmoles) of 1-(pyrrolidin-1-yl)methyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline, 3.04 g (22.0 mmoles) of anhydrous potassium carbonate and 2.45 g (11.01 mmoles) of 4-trifluoromethylphenylacetyl chloride in 40 ml of dry chloroform.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[N:10][CH:11]=1.[C-:14]#[N:15].[K+].CO>O>[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:14]#[N:15])[CH:9]=[N:10][CH:11]=1
Reactant: OCc1cncc(Br)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: N#CCc1cncc(Br)c1
Temperature: 0 °C

Procedure:
To SOCl2 (26.7 ml) cooled with an ice-bath was added portionwise (5-bromo-pyridin-3-yl)-methanol (ABCR, Karlsruhe, Germany, 26.6 mmol). The RM was refluxed for 1 h then was cooled at 0° C. and quenched with diethyl ether. The resulting precipitate was filtered, washed with cooled diethyl ether and dried under vacuum at 50° C. The solid was mixed with potassium cyanide (64.5 mmol), MeOH (35 ml) and water (14 ml) and the RM was refluxed for 2 h. The RM was cooled, quenched with aqueous K2CO3 and extracted with diethyl ether (3×). The combined organic layers dried over Na2SO4, filtered and evaporated to give the title compound as a purple solid. (HPLC: tR 2.16 min (Method A); M+H=197, 199 MS-ES)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].CCN(CC)CC.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])=[O:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of o-tolylamine (21.4 g, 0.20 mol) and Et3N (22.3 g, 0.22 mol) in CH2Cl2 was added 2,2-dimethyl-propionyl chloride (25.3 g, 0.21 mol) at 10° C. The mixture was stirred overnight at room temperature, washed with aq. HCl (5%, 80 mL), saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated under vacuum to give 2,2-dimethyl-N-o-tolyl-propionamide (35.0 g, 92%).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][O:12]/[N:13]=[C:14]1/[C:15]([CH3:35])([CH3:34])[C:16]2[C@:29]([CH3:32])([CH2:30][CH2:31]/1)[C@@H:28]1[C@H:19]([C@H:20]3[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([OH:33])[CH2:22][CH2:21]3)[CH2:18][CH:17]=2.CCN(CC)CC.[CH:43]1[C:55]2[CH:54]([CH2:56][O:57][C:58](Cl)=[O:59])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]=2[CH:46]=[CH:45][CH:44]=1.O>C(Cl)Cl>[CH:43]1[C:55]2[CH:54]([CH2:56][O:57][C:58]([NH:9][CH2:10][CH2:11][O:12]/[N:13]=[C:14]3/[C:15]([CH3:35])([CH3:34])[C:16]4[C@:29]([CH3:32])([CH2:30][CH2:31]/3)[C@@H:28]3[C@H:19]([C@H:20]5[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C@@H:23]([OH:33])[CH2:22][CH2:21]5)[CH2:18][CH:17]=4)=[O:59])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]=2[CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC1(C)C2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC/C1=N\OCCN
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)C2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC/C1=N\OCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 128.9 %

Procedure:
To a stirred solution of a mixture of (E)-3-(2-aminoethoxyimino)-4,4-dimethylandrost-5-en-17β-ol (Example 2, 250 mg) and Et3N (0.14 ml) under N2 in DCM (10 ml) at 0° C., 9-fluorenylmethoxycarbonyl chloride (170 mg) was added. After stirring at RT for 15 minutes, water was added and the mixture was extracted with DCM. The organic phase was washed with 5% NaHCO3 dried over Na2SO4 and evaporated to dryness to give 3-(E)-{2-[N-(9-fluorenylmethoxy-carbonyl)]aminoethoxyimino}-4,4-dimethylandrost-5-en-17β-ol (392 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].CCOC(C)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([F:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (182 mg, 1.00 mmol) in THF (1.70 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (60 mg, 1.50 mmol) in THF (1.70 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then 4-fluoro-3-nitrobenzaldehyde (169 mg, 1.00 mmol) in THF (0.50 mL) was added. After 1 hour, EtOAc/water was added and the organic layer washed with more water, dried (Na2SO4), and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 33% EtOAc in heptane to give the title compound. Yield: 160 mg, 71%; LC-MS 41.31 min; HPLC Purity: >75%; MS (ES+) m/z not detectable (M+H)
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([O:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[N:16]=[C:15]([NH:32][NH2:33])[C:14]1=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1.CN(C)C=O>[CH2:5]([O:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[N:16]2[C:1](=[S:2])[NH:33][N:32]=[C:15]2[C:14]1=[O:34])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNc1nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1c2n[nH]c(=S)n2c2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Yield: 51.1 %

