Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[C:27]([CH3:28])=[C:26]([Cl:29])[C:25]([C:30]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])=[N:24]3)=[C:19]([C:41]([N:43]3[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]3)=[O:42])[CH:18]=1)=[O:16])(=[O:13])=[O:12])[N:7]([CH2:53][CH3:54])[CH2:6][CH2:5]2.[NH:55]1[CH2:62][CH2:61]C[C@H:56]1[C:57](O)=[O:58].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl.CCOC(C)=O.[Cu]I>[CH2:33]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[C:30]([C:25]1[C:26]([Cl:29])=[C:27]([CH3:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[NH:14][S:11]([C:10]3[CH:9]=[C:8]4[C:4]([CH2:5][CH2:6][N:7]4[CH2:53][CH3:54])=[CH:3][C:2]=3[N:55]3[CH2:56][CH2:57][O:58][CH2:61][CH2:62]3)(=[O:13])=[O:12])=[CH:18][C:19]=2[C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[N:24]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3cc4c(cc3Br)CCN4CC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3cc4c(cc3N3CCOCC3)CCN4CC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 102 °C
Yield: 16.9 %

Procedure:
A solution of 1-(4-(5-bromo-1-ethylindolin-6-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 71, 35 mg, 0.042 mmol), L-(−)-proline (5 mg, 0.042 mmol), K2CO3 (12 mg, 0.084 mmol) and CuI (4 mg, 0.021 mmol) in DMSO (1.5 mL) was purged with air for 1 min. The resulting mixture was heated at 102° C. open to air for 20 h. The reaction mixture was then diluted with 1N aq. HCl solution and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (6 mg, 16%) as a white solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.24 (dd, J=8.3, 1.9 Hz, 1H), 8.13-8.10 (m, 1H), 7.60-7.50 (m, 1H), 7.48 (s, 1H), 7.25-7.09 (m, 3.5H), 6.95 (s, 1H), 6.93 (d, J=7.5 Hz, 0.5H), 4.90-4.50 (m, 2H), 4.20-3.99 (m, 4H), 3.71-3.60 (m, 4H), 3.55-3.49 (m, 2H), 3.26-3.20 (m, 4H), 3.09-3.03 (m, 2H), 2.90-2.60 (m, 4H), 2.33 (s, 2H), 2.28 (s, 1H), 1.55-1.00 (m, 13H), 0.95-0.88 (m, 3H), 0.79-0.75 (m, 2H), 0.72-0.68 (m, 1H); MS(ESI+) m/z 844.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[Cl:9][C:10]1[C:11]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:11]2[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][N:12]=2)=[N:22]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 70 °C
Reaction time: 9 h
Yield: 11.1 %

Procedure:
Diethylcarbamoyl chloride (1.52 g, 7.8 mmol) was added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.39 g, 5.0 mmol) and potassium carbonate (1.98 g, 14.3 mmol) in DMF (15 ml), the mixture was stirred at 70° C. for 9 hours and further stirred at room temperature for 2 days. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (20 ml×3). An organic-layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a colorless viscous substance of N,N-diethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.21 g, yield: 11.2%). 1H-NMR (CDCl3, TMS, ppm): δ 1.21 (t, J=7.0 Hz, 6H), 2.48 (d, J=0.6 Hz, 3H), 3.47 (q, J=7.0 Hz, 4H), 6.00 (q, J=0.6 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 8.33 (m, 1H).
Reaction SMILES: [OH:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:8]=1)=[O:6])([CH3:4])[CH3:3].[N-:27]=[N+:28]=[N-:29].[Na+].O.CCOCC>CS(C)=O.C(OC)(C)(C)C>[OH:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:27]=[N+:28]=[N-:29])=[CH:9][CH:8]=1)=[O:6])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C(=O)C(C)(C)O)cc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CC(C)(O)C(=O)c1ccc(OCCN=[N+]=[N-])cc1

Procedure:
37.8 g (0.1 mol) of 4-(2-p-tolylsulfonyloxyethoxy)-phenyl 2-hydroxy-2-propyl ketone (obtained by reacting compound IIa with p-toluenesulfonyl chloride) and 9.8 g (0.15 mol) of sodium azide are stirred for one hour in 100 ml of DMSO at 60° C. Through extractive work-up using water and ether or methyl t-butyl ether, 22.4 g of compound IIf are obtained as a pale yellow, readily mobile oil. IR: v=2114 cm-1 (N3).
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9][C@@H:5]2[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:3][CH2:4][C@@H:5]1[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH2:9]1
Reactant: CC1(C)C[C@@H]2COC(C)(C)N2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1(C)C[C@H](CO)NC1=O
Yield: 123.9 %

