Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:15]([CH3:17])=O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][NH2:21]>CO>[CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:21][O:20][CH3:19])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: COC(=O)C(=NOCc1ccccc1)C(C)=O
Agent: Cl
Solvent: CO
Product: CON=C(C)C(=NOCc1ccccc1)C(=O)OC
Yield: 83.2 %

Procedure:
To a solution of 4.0 g (17 mol) of methyl 2-benzyloxyiminoacetoacetate in 50 ml of methanol, 1.56 g (18.7 mmol) of methoxyamine hydrochloride was added and the mixture was heated under reflux for 3 hours. After distilling the solvent off under reduced pressure, 50 ml of water was added and the mixture was extracted twice with 50 ml of diethylether and then washed with water and a saturated aqueous sodium chloride. The organic layer was dried over with anhydrous magnesium sulfate and the solvent was distilled off to obtain a residue, which was then purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 4.11 g (yield:91%) of methyl 2-benzyloxyimino-3-methoxyiminobutyrate as a colorless oil. 1H-NMR(CDCl3) δ ppm:1.99(3H, s), 3.86(3H, s), 3.94(3H, s), 5.21(2H, s), 7.33(5H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Cl:21][C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:29][CH2:28][N:27]([CH2:26][C:25]2[CH:34]=[CH:35][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:31][CH2:32]1)=[O:20])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccc(Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 13.5 mmol) and (4-chloro-benzyl)-bis-(2-chloro-ethyl)-amine (4.9 g, 16.2 mmol). Yield 3.5 g (53%); white crystals; MP 91.8° C.; MS: 490 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31](C(O)=O)[CH:32]=[CH:33][C:26]=12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH:31]1[C:27]2=[N:28][CH:29]=[CH:30][C:25]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)=[C:26]2[CH:33]=[CH:32]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: O=C(O)n1ccc2c(Br)ccnc21
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tent-butyl ester (1 equiv), tris(dibenzylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. Tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS (ESI): m/z 379.2 [M+1]+.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.[F:37][C:38]([F:51])([F:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46]>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:48]([NH:47][C:45](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([F:37])([F:51])[F:50])=[S:49])=[C:31]([F:36])[CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 80%).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[O:12]=[C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]3)[C:11]=2[O:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COc2c(CBr)cccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
A solution of 7-bromomethylbenzofuran-3(2H)-one (0.573 g, 2.52 mmol) in methylene chloride (20 mL) was added with sodium acetate (0.412 g, 5.03 mmol) and 1-tert-butoxycarbonylpiperazine (0.721 g, 3.87 mmol), and the mixture was stirred at room temperature for 6 hours. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.391 g, 46%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:38])=[C:27]([C:29]3[C:30]([C:36]#[N:37])=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH:28]=2)OC1>>[F:35][C:32]1[CH:31]=[C:30]([C:36]#[N:37])[C:29]([C:27]2[CH:28]=[C:23]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:24]=[CH:25][C:26]=2[F:38])=[CH:34][CH:33]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Product: N#Cc1cc(F)ccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 14.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile (77 mg, 0.24 mmol) as described in Example 7 part g), affording 4,2′-difluoro-5′-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (13 mg, 14%). δH (400 MHz, CDCl3) 7.41-7.49 (2H, m), 7.54-7.63 (5H, m), 7.88 (1H, d, J 9.0), 8.68 (1H, d, J 8.2), 9.29 (1H, d, J 4.3). m/z (ES+) 412 [MH]+.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:11])=[O:8])=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCP(=O)(O)CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCP(=O)(O)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
13.8 g (0.1 mol) of ethyl-(2-hydroxyethyl)phosphinic acid (produced as in Example 8) in 500 ml of acetone were admixed with 0.11 mol of Jones reagent (12.7 g of chromium trioxide in 36.7 ml of water and 11.0 ml of concentrated sulfuric acid) at 0° C. by dropwise addition. The reaction mixture was additionally stirred for 3½ hours with ice cooling and for 1 hour at room temperature. After 12 ml of isopropanol have been added, the mixture is poured onto ice-water. Volatile constituents are subsequently distilled off in vacuo. The residue was taken up in tetrahydrofuran and extracted. Insoluble salts were filtered off. The solvent of the filtrate was removed in vacuo and the residue was recrystallized from acetone to obtain 12.3 g (81% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as colorless solid.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH:1]1([CH2:6][O:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OCC1CC=CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OCC1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
In a flask under argon was placed cyclopent-3-enyl-methanol (7.86 g, 80 mmol) and pyridine (100 mL). To this mixture was slowly added benzoyl chloride (9.30 mL, 80 mmol). After addition was complete, the mixture was stirred at 25° C. for 1.5 h. After this time, the mixture was slowly treated with water (15 mL) and concentrated in vacuo to remove most of the pyridine. The mixture was taken up into chloroform (400 mL) and washed with water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford benzoic acid cyclopent-3-enylmethyl ester (15.86 g, 98%) as a light yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:41])=[C:18]([CH2:20][N:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[CH:27][CH:28]=4)[CH2:23][CH:22]3[CH3:40])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].O1CCCC1>[CH3:41][C:17]1[O:16][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:19][C:18]=1[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:39])([C:31]([F:34])([F:33])[F:32])[C:35]([F:36])([F:37])[F:38])=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH3:40]
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(O)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Reaction time: 10 h
Yield: 38.2 %