Procedure:
A solution of thiophosgene (1.1 ml, 14 mmol) in 10 ml of dry tetrahydrofuran was added dropwise to a stirred solution of 2.91 g (7 mmol) of 1-benzyloxy-3-hydrazino-6-(1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in a mixture of 100 ml of dry tetrahydrofuran and 25 ml of dry N,N-dimethylformamide at 0° C. The mixture was stirred for 2h at 0° C. and evaporated to dryness. The solid residue was suspended in 100 ml of water, neutralized with solid sodium hydrogen carbonate and filtered. Recrystallization from ethanol afforded 1.64 g (51%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH:9]12[O:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][NH:11][CH2:10]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:11]2[CH2:10][CH:9]3[O:16][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C1CC2CNCC1O2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1cccc(N2CC3CCC(C2)O3)c1
Temperature: 80 °C
Yield: 67.3 %

Procedure:
A mixture of 1,3-dibromobenzene (242 μL, 2.00 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (226 mg, 2.00 mmol), Pd2(dba)3 (45.8 mg, 0.0500 mmol), rac-BINAP (96.3 mg, 0.150 mmol) and NaOtBu (231 mg, 2.40 mmol) in toluene was heated at 80° C. for 13 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1) to afford desired product (361 mg, 67.3%) as colorless oil.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:28]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=1)=[CH:8][C:7]2=[N:6][OH:5])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: BrCCc1ccccc1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3ccccc3)cc12

Procedure:
6-Phenethyloxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 21% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and (2-Bromo-ethyl)-benzene.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1F

Procedure:
2-fluoro-4-nitrobenzoic acid (Fluorochem; 2.5 g, 13.51 mmol) was suspended in toluene (25 mL) and thionyl chloride (2.96 mL, 40.52 mmol) added. The reaction mixture was heated at reflux for 1.5 hours, allowed to cool and evaporated to give the title compound as a yellow liquid which gradually solidified on standing (2.74 g, 100%)
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11].O>C1COCC1>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)cn1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A slurry of NaH (1.94 g, 48.5 mmol) in THF (40 mL) at 0° C. was treated with a solution of 4-iodopyrazole (8.97 g, 46.2 mmol) in THF (20 mL), stirred for 1 h, treated with SEM chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate/hexanes to provide 14.4 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][OH:9].[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOCCl
Reactant: OCCc1ccsc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCCc1ccsc1Br
Yield: 91.4 %

Procedure:
A solution of 2-bromo-3-(2-hydroxyethyl)thiophene (40.0 g, 0.193 mol) in methylene chloride (200 ml) was cooled in ice and methoxyethoxymethyl chloride (41.9 g, 0.336 mol) was added with stirring. After several minutes N,N-diisopropylethylamine (44.3 g, 0.336 mol) was added and the solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in ether (150 ml) and water (75 ml). The ether layer was separated and was washed with saturated NaHCO3 solution and with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature to give 52.1 g of an amber liquid. TLC indicated that the product was pure and NMR confirmed the structure. Field desorption mass spectral analysis gave a molecular ion of M/Z 294. The yield was 91%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17]Br>CN(C=O)C>[O:8]1[CH2:17][CH2:16][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: BrCCBr
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)NCCO2
Temperature: 125 °C
Yield: 65.1 %

Procedure:
To a suspension of 2-aminophenol (1.0 g, 9.2 mmol) and potassium carbonate (6.36 g, 46 mmol) in dry DMF (10 mL) was added 1,2-dibromoethane (2.59 g, 13.8 mmol). The mixture was then heated at 125° C. for 15 hours. After cooling, the mixture was treated with crushed ice and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether 1:10 (v:v) as eluent to give 3,4-dihydro-2H-benzo[b][1,4]oxazine as reddish oil (0.81 g, 65%). LC-MS (ES-API); rt 7.51 min; m/z calculated for C8H9NO [M+H]+ 136.1, found 136.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH2:24]([N:27]([CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH3:26].C(OC)(OC)OC>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:32][CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:33][CH2:34][CH3:35])[CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CCCN(CCC)CCCCN
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1ncc[nH]1
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCN=Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 103.3 %

