Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][CH2:3][NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(N)cc1
Reactant: Clc1cccc(NCCBr)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(NCCNc2cccc(Cl)c2)cc1
Yield: 76.6 %

Procedure:
A mixture consisting of 15.8 gm of N-(2-bromo-ethyl)-3-chloro-aniline hydrobromide, 10.7 gm of 4-methyl-aniline, 50 ml of toluene and 15 gm of anhydrous sodium carbonate was refluxed for eight hours, while stirring. Thereafter, the reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was evaporated in vacuo, leaving 10 gm of an oil which was used as the starting material in Example 11 without further purification. It was identified to be N-(3-chloro-phenyl)-N'-(4-methyl-phenyl)-ethylenediamine.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:15]([C:16]2[C:20]3[CH:21]=[C:22]([N:25]4[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]4=[O:37])[CH:23]=[CH:24][C:19]=3[S:18][N:17]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:38]>CC(C)=O>[OH:9][CH:10]1[C:15]([C:16]2[C:20]3[CH:21]=[C:22]([N:25]4[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]4=[O:37])[CH:23]=[CH:24][C:19]=3[S:18][N:17]=2)([I:1])[CH:14]=[CH:13][CH:12]=[C:11]1[CH3:38]
Reactant: Cc1cccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: CC1=CC=CC(I)(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A solution of N-iodosuccinimide (0.240 g, 0.00107 mol) in acetone is added dropwise to a solution of 3-[3-(2-hydroxy-m-tolyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.430 g, 0.000992 mol) in acetone and the resultant mixture is stirred overnight at room temperature. Additional N-iodosuccinimide (0.120 g, 0.000635 mol) is added and the mixture is stirred three hours at room temperature. The mixture is concentrated in vacuo to afford a red gum which is chromatographed on silica gel with ether:methylene chloride. The fractions containing the title compound are washed with 1M sodium thiosulfate and brine, dried over anyhdrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow solid (0.280 g, 46.8%, mp 241-242° C.).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].P([O-])([O-])([O-])=O>>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[S:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(-c2nc(CCl)cs2)cc1
Agent: O=P([O-])([O-])[O-]
Product: CN(C(=O)Oc1ccc(-c2nc(CCl)cs2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-chloromethyl-thiazol-2-yl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The aqueous phase was adjusted to PH 7.0 (phosphate buffer), before extraction with ethyl acetate. The crude product was subjected to preparative HPLC (21%, white crystals). HPLC-MS m/z=359.0 (M+1), Rt: 4.60.
Reaction SMILES: C1C(O)=C(O)C(O)=CC=1C([O:12][C:13]1[CH:14]=[C:15]([C:21]([O:23][CH2:24][C@H:25]2[O:30][C@@H:29]([O:31][C:32]([C:34]3[CH:35]=[C:36]([OH:53])[C:37]([OH:52])=[C:38]([O:40]C(C4C=C(O)C(O)=C(O)C=4)=O)[CH:39]=3)=[O:33])[C@H:28]([O:54][C:55]([C:57]3[CH:58]=[C:59]([OH:76])[C:60]([OH:75])=[C:61]([O:63]C(C4C=C(O)C(O)=C(O)C=4)=O)[CH:62]=3)=[O:56])[C@@H:27]([O:77][C:78]([C:80]3[CH:81]=[C:82]([OH:99])[C:83]([OH:98])=[C:84]([O:86]C(C4C=C(O)C(O)=C(O)C=4)=O)[CH:85]=3)=[O:79])[C@@H:26]2[O:100][C:101]([C:103]2[CH:104]=[C:105]([OH:122])[C:106]([OH:121])=[C:107]([O:109]C(C3C=C(O)C(O)=C(O)C=3)=O)[CH:108]=2)=[O:102])=[O:22])[CH:16]=[C:17]([OH:20])[C:18]=1[OH:19])=O.C([O-])(=O)C>CO>[C:32]([O:31][C@@H:29]1[O:30][C@H:25]([CH2:24][O:23][C:21](=[O:22])[C:15]2[CH:14]=[C:13]([OH:12])[C:18]([OH:19])=[C:17]([OH:20])[CH:16]=2)[C@@H:26]([O:100][C:101](=[O:102])[C:103]2[CH:108]=[C:107]([OH:109])[C:106]([OH:121])=[C:105]([OH:122])[CH:104]=2)[C@H:27]([O:77][C:78](=[O:79])[C:80]2[CH:85]=[C:84]([OH:86])[C:83]([OH:98])=[C:82]([OH:99])[CH:81]=2)[C@H:28]1[O:54][C:55](=[O:56])[C:57]1[CH:62]=[C:61]([OH:63])[C:60]([OH:75])=[C:59]([OH:76])[CH:58]=1)(=[O:33])[C:34]1[CH:39]=[C:38]([OH:40])[C:37]([OH:52])=[C:36]([OH:53])[CH:35]=1
Reactant: O=C(OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c(O)c(O)c2)c1)c1cc(O)c(O)c(OC(=O)c2cc(O)c(O)c(O)c2)c1
Agent: CC(=O)[O-]
Solvent: CO
Product: O=C(OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(O)c2)[C@H](OC(=O)c2cc(O)c(O)c(O)c2)[C@@H](OC(=O)c2cc(O)c(O)c(O)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(O)c1)c1cc(O)c(O)c(O)c1
Yield: 51 %

