Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5](C)[CH2:6][NH:7][C:8](=[O:41])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:11](C)[CH:10]=1)C.[Li+].[OH-:45].Cl>C1COCC1>[CH:18]1([CH2:17][CH:16]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[O:15][C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:45])[C:4]([OH:3])=[O:43])=[O:41])=[CH:10][CH:11]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: [OH-]
Reactant: CCOC(=O)C(C)CNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(C)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC(O)C(=O)O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
To a mixture of (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-3-methyl-benzoylamino}-2-methyl-propionic acid ethyl ester (0.0571 g, 0.0978 mmol) in THF (1.0 mL) is added LiOH (1N aqueous, 1.0 mL) and stirred at RT for 4 d. The reaction mixture is acidified with 1N HCl (1.0 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are dried over Na2SO4, filtered, and conc. to provide (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-2-hydroxy-propionic acid (0.0474 g, 87%) as a white foam. MS (ES): 554.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:26].[Na+].C(OCC)(=O)C.O>C(#N)C.[Ru](Cl)(Cl)Cl>[C:21]([O:20][C:18]([N:11]1[CH2:10][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C@H:15]([C:16]([OH:26])=[O:17])[O:14][CH2:13][CH2:12]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a mixed solution of tert-butyl (6R,7R)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3.0 g) and sodium periodate (3.41 g) in acetonitrile (16 mL)/ethyl acetate (16 mL)/water (24 mL) was added ruthenium (III) chloride (17 mg), and the mixture was stirred at room temperature for 10 min. The solid was filtered off through celite, and the filtrate was concentrated. The residue was crystallized from ethyl acetate to give the title compound (311 mg) as a colorless amorphous powder.
Reaction SMILES: [O-2].C[Si](C)(C)[O:4][V+2:5]([O:11][Si](C)(C)C)O[Si](C)(C)C.Br[C:19]1[CH:24]=[CH:23][C:22]([Si](C2C=CC(Br)=CC=2)(C2C=CC(Br)=CC=2)[OH:26])=[CH:21][CH:20]=1.C1(O)CCCCC1>>[O-2:4].[CH:19]1([O:11][V+4:5])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[O-2:26]
Reactant: C[Si](C)(C)O[V+2](O[Si](C)(C)C)O[Si](C)(C)C
Reactant: O[Si](c1ccc(Br)cc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [O-2]
Solvent: OC1CCCCC1
Product: [V+4]OC1CCCCC1