Procedure:
To a stirred suspension of (R)-3,3,6,6-tetramethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (D35) (714 mg, 3.89 mmol) in MeOH (15 ml), p-TSA (74 mg, 0.39 mmol) was added and the resulting mixture was heated at reflux for 2 hrs. Solvent was evaporated off and the residue was loaded on SPE-SCX cartridge (5 g). The cartridge was washed with MeOH (3 column volume). The methanolic phase was collected and evaporated to afford the title compound (D36) (690 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:8]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:6][N:5]2[CH:15]=1.CN(C)[C:18]([C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)=[O:19]>>[CH3:25][N:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:18]([C:15]1[N:5]2[CH2:6][CH2:7][CH:8]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])[C:4]2=[CH:3][C:2]=1[CH3:1])=[O:19]
Reactant: CN(C)C(=O)c1cccn1C
Reactant: Cc1cc2n(c1)CCC2C(=O)OC(C)C
Product: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)OC(C)C

Procedure:
In accordance with the method of Example 8, isopropyl 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate is condensed with N,N-dimethyl-1-methylpyrrole-2-carboxamide, to produce isopropyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XI, R and R1 = CH3, R2 = iC3H7).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[Br:12][C:10]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]([NH2:11])=[N:8][CH:9]=1
Reactant: CC(C)(C)c1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)ncc1Br
Yield: 43.6 %

Procedure:
Dissolve 4-tert-butyl-pyridin-2-ylamine (3 g, 20 mmol) in anhydrous acetonitrile (25 mL). Add N-bromosuccinimide (3.56 g, 20 mmol). Stir the reaction in the dark for overnight at room temperature. Dilute with EtOAc and wash with 1 N NaOH (aq.) and saturated aqueous sodium bicarbonate. Extract the organic layer. Wash the aqueous layer further with DCM. Dry the combined organic layers (MgSO4), and purify by silica gel column chromatography (EtOAc/hexane) to yield 2 g of the title compound (44%). LCMS (ES), m/z 231 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CCOCC>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCCC1=CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCCCCCCC1=CC1
Temperature: 0 °C

Procedure:
A solution of 3.8 mmol of 1-(7-hydroxyheptyl)-cyclopropene in 50 ml of ether was cooled in an ice bath. Triethylamine (1 ml) and 0.48 g of methanesulfonyl chloride (4.2 mmol) were added and the reaction mixture was stirred for 2½ hours at 0° C. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 1-(7-methanesulfonyloxyheptyl)-cyclopropene which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:5][CH2:4]1.[NH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:7]1([N:6]2[CH2:4][CH:3]([OH:5])[CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCC1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: OC1CN(C2CCCC2)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 1-chloro-2,3-epoxypropane (784 μL, 10 mmol) and amino cyclopentane (988 μL, 10 mmol) in dry acetonitrile (10 ml), sodium bicarbonate (1.68 g, 20 mmol) was added, and the resulting mixture was heated to reflux until the completion of reaction (TLC, 5h). The reaction mixture was cooled to room temperature and filtered through Celite. Filtrate was concentrated in vacuo to afford an oily residue, which was purified by flash chromatography (silica gel, EtOAC/MeOH, 9:1) to furnish the title compound (565 mg, 40%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 4.40-4.32 (m, 1H), 3.58-3-53 (m, 2H), 2.90-2.84 (m, 2H), 2.72-2.65 (m, 1H), 1.70-1.23 (m, 8H), ESIMS m/z [M+H]+ 142.5.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]([N:34]2[CH2:43][C:42]3[CH:41]=[N:40][N:39]([CH3:44])[C:38]=3[NH:37][C:36]3[CH:45]=[CH:46][CH:47]=[CH:48][C:35]2=3)=[O:33])[CH:29]=[CH:28][C:27]=1[CH2:49][CH2:50][C:51](O)=[O:52].[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][NH:68][CH:69]2[CH2:71][CH2:70]2)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CCN(C(C)C)C(C)C>ClCCl.CCOC(C)=O>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][N:68]([CH:69]2[CH2:70][CH2:71]2)[C:51](=[O:52])[CH2:50][CH2:49][C:27]2[CH:28]=[CH:29][C:30]([C:32]([N:34]3[CH2:43][C:42]4[CH:41]=[N:40][N:39]([CH3:44])[C:38]=4[NH:37][C:36]4[CH:45]=[CH:46][CH:47]=[CH:48][C:35]3=4)=[O:33])=[CH:31][C:26]=2[CH3:25])[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CNC2CC2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73 %