Procedure:
The compound (210 mg) obtained in Example 84-5 was dissolved in anhydrous methanol (6.3 ml) and added with the compound (117 mg) obtained in Example 1-2. The solution was added with trimethyl orthoformate (297 μl) and the whole was stirred at room temperature for 6.5 hours. After completion of the reaction, the solvent was distilled off, thereby obtaining the subject compound (325 mg) as a brown oily substance.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]1([OH:53])[CH2:52][CH2:51]1)[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:50]4([OH:53])[CH2:51][CH2:52]4)([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C5(O)CC5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5(O)CC5)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
To a solution of 1-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]cyclopropanol 6a (75 mg, 0.1 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (74.97 mg, 0.51 mmol) and 10% Pd/C (15 mg, 0.01 mmol) in turn. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/4 to give the title compound 6 as colourless oil (24 mg, 50.0%, HPLC: 83.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 463.1[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.38 (m, 2H), 7.29 (m, 1H), 7.10 (m, 2H), 6.84 (m, 2H), 5.27 (s, 1H), 5.19 (d, 1H), 5.02 (d, 1H), 4.95 (d, 1H), 4.06 (m, 1H), 3.99 (m, 3H), 3.96 (m, 1H), 3.80 (t, 1H), 3.41 (m, 2H), 3.29 (m, 1H), 1.31 (t, 3H), 0.55 (m, 4H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.Cl.CN.[CH2:24]([N:26](CC)[CH2:27][CH3:28])[CH3:25].C(=O)([O-])O.[Na+]>ClCCl>[CH2:24]([N:26]([CH2:27][CH3:28])[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1)[CH3:25]
Reactant: CCN(CC)CC
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCN(CC)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 45 °C
Yield: 70.7 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (100 mg, 0.35 mmol) was dissolved in dichloromethane (5 ml) in a sealed tube, then methylamine hydrochloride (26 mg, 0.38 mmol) and triethylamine (122 μl, 0.87 mmol) were successively added. The reaction system was heated at 45° C. for 3 hours. After cooling to room temperature, the reaction liquid was fractionated with dichloromethane and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was separated, this was extracted twice with dichloromethane. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform) to obtain the entitled compound (80 mg, 82%) as a white solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:30])[C:13](=[O:29])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br>CN(C)C=O.ClCCl>[Br:31][C:16]1[CH:15]=[C:14]2[C:19]([C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[C:11]([CH:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[N:12]([CH3:30])[C:13]2=[O:29])=[CH:18][CH:17]=1
Reactant: BrBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
An ice cold mixture of methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (187 mg, 0.459 mmol) in N,N-Dimethylformamide (DMF) (2.0 mL) was treated with a solution of bromine (0.071 mL, 1.377 mmol) in dichloromethane (DCM) (2.0 mL). The ice bath was removed and the mixture, which was excluded from light by wrapping the reaction vessel with aluminum foil, was allowed to stir at ambient temperature overnight. The mixture was quenched by adding saturated sodium bicarbonate and then extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel to afford the title compound as a thick colorless oil (123 mg, 55%) that solidified upon standing. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.63 (d, J=2.1 Hz, 1 H), 7.56 (ddd, J=2.2, 6.0, 8.6 Hz, 1 H), 7.31-7.22 (m, 1 H), 7.20-6.88 (m, 3 H), 5.20 (s, 1 H), 3.83-3.74 (m, 3 H), 3.69 (m, 3 H), 2.37 (s, 3 H), 2.31 (s, 3 H), 1.01 (m, 9 H); LC/MS (m/z) ES+=486 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:3]=1[C:4]([NH:6][C:7](=[O:24])[NH:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:5].C[N:32](C=O)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>O>[Cl:1][C:2]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:3]=1[C:4]([NH:6][C:7](=[O:24])[NH:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][CH:18]([C:21]([NH2:32])=[O:23])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cccnc1N1CCC(C(=O)O)CC1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)C1CCN(c2ncccc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 50 mg of 3′-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid, 0.5 ml of DMF, 6.1 mg of ammonium chlorid, 40 μl of Hunig's base and 37.3 mg of Totu was stirred at room temperature for 2 hours. Afterwards, it was diluted with 5 ml of water and the mixture was stirred briefly. The precipitate was filtered of with suction and dried under reduced pressure.