Procedure:
tris-(trimethylsiloxy)-vanadium oxide is reacted with tri-(p-bromophenyl)-silanol and cyclohexanol in a molar ratio of 1:2:1 to produce bis-[tri-p-bromophenyl)-siloxy]-cyclohexyloxy-vanadium oxide [mol peak = 1184 ref to 79Br]; and
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:38](Cl)=[O:39])=[N:29][N:30]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:31]=1)[CH3:25]>>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[N:29]=2)=[O:39])=[CH:18][C:17]=1[F:23]
Reactant: CCOc1cn(-c2cccnc2)nc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Product: CCOc1cn(-c2cccnc2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X19 was prepared from A2 and 4-ethoxy-1-(pyridin-3-yl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.39 (t, J=7.0 Hz, 3H), 3.96 (s, 6H), 4.10 (q, J=7.0 Hz, 2H), 6.56 (d, J=5.5 Hz, 1H), 7.43 (s, 1H), 7.49 (t, J=9.0 Hz, 1H), 7.57 (s, 1H), 7.60 (dd, J=4.7 Hz, J=8.4 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 8.04 (dd, J=2.4 Hz, J=13.2 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.57 (dd, J=1.4 Hz, J=4.7 Hz, 1H), 8.59 (s, 1H), 9.24 (s, 1H), 10.25 (s, 1H). MS (ES) C28H24FN6O6 requires: 529. Found: 530 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[C:30](O)([CH3:33])([CH3:32])[CH3:31]>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
3-Methyl-4-nitrobenzoic acid (500 g, 2.76 mol) was added to pyridine (1.25 L) and stirred until it dissolved. Benzenesulfonyl chloride (609 g, 3.45 mol) was added rapidly while maintaining the internal temperature <30° C. with an ice bath. A precipitate formed towards the end of the addition and pyridine (500 mL) was added to improve stirring. The mixture was stirred for 30 min and t-butanol (523 mL) was added dropwise over 30 min at <30° C. The mixture was stirred for 2 h, dissolved in hexane:ethyl acetate (4:1; 2.5 L) and the resulting mixture was extracted with water. The organic phase was concentrated to give a light yellow oil which crystallized on cooling to give the title compound (635 g, 97%). mp 56-58° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[OH:28][CH2:29][CH:30]1[O:35][CH2:34][CH2:33][N:32]([C:36]2[S:37][CH2:38][C:39](=[O:41])[N:40]=2)[CH2:31]1>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:38]3[S:37][C:36]([N:32]4[CH2:33][CH2:34][O:35][C@H:30]([CH2:29][OH:28])[CH2:31]4)=[N:40][C:39]3=[O:41])=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CSC(N2CCOC(CO)C2)=N1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2(S)-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following General Procedure E.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C:27]([F:35])([C:30]([F:34])([F:33])[CH2:31][NH2:32])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH2:31][C:30]([F:34])([F:33])[C:27]([F:35])([F:26])[CH2:28][NH2:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC(F)(F)C(F)(F)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(F)(F)C(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2,3,3-tetrafluorobutane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 497, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J=6.8 Hz, 1 H), 7.78 (d, J=6.4 Hz, 1 H), 7.58-7.62 (m, 2 H), 7.43-7.47 (m, 2 H), 7.30-7.32 (m, 1 H), 6.19 (s, 1 H), 5.13 (s, 2 H), 4.58 (brs, 2 H), 4.12 (t, J=16 Hz, 2 H), 3.58 (t, J=4.8 Hz 2 H), 3.34-3.20 (m, 2 H), 2.43 (s, 3 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.C1(S[C:19]2([O:22][C:23]3[CH:43]=[CH:42][C:26]([C:27]([NH:29][C:30]4([C:39]([OH:41])=[O:40])[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31]4)=[O:28])=[CH:25][C:24]=3[O:44][CH2:45][CH2:46][C:47]3[CH:48]=[C:49]([CH3:53])[CH:50]=[CH:51][CH:52]=3)[CH2:21][CH2:20]2)C=CC=CC=1.P([O-])([O-])(O)=O.[Na+].[Na+]>C(Cl)Cl.C(=O)([O-])O.[Na+].[Na].[Hg]>[CH:19]1([O:22][C:23]2[CH:43]=[CH:42][C:26]([C:27]([NH:29][C:30]3([C:39]([OH:41])=[O:40])[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31]3)=[O:28])=[CH:25][C:24]=2[O:44][CH2:45][CH2:46][C:47]2[CH:48]=[C:49]([CH3:53])[CH:50]=[CH:51][CH:52]=2)[CH2:20][CH2:21]1
Reactant: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OC2(Sc3ccccc3)CC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Solvent: ClCCl
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Chloroperbenzoic acid (43 mg, 0.177 mmol) was added to the compound of step 1 (35 mg, 0.059 mmol) in DCM (2 ml) and saturated aqueous sodium hydrogencarbonate solution (2 ml). The mixture was stirred for 30 min at room temperature and then partitioned between EA and a sodium carbonate solution. The aqueous phase was extracted with EA and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue (44 mg) was dissolved in a mixture of 0.5 ml of THF and 1 ml of methanol. Disodium hydrogenphosphate (40 mg, 0.28 mmol) and sodium mercury amalgam (5% sodium) (250 mg) were added and the mixture was stirred for 30 min at room temperature and stored for 6 days at 5° C. Then the mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/methanol/28% ammonia gradient, 90:10:1 to 85:15:1.5). The product fractions were evaporated to dryness and the residue partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][C@H:27]([NH2:38])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH:27]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:20]
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), S-(-)-1-(1-naphthyl)ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl}-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 27.9% yield).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].CON(C)[C:8](=[O:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCOCC>C1COCC1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:8](=[O:18])[C:1]#[CH:2])=[CH:16][CH:15]=1
Reactant: C#C[Mg]Br
Reactant: CON(C)C(=O)COc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(=O)COc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 209.7 %