Procedure:
To 1 g of tannic acid according to Japanese Pharmacopoeia (available from Iwaki Seiyaku Co., Ltd.), there were added 50 ml of methanol and 25 ml of acetate buffer (pH 5.5) and the resultant mixture was stirred at 50° C. for 18 hours. After distilling off methanol under a reduced pressure, the residue was extracted three times with ethyl acetate and then the solvent was distilled off under a reduced pressure. This crude product was fractionated by HPLC (YMC-PACK, D-ODS-5 20×250 mm; eluent=methanol: tetrahydrofuran: phosphate buffer (pH 4.5)=3:1:7) to obtain 282 mg of 1,2,3,4,6-penta-O-galloyl-β-D-glucose.
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=3)[C:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[C:32]([OH:34])=[O:33]>C(Cl)Cl>[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:12]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[C:32]([OH:34])=[O:33]
Reactant: COc1ccc(-c2nc3cc(O)c(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1cc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
BBr3 (1.26 g, 5.02 mmol, 10.00 equiv) was added dropwise with stifling at 0° C. to a solution of 7-hydroxy-2,3-bis(4-methoxyphenyl)quinoxaline-6-carboxylic acid (200 mg, 0.50 mmol, 1.00 equiv) in DCM (20 mL) in a 50-mL round-bottom flask. The resulting solution was allowed to react, with stirring, overnight at room temperature. The reaction was quenched by the addition of 10 mL of 1N (aq) NaOH. The pH of the solution was adjusted to 3-4 with HCl (1M). The solution was extracted with 2×100 mL of CH2Cl2: MeOH (10:1), and the organic layers combined and concentrated under vacuum, yielding 120 mg (64%) of 7-hydroxy-2,3-bis(4-hydroxyphenyl)quinoxaline-6-carboxylic acid as a red solid.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17](OC)[C:16]([O:21][CH3:22])=[C:15](OC)[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.COC1C=CC(C[C@@H](C(O)=O)N)=CC=1>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Agent: COc1ccc(C[C@H](N)C(=O)O)cc1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using O-methyl-L-tyrosine (Bachem).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)C1C=CC=CC=1>C(O)C>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]1=[O:23]
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CCO
Product: O=c1cc(O)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a Fischer-Porter bottle, added a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.5 g, 14.56 mmol) in absolute ethanol (20 mL). Flushed the solution with nitrogen then added palladium catalyst (1.05 g). Sealed bottle and evacuated system. The system was purged with hydrogen gas (2×15 psi) to check for leaks. The reaction was charged with hydrogen (35 psi) and stirred at room temperature for 45 min. The system was evacuated and flushed with nitrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethanol. The filtrate was concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15])[CH3:2]
Reactant: O=CCCl
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(CC)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (120 grams), the diethyl acetal of 2-chloroacetaldehyde )78.8 grams) and sodium carbonate (42.4 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150°C for a period of about 30 hours. After this time th mixture was filtered and the filrate was distilled to yield the desired product the diethyl acetate of 2-(2,6-diethylanilino)acetaldehyde having a boiling point of 130°C at 1 mm of Hg pressure.
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[F:22][C:23](=[CH:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:5][CH2:6][CH3:7])[P:8]([CH:29]([CH3:30])[CH:23]([F:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])([O:9][CH2:10][CH3:11])=[O:12])[CH3:2]
Reactant: CC=C(F)C(=O)OCC
Reactant: CCOC(OCC)[PH](=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)C(C)P(=O)(OCC)C(OCC)OCC
Temperature: 25 °C
Yield: 116.3 %