Procedure:
A solution of 1.2 g (2.1 mmol) of 2-{1-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-2,3-dihydro-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 79) in 15 ml of a 2:1-mixture of methanol and tetrahydrofuran was treated with 400 mg of Pd/C (10% Pd) and stirred vigorously under H2 at atmospheric pressure during 10 hrs. Filtration, evaporation of the solvent, and chromatography on silica gel with toluene/EtOAc (gradient from 9:1 to 1:1) gave 390 mg (39%) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-phenol, light yellow foam, MS: 487 (MH+).
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:4]2([CH3:5])[CH2:3]1)[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][CH2:9]3.[N-:22]=[N+:23]=[N-:24].[Li+].O>CS(C)=O>[N:22]([C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:4]2([CH3:5])[CH2:3]1)[C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[CH:12][C:11]=1[CH2:10][CH2:9]3)=[N+:23]=[N-:24]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@H](Br)C[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](N=[N+]=[N-])C[C@@H]12

Procedure:
A stirred solution of 1.56 g (4.5 mmol) 16α-bromo-3-methoxy-estra-1,3,5(10)-triene and 0.67 g (13.7 mmol) lithium azide in 30 ml of DMSO is heated for 1 h to 80° C. After cooling, water is added dropwise and the resulting precipitate is collected by filtration, washed with water and dried under vacuum. 1.33 g (96%). F=80-85° C., after recrystallization from ether/methanol: F=84-87° C. [α]D+60° (c=10.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.CC1C=CC(C)=CC=1C.[K+].[Br-:37]>O>[Br:37][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Reactant: [Br-]
Agent: Cc1ccc(C)c(C)c1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Br)nc2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A mixture of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 2, Step 3) (0.66 g, 1.81 mMol), 12 ml of 1,2,4-trimethylbenzene, 1.0 g of KBr, and 5 g of PBr5 was heated to 80° C. for 2 hours and then to 180° C. overnight. The reaction mixture was cooled to room temperature and stirred with 75 ml of water for 1 hour. The organic portion was extracted into dichloromethane. The dichloromethane extract was washed once with brine, dried over MgSO4, and evaporated to dryness. The residual oil was purified by HPLC to give 0.55 g (72% yield) of solid: m.p. 229.5-231.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=3)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)OCC
Yield: 74.9 %

Procedure:
The title compound (0.375 g, 75%) was prepared as a colourless gum from (E)-3-(4′-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol (0.280 g, 1.00 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.250 g, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[Cl:3][C:4]1[CH:12]=[C:11]([NH:2][CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Solvent: O
Product: CNc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methylamine (40% aq solution, 8.25 mL) is added to an ice-cooled mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (7.00 g, 31 mmol) and 70 mL water. After 2 h additional 0.5 mL methylamine solution is added and it is stirred for additional 3 h. Then 200 mL of water and 47 mL 1N aq HCl are added and the resulting precipitate is filtered off, washed with water and dried.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([C:8](=[O:10])[CH2:7][CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: O=C(O)CC1CCOCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCOCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from tetrahydro-2H-pyran-4-ylacetic acid (Combi-Blocks, Cat. #AM-1005) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=451.1.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[O:8]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](CC)([O-])=O>[CH2:10]1[CH2:9][O:8][C:13]2=[CH:14][C:15]3[S:2](=[O:4])(=[O:3])[NH:5][C:6](=[O:7])[NH:18][C:16]=3[CH:17]=[C:12]2[O:11]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1Nc2cc3c(cc2S(=O)(=O)N1)OCCO3
Temperature: 0 °C
Yield: 51.9 %