Procedure:
A solution of ethynylmagnesium bromide (0.5 M in THF, 508 mL, 254 mmol), was added slowly, as a stream down the side of the flask, to an ice water cooled solution of N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide (20.00 g, 74 mmol) in THF (100 mL). After an additional 30 minutes at 0° C., the reaction mixture was poured into a vigorously stirred mixture of 1 M NaH2SO4 (1700 mL) and ether (1 L). The layers were separated and the aqueous layer then extracted with ether (700 mL). The combined organic phases were washed with brine and dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by eluting through a plug of silica gel (10 cm×3 cm) with 1:4 ether:pet. ether to afford 27.65 g (91% yield) of 4-(4-fluorophenoxy)-1-butyn-3-one, a compound of formula (AA), as a low melting solid; 1H NMR (CDCl3) δ 3.40 (s, 1H), 4.70 (s, 2H), 6.85 (m, 2H), 7.0 (t, 2H) ppm.
Reaction SMILES: C([OH:3])C.[OH-].[K+].[O:6]=[C:7]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][C:9]2[CH:18]=[CH:19][C:20]([CH2:22][C:23](N)=[O:24])=[CH:21][C:8]1=2>O>[O:6]=[C:7]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][C:9]2[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:24])=[O:3])=[CH:21][C:8]1=2
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Reaction time: 5 h
Yield: 77 %

Procedure:
To a mixture of 2 ml of water, 2 ml of ethanol and 0.4 g of potassium hydroxide was added 100 mg of (10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-acetamide, and the resulting mixture was refluxed with stirring for 5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow crystals, which were chromatographed over 9 g of silica gel and eluted with chloroform/methanol (50/1), thereby obtaining 77 mg (yield: 77%) of (10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-acetic acid. This acid was recrystallized from acetone/n-hexane to give colorless crystals having a melting point of 155.7°-157° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[C:9]2[C:10](=[CH:17][C:18]3[C:23]=2[CH2:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[N:11]([CH2:13][CH:14](O)[CH3:15])[N:12]=1.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:33]([CH:14]([CH3:15])[CH2:13][N:11]1[C:10]2=[CH:17][C:18]3[C:23]([CH2:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[C:9]2[C:8]([O:7][CH3:6])=[N:12]1)=[N+:34]=[N-:35]
Reactant: COC1=C2C=c3c(c(OC)nn3CC(C)O)=C2CC=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1=C2C=c3c(c(OC)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 48.8 %

Procedure:
1.21 ml (15.2 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0% of 2.08 g (7.6 mmol) of (RS)-1-(3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 4.3 ml (30.4 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 110 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1 g (15.4 mmol) of sodium azide and the reaction mixture was heated to 70° for 20 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.11 g (49%) of (RS)-1-(2-azido-propyl)-3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[N:18]=1>O1CCOCC1>[CH3:35][O:34][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([NH:1][C:2]3[CH:11]=[CH:10][C:5]4[O:6][CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[S:12]([NH2:15])(=[O:14])=[O:13])[CH:22]=[CH:21][N:20]=2)[CH:29]=[C:28]([O:30][CH3:31])[C:27]=1[O:32][CH3:33]
Reactant: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Reactant: Nc1ccc2c(c1S(N)(=O)=O)OCCO2
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)OCCO4)n2)cc(OC)c1OC
Temperature: 120 °C

Procedure:
6-Amino-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide (87 mg, 0.38 mmol) and (4-chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (112 mg, 0.38 mmol) are dissolved in dioxane (1.3 ml). The mixture is heated to 120° C. for 1 h. The reaction mixture is purified by repeated chromatography on silica gel using different solvent mixture, yielding 6-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-ylamino]-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:29]=1[CH3:43]>>[CH3:43][C:29]1[N:28]=[CH:33][C:32]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-picoline-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 194. NMR (CDCl3): 2.63 (3H, s), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.23 (1H, d, J=8.1), 7.35 (1H, s), 8.55 (1H, dd, J=8.1, 2.1), 9.50 (1 h, d, J=2.1). MS (ESI+): MH+ 489.24 (95%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](O)[CH2:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].C1(B(O)O)C=CC=CC=1.C(O)(=O)CC.COC1C=CC2C3C(C(C)(C)N(C)C=2C=1)CCC(C)C3>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]2[C@H:11]3[C@H:16]([C:17]([CH3:19])([CH3:18])[N:2]([CH3:1])[C:3]=2[CH:8]=1)[CH2:15][CH2:14][C@@H:13]([CH3:20])[CH2:12]3
Reactant: CNc1cc(OC)ccc1C(O)C[C@H](C)CCC=C(C)C
Agent: COc1ccc2c(c1)N(C)C(C)(C)C1CCC(C)CC21
Agent: OB(O)c1ccccc1
Solvent: c1ccccc1
Solvent: CCC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)N(C)C(C)(C)[C@@H]1CC[C@@H](C)C[C@@H]21