Procedure:
A mixture of ethyl (diethoxymethyl)phosphinate (21.7.0 g, 110 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (23.3 mL, 110 mmol) was heated to reflux for 2 h under an argon atmosphere. The mixture was cooled to room temperature and a diastereomeric mixture ethyl 2-fluorobut-2-enoate (14.6 g, 110 mmol) was added. The reagents were heated to 80° C. for one day and 120° C. for 2 hours under an argon atmosphere. The mixture was cooled to room temperature and another portion of trimethylsilyl activated ethyl (diethoxymethyl)phosphinate was added (this had been prepared from ethyl (diethoxymethyl)phosphinate (21.7.0 g, 110 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (23.3 mL, 110 mmol) in the same way as above). The mixture was heated to 100° C. for three days and still another portion of trimethylsilyl activated ethyl (diethoxymethyl)phosphinate was added. The mixture was heated to 100° C. for three days under an argon atmosphere, cooled to room temperature and then diluted with ethyl acetate (300 mL). The solution was washed with 1 N HCl (2×200 mL) and saturated sodium chloride. The organic layer was dried over MgSO4, filtered, and evaporated to give 42.0 g of a yellow oil. The residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride and then with 98:2 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 3.6 g (10%) of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl)]-2-fluorobutanoate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 4.9-5.6 (m, 1H), 4.7-4.8 (m, 1H), 4.2-4.4 (m, 4H), 3.6-4.0 (m, 4H), 2.6-2.9 (m, 1H), 1.2-1.4 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:32]([NH:31][C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])=[O:33])=[CH:3][CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2cc1C#N
Yield: 70 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (180 mg) was added to 5.5 ml of toluene, and the mixture was heated to reflux. After then adding 2,4-difluorophenyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 195 mg of the title compound as light brown crystals (70% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])[O-].[K+].[K+].[Cl:11]C(OCC)=O.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[C:40]3[C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:33](=[O:41])[NH:32][C:31]=3[N:30]([CH3:42])[N:29]=2)[CH2:24][CH2:23]1)=O)C.C(OC(N1C2N(C)N=C(C3CCN(C(OCC)=O)CC3)C=2C2C=CC=CC=2C1=O)=O)C.Cl>C(O)(=O)C>[ClH:11].[NH:22]1[CH2:23][CH2:24][CH:25]([C:28]2[C:40]3[C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:33](=[O:41])[NH:32][C:31]=3[N:30]([CH3:42])[N:29]=2)[CH2:26][CH2:27]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1CCC(c2nn(C)c3[nH]c(=O)c4ccccc4c23)CC1
Agent: CCOC(=O)N1CCC(c2nn(C)c3c2c2ccccc2c(=O)n3C(=O)OCC)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: Cn1nc(C2CCNCC2)c2c3ccccc3c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hrs and ice-cooled. Aluminum chloride (13.6 g) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the completion of the reaction, the reaction mixture was poured into ice-water, and potassium carbonate was added to alkalify the reaction mixture. An excess amount of ethyl chloroformate was added to the reaction mixture, and the mixture was stirred at room temperature. The insoluble material was remove by filtration, and the aqueous layer was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated to give a mixture of 1-(1-ethoxycarbonylpiperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5(4H)-one and 4-ethoxycarbonyl-1-(1-ethoxycarbonylpiperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5-one as solid. Further purification was not performed and the mixture was used in the next reaction. The total amount of the above-mentioned mixture was dissolved in acetic acid (100 mL) and concentrated hydrochloric acid (100 mL), and the mixture was heated under reflux for 24 hrs. After the completion of the reaction, the solvent was evaporated, and the precipitated crystals were collected by filtration to give 1-(piperidin-4-yl)-3-methyl-pyrazolo[3,4-c]isoquinolin-5(4H)-one hydrochloride (3.7 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:15][CH:16]([O:21][CH2:22][CH2:23][CH3:24])[O:17][CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>O>[CH2:18]([O:17][CH:16]([O:21][CH2:22][CH2:23][CH3:24])[CH2:15][S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:19][CH3:20]
Reactant: CCCOC(CCl)OCCC
Reactant: Oc1ccc(S)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(CSc1ccc(O)cc1)OCCC
Temperature: 90 °C

Procedure:
The S-monosodium salt of 4-mercaptophenol (0.05 mole) and dimethylformamide (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-dipropoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is blanketed with nitrogen gas and is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 4-(2,2-dipropoxyethylthio)phenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]2[C:12](=[C:13]([F:24])[C:14]([O:21][CH2:22][CH3:23])=[C:15]([N+:18]([O-])=O)[CH:16]=2)[N:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([F:24])[C:14]=1[O:21][CH2:22][CH3:23])[N:11]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[N:10]=[C:9]2[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: [H][H]
Reactant: CCOc1c([N+](=O)[O-])cc2c(NC(=O)OC(C)(C)C)nn(C(=O)OC(C)(C)C)c2c1F
Agent: [Ni]
Solvent: CO
Product: CCOc1c(N)cc2c(NC(=O)OC(C)(C)C)nn(C(=O)OC(C)(C)C)c2c1F
Yield: 36 %