Procedure:
PyBroP (238 mg, 0.51 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (200 mg, 0.51 mmol) and 4-cyclopropylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.51 mmol) in dichloromethane (10 ml) and DIEA (0.18 ml, 1.02 mmol). The mixture was stirred for 4 days at room temperature, diluted with EtOAc, washed with 5% KHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (235 mg, 73%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH:23]([C:25]1[CH:26]=[C:27](OB(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=[O:24]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:27]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([CH:26]=4)[CH:23]=[O:24])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCNC1
Reactant: COc1ccc(OB(O)O)cc1C=O
Product: COc1ccc(N2CCCC(NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)cc1C=O
Yield: 14 %

Procedure:
Using N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (254 mg, 0.756 mmol) and 3-formyl-4-methoxyphenylboric acid (273 mg, 1.52 mmol), the same procedure was followed as in Example 2 to give 49.8 mg (14%) of the desired compound as a yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:17]([NH:24][CH:6]1[CH2:7][CH2:8][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([N:2]([CH3:16])[CH3:1])[CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(NCc2ccccc2)CC1

Procedure:
2.00 g 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in 30 ml analytical grade tetrahydrofuran, and 986 mg benzylamine followed by 794 μl glacial acetic acid were added, while stirring in an ice-bath. 2.72 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 15 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 25 ml diethyl ether each time. The combined organic phases were then washed twice with 20 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with diethyl ether with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 844 mg of the nonpolar diastereoisomer of N′-benzyl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained, and were converted into 843 mg of the corresponding hydrochloride by dissolving in 6.8 ml 2-butanone and addition of 27.1 μl water followed by 381 μl chlorotrimethylsilane and stirring overnight.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.CC(O)=O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2ccc(O)cc2O1

Procedure:
A mixture of ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate (10 g, 41 mmol) in MeOH (20 ml) and AcOH (20 ml) was hydrogenated at 50 Psi for 4 days. Filtration and evaporation gave the title compound. Yield: 9.2 g. MS m/z (rel. intensity, 70 eV) 222 (M+, 44), 149 (bp), 148 (22), 147 (46), 121 (25).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:27][C:26]([C:28]4[CH:29]=[CH:30][C:31]([NH:34]C(OC(C)(C)C)=O)=[N:32][CH:33]=4)=[N:25][C:24]=3[CH3:42])=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:27][C:26]([C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=4)=[N:25][C:24]=3[CH3:42])=[O:22])[CH2:17][CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: Cc1nc(-c2ccc(NC(=O)OC(C)(C)C)nc2)sc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(N)nc2)sc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A mixture of 1-(6-chloronaphthalene-2-sulfonyl)-4-(2-(2-tert-butoxycarbonylamino-5-pyridyl)-4-methyl-thiazole-5-carbonyl)piperazine (180 mg) and trifluoroacetic acid (1.0 ml) was stirred at room temperature for 1 hour and concentrated. To the residue was added sodium hydrogen carbonate aqueous solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was crystallized from ethyl acetate to give solvate of the title compound (134 mg).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:19])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.C1COCC1.O.[OH-].[K+].OO>C1COCC1>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:19])[CH2:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: CC1=CO[C@@H]2O[C@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@H]2[C@@H](C)CO[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of anhydrodihydroartemisinin (AHA) (2.08 g, 7.8 mmol) in THF (20 ml), was dropwise added a solution of BH3/THF complex in THF soln. (1 M; 14 ml) with ice-cooling. After being stirred at room temperature for 1 h, the mixture was treated with THF-water (1:1; 4 ml), followed by a mixture of aq. KOH (10%; 10 ml) and aq. H2O2 (50%; 4 ml).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([NH:16]N)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](=O)[CH:19]([CH3:21])[CH3:20].Cl.O1CCOCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:13]([C:19]([CH3:21])([CH3:20])[CH2:18][NH:16]3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C=O
Reactant: NNc1cccc(S(=O)(=O)c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC1(C)CNc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A mixture of (3-benzenesulfonyl-phenyl)-hydrazine (0.824 g, 3.3 mmol), isobutyraldehyde (0.245 g, 3.4 mmol) and toluene (12 mL) was stirred at 20° C. for 2 h. Acetic acid (12 mL) was added, followed by a solution of HCl in 1,4-dioxane (4 M, 0.83 mL, 3.3 mmol) and stirring was continued for 2 h. 1,2-Dichloroethane (12 mL) was added followed by sodium triacetoxyborohydride (1.05 g, 5 mmol) and stirring was continued for 1 h. The mixture was concentrated to 5 mL in vacuo and residue partitioned between saturated aqueous sodium hydrogen carbonate (200 mL) and DCM (3×60 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an orange oil. Chromatography (SiO2; gradient elution with 0-30% Et2O in petrol) gave the title compound (0.044 g). MS: [M+H]+=288.
Reaction SMILES: OCCCC[CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NCCCC[CH2:50][CH2:51][OH:52]>>[OH:52][CH2:51][CH2:50][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: NCCCCCCO
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCO)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using 6-aminohexanol in place of 8-aminooctanol. ES/MS calcd. for C31H35N4O6S+ 591.2. Found m/z=591.3 (M+H)+.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH:19]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=3[CH:22]=2)O)[CH:10]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][C:21]2[S:25][C:24]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=3[CH:22]=2)[CH:10]=1
Reactant: OC(c1cc(Br)c2ccccc2c1)c1cc2cc(F)ccc2s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 215.5 %