Procedure:
A mixture of (3R)-1-(2-methylamino-4-methoxy-phenyl)3,7-dimethyl-oct-6-en-1-ol (291 mg, 1 mmol), phenylboronic acid (365 mg, 3 mmol) and propionic acid (22 rag, 0.3 mmol) in benzene (10 mL) was refluxed for 20 h to give, after chromatography, 140 mg (51%) of (6aR,9 R, 10aR)-3-methoxy-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-phenanthridine: [α]D +37 (c 4.5, CHCl3); 1H nmr (400 MHz, CD3COCD3), δ 0.83 (q, 1H, J=11.6 Hz, H-10ax), 0.98 (d, 3H, J=6.5 Hz), 1.0 (s, 3H), 1.20 (m, 2H), 1.22 (m, 1H), 1.29 (s, 3H), 1.54 (m, 1H), 1.82 (m, 1H), 1.89 (m, 1H), 2.37 (dr, 1H, J=10.3, 2.7 Hz), 2.45 (m, 1H), 2.83 (s, 3H), 3.71 (s, 3H), 6.12 (d, 1H, J=2.4 Hz), 6.16 (dd, 1H, J=8.3, 2.4 Hz), 7.0 (d, 1H, J=8.3 Hz); 13C nmr (100.6 MHz, CD3COCD3), δ 19.1, 23.1, 26.5, 28.7, 32.4, 33.0, 35.8, 36.0, 41.3, 48.9, 55.1, 57.7, 99.2, 100.7, 120.2, 125.9, 147.8, 160.0. Exact Mass calcd. for C18H28NO (M+1): 274.2170; found: 274.2172.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]#[N:46])[CH:43]=3)[N:38]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[N:37]=2)[CH:33]=[CH:34][CH:35]=1>ClCCl>[C:45]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[N:38]([CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1)[N:37]=[C:36]2[C:32]1[CH:31]=[C:30]([NH:29][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:35]=[CH:34][CH:33]=1)#[N:46]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-[(tert-butyl)oxycarbonyl]piperidine-4-carboxylic acid (0.317 g, 1.38 mmol) in 12 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.287 g, 1.5 mmol). The solution was stirred at room temperature for 10 min before 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.25 mmol) was added as a solid. (A small volume of dichloromethane was used to rinse the flask containing the core). The reaction was stirred at room temperature for 12 hours. Even after addition of 0.5 equivalent of carboxylic acid and EDCI, the reaction could not be driven to completion. The crude mixture was partitioned between water and dichloromethane. The crude was isolated as a brown oil. The yield was not calculated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].C(=O)([O-])[O-].[Ca+2].Br[C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[O:14][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Reactant: CC(C)(Br)C=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CC(C)(C=O)Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.1 %

Procedure:
To a mixture of 10 g of 2-nitro-4-trifluoromethylphenol, 8.0 g of anhydrous calcium carbonate and 30 ml of N,N-dimethylformamide was added dropwise a solution of 8.8 g of 2-bromoisobutyraldehyde in 23 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 4 days. The reaction mixture was then poured in ice-water and extracted with toluene. The organic layer was washed with 0.5 N aqueous sodium hydroxide solution and water in that order and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with hexane-ethyl acetate (3:1). The Crystals from the eluate were recrystallized from 15 ml of hexane twice to give 4.428 g of 2-(2-nitro-4-trifluoromethylphenoxy)isobutyraldehyde.