Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:24][C:25]1[C:30]([C:31]#[N:32])=[CH:29][C:28]2[C:33]3([CH2:43][O:44][C:27]=2[CH:26]=1)[C:41]1[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=1)[N:35]([CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[C:34]3=[O:42]
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ncccc2C(F)(F)F)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-(chloromethyl)-3-(trifluoromethyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (67%): mp 209-211° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=6.0 Hz, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.42-7.40 (m, 1H), 7.31-7.23 (m, 3H), 7.06-7.01 (m, 1H), 6.93-6.91 (m, 1H), 5.21 (s, 2H), 5.03 (s, 2H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([C@@H:53]([NH2:55])[CH3:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:55][C@H:53]([CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@H](N)C1CCCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)C2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-((S)-1-cyclohexyl-ethyl)amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H58Cl2N5O3 [(M+H)+] 774.391 1, observed 774.3913.
Reaction SMILES: [Na].[C:2]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:3][SH:4].[Cl:9][C:10](Cl)=[CH:11][C:12](OCC)=[O:13].CC[O-].[Na+]>C(O)C>[CH2:7]([O:6][C:2]([C:3]1[S:4][C:10]([Cl:9])=[CH:11][C:12]=1[OH:13])=[O:5])[CH3:8]
Reactant: CCOC(=O)C=C(Cl)Cl
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1sc(Cl)cc1O
Reaction time: 0.25 h

Procedure:
A solution of 23.6 mm of the sodium salt of ethyl thioglycolate in 100 ml of ethanol was added over 5 minutes at 30° C. to a a mixture of 4 g of ethyl dichloroacrylate in 50 ml of ethanol and the mixture was stirred at 25°-30° C. for 15 minutes and was then returned to room temperature. A mixture of 3.22 g of sodium ethylate in 75 ml of ethanol was added thereto and the mixture was stirred for 18 hours. The mixture was concentrated and poured into water and the mixture was extracted with ether. The aqueous phase was acidified with hydrochloric acid and was extracted with ether. The ether phase was evaporated to dryness and the 4.2 g of residue was chromatographed over silica gel. Elution with benzene yielded 1.75 g of 2-ethoxycarbonyl-3-hydroxy-5-chloro-thiophene with Rf = 0.4-0.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:20][O:21]C(Cl)Cl>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:12]([C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=1[S:9][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:20]=[O:21])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccccc1Sc1ccccc1OC
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccccc1Sc1cc(C=O)ccc1OC

Procedure:
Dissolve 117 g (0.427 mole) of the ester of Step B in 1500 ml of 1,2-dichloroethane and cool with stirring in an ice-bath. Add 200 ml (345 g, 1.82 mole) of titanium tetrachloride at a rapid dropwise rate. Add also fairly rapidly 154 g (1.34 mole) of dichloromethyl methyl ether. Stir the mixture under a nitrogen atmosphere overnight then pour into ice. After shaking, separate the organic phase and extract the aqueous phase twice with methylene chloride. Wash the combined organic phases twice with water, dry and strip to an oil which crystallizes. (m.p. 99°-104° C.).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH2:14][CH3:15])[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH2:14][CH3:15])[CH3:13]
Reactant: CCC(C)c1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCC(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and sec-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2.5 hours. Using the same procedure as in Example 1, 4'-sec-butylbenzoin was obtained as crystal (200.6 mg, 37.3% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:23][CH3:24])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2F)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:32][CH:33]1[N:38]([CH2:39][CH2:40][CH2:41][NH2:42])[CH2:37][CH2:36][CH2:35][CH2:34]1>C(#N)C>[CH2:1