Procedure:
In a nitrogen stream, triethylsilane (0.18 ml, 2.11 mmol) and a boron trifluoride-diethyl ether complex (0.25 ml, 1.94 mmol) were added to a solution of (4-bromo-naphthalen-2-yl)-(5-fluorobenzo[b]-thiophen-2-yl)methanol (260 mg, 0.65 mmol) in methylene chloride (10 ml) at 0° C. and the mixture was stirred a room temperature for two hours. A saturated sodium hydrogen carbonate aqueous solution was added and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:100)] to obtain the title compound (520 mg, 80%).
Reaction SMILES: C([Li])CCC.CCCCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)F)(=O)=O)=CC=1.[F:32][C:33]1[CH:37]=[C:36]([CH2:38][O:39]COC)[S:35][C:34]=1[C:43]([F:46])([F:45])[F:44].COCOCC1SC(C(F)(F)F)=CC=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(O)C.O>[F:32][C:33]1[CH:37]=[C:36]([CH2:38][OH:39])[S:35][C:34]=1[C:43]([F:44])([F:45])[F:46]
Reactant: COCOCc1cc(F)c(C(F)(F)F)s1
Agent: COCOCc1ccc(C(F)(F)F)s1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1cc(F)c(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of the above compound (358 mg, 1.17 mmol) in tetrahydrofuran (4 mL) was added dropwise a solution of 1.67 mol/L n-butyllithium in hexane (0.84 ml, 1.41 mmol) at −78° C. under argon atmosphere. The mixture was stirred at the same temperature for 90 minutes, and then thereto was added a solution of N-fluorobenzene sulfonimide (553 mg, 1.76 mmol) in tetrahydrofuran (6 mL). The reaction solution was slowly warmed to room temperature, and stirred overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→19:1) to give an about 1:1 mixture of 3-fluoro-5-[(methoxymethoxy)methyl]-2-(trifluoromethyl)thiophene and 2-[(methoxymethoxy)methyl]-5-(trifluoromethyl)thiophene. The resulting mixture was dissolved in ethanol (2 mL), and then thereto was added 6 mol/L hydrochloric acid solution (1 mL) at room temperature. The mixture was stirred at the same temperature overnight, and then the reaction solution was alkalified by the addition of saturated aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give the title compound, [4-fluoro-5-(trifluoromethyl)-2-thienyl]methanol (34 mg, 15%) as a colorless and clear oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cccs1
Yield: 85 %

Procedure:
The procedure of Example 4B was followed with 2-thiophenesulfonamide (4.2 g, 26 mmole) in 40 ml of acetone, 1N NaOH (26 ml, 26 mmole) and 4-chlorophenyl isocyanate (4.0 g, 26 mmole) in 40 ml of acetone. 7 g of named product were obtained