Procedure:
This compound was prepared according to the method of Girard et. al., J. Chem. Soc., Perkin I; 1979, 1043-1047, incorporated by reference herein in its entirety. To a solution of chlorosulfonyl isocyanate (5.6 g, 40.0 mmol) in nitroethane (35 ml) at -40° C. was added dropwise over five minutes a solution of 1,4-benzodioxan-6-amine (5.0 g, 33.1 mmol) in nitroethane (5 ml). The mixture was allowed to warm to 0° C. and stirred for one hour at which time anhydrous aluminum chloride was added. The mixture was warmed to 110° C. and stirred for 30 minutes (copious HCl evolution) and allowed to cool to ambient temperature before being added dropwise to a vigorously stirred ice-water (~150 g) mixture. The resulting precipitate was collected by suction filtration, washed with water and air-dried to give 4.4 g (52%) of the title compound as a light gray powder; MS: 255 m/z (M-H)-.
Reaction SMILES: [CH3:1][C:2]([O:5][C@@H:6]([C:9]1[N:10]([CH3:28])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][OH:8])([CH3:4])[CH3:3].[O:29]1CCCC1.CC(=C(C)C)C.[O-]Cl=O.[Na+]>CS(C)=O.O>[C:2]([O:5][C@@H:6]([C:9]1[N:10]([CH3:28])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([OH:29])=[O:8])([CH3:1])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2c([C@@H](CO)OC(C)(C)C)n(C)c(=O)c3ccccc23)cc1C
Agent: CC(C)=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c([C@H](OC(C)(C)C)C(=O)O)n(C)c(=O)c3ccccc23)cc1C
Reaction time: 18 h

Procedure:
A solution of 3-{(1S)-1-[(1,1-dimethylethyl)oxy]-2-hydroxyethyl}-4-(3,4-dimethylphenyl)-2-methyl-1(2H)-isoquinolinone (4 mg, 10.54 μmol) in DMSO is treated with DMP (13 mg, 0.032 mmol). After 18 h, the reaction mixture was filtered through a pad of silica gel and washed with 1:1 EtOAc-hexanes. The filtrate was concentrated, dissolved in EtOAc and washed with H2O (3×), brine, dried (Na2SO4), filtered and concentrated. The residue was then dissolved in tert-Butanol (51.5 μl) and Tetrahydrofuran (THF) (51 μl) and treated with 2,3-dimethyl-2-butene (3 μl, 0.02 mmol) and a solution of NaClO2 (1.787 mg, 0.016 mmol) and NaH2PO4 (1.2 mg, 10.5 μmol) in water (100 uL). The crude reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in DMF (250 uL) and purified by Gilson to afford the title compound: Rt=0.95, 0.97 (atropisomers), ES+ MS: 394 (M+1). The chirality of the above compound was established by comparison to authentic material of (R)- and (S)-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetic acid using a Chiral SFC 20% MeOH/80% CO2; 4.6×250 mm IC column; Rt (R)=1 min; (S)=7.22 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[C@H:32]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][C@@H:32]([CH3:33])[C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CC(C)C(=O)[C@H](C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)[C@H](C)OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 35.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (2.0 g, 5.0 mmol) dissolved in 25 mL of anhydrous dichloromethane (DCM) was reacted with 0.90 mL (1.31 g, 10 mmol) of oxalyl chloride. Upon completion of the reaction, a solution of 2 mL (1.2 g, 10.0 mmol) of (2S)-2-hydroxy-4-methylpentan-3-one (synthesized following procedures according to Gallop et al., U.S. Pat. No. 6,927,036) and 0.85 mL of pyridine (0.79 g, 10.0 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:9) as eluent to provide 0.9 g (36% yield) of the title compound (30a) as a colorless oil. Rf=0.39 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.05 (s, 3H), 0.10 (s, 3H), 0.94 (s, 9H), 1.09 (s, 6H), 1.12 (d, J=7.2 Hz, 3H), 1.19 (d, J=7.2 Hz, 3H), 1.46 (d, J=7.2 Hz, 3H), 2.32-2.39 (m, 2H), 2.83 (sept., J=7.2 Hz, 1H), 3.31-3.35 (m, 2H), 3.69-3.72 (m, 2H), 4.10-4.13 (m, 3H), 5.24 (q, J=7.2 Hz, 1H) ppm. MS (ESI) m/z 501.09 (M+H)+, 523.03 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([CH3:22])[CH3:21])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](N=C(N(C)C)N(C)C)([CH3:26])([CH3:25])[CH3:24].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:24][CH:23]([CH3:26])[CH3:25])[C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([CH3:22])[CH3:21])=[CH:14][N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
The title compound (46.8 mg) was prepared from 4-fluoro-N-(5-isopropyl-3-methoxypyridin-2-yl)benzenesulfonamide (55 mg, 0.170 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.068 mL, 0.339 mmol) in acetonitrile (4 mL) and 1-bromo-2-methylpropane (0.037 mL, 0.339 mmol) following the procedure described for Example 40. LCMS (2 min, formic) Rt 1.34 min, m/z (ES+) 381 (M+H).