Procedure:
4.2 2.50 g of tert-butyl 3-tert-butoxycarbonylamino-6-ethoxy-7-fluoro-5-nitroindazole-1-carboxylate are hydrogenated in 20 ml of methanol at RT (catalyst: Raney nickel 0.5 g, hydrogen uptake: 300 ml). The reaction batch is filtered and evaporated. Purification of the residue by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate 7:3) gives 3.30 g (36%) of tert-butyl 5-amino-3-tert-butoxycarbonylamino-6-ethoxy-7-fluoroindazole-1-carboxylate, MS-FAB (M+H+)=441.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[OH-].[Na+]>CN(C)C=O>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:19]=1
Reactant: Oc1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a solution of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (3 g, 11.81 mmol) in dimethylformamide (20 mL) was added 3-bromophenol (1 g, 5.78 mmol) and NaOH (500 mg, 12.50 mmol). The resulting solution was stirred at 100° C. for 3 h. The reaction mixture was quenched by the adding H2O (100 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated, and the residue purified by silica gel column chromatography (1:20 EtOAc/petroleum ether) to provide 1.1 g (31%) of 1-bromo-3-(2,2,2-trifluoroethoxy)benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[NH2:12].CC(C)([O-])C.[K+].[Cl-].[NH4+]>CN(C=O)C.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.CCCCCC>[NH2:12][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccncc1
Reactant: CON
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cnccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 25.2 %

Procedure:
4-Nitropyridine (124 mg, 1 mmol) and O-methylhydroxylamine (71 mg, 1.5 mmol) were dissolved in DMF (2 ml), and a resulting solution was added dropwise to a DMF solution (3 ml) containing potassium tert-butoxide (336 mg, 3 mmol) and zinc (II) chloride (136 mg, 1 mmol) at 25° C. After completion of the addition, the resulting mixture was at 25° C. for one hour and an aqueous saturated ammonium chloride solution (50 ml) was added, followed by extraction with ethyl acetate (80 ml). A resulting organic layer was dried over anhydrous magnesium sulfate, and then isolated and purified by subjecting to silica gel thin layer chromatography (eluent: ethyl acetate/hexane=1/1] to obtain 35 mg of 3-amino-4-nitropyridine (yield: 25%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10]O)[C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:9]1[C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc2c1OCO2
Product: ClCc1cccc2c1OCO2
Yield: 89.1 %

Procedure:
Dissolve benzo[1,3]dioxol-4-yl-methanol (1.9 g, 12.5 mmol) in thionyl chloride (3 mL, 41.1 mmol) and reflux the reaction mixture for 1 h. Concentrate in vacuo to obtain the desired intermediate as a yellow oil (1.9 g, 91%) that was used without further purification. GC-MS m/z: 170 (M+).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To 15 ml of a dichloromethane solution of 922.6 mg (3.06 mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (isomer B) was added 0.874 ml (6.12 mmol) of benzyl chloroformate at room temperature, followed by stirring at the same temperature overnight. To the reaction mixture was further added 0.502 ml (3.52 mmol) of benzyl chloroformate, followed by stirring for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 685.5 mg (64.8%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:36][CH3:37])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: CCI
Product: CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 67 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and ethyl iodide was used in place of methyl iodide. As a result, 213.1 mg (yield: 67%) of Compound 2 was obtained as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 70.1 %

Procedure:
A mixture of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methylbenzamide (50 mg, 0.17 mmol), 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (49 mg, 0.25 mmol) and camphorsulfornic acid (4 mg, 0.02 mmol) in IPA (5 mL) was microwave-heated at 120° C. for 3.5 h. The mixture was concentrated and chromatographed with preparative TLC (methylene chloride and ethyl acetate (4:1)) to give 54 mg of 2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (71%): 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 7.95 (s, 1H), 7.56 (d, 1H), 7.43 (dd, 1H), 7.34 (d, 1H), 7.26 (m, 1H), 7.1 (t, 1H), 7.05 (d, 1H). 4.35 (t, 2H), 3.3 (s, 3H), 2.9 (s, 3H), 2.85 (t, 2H); MS (m/e): 453.3 (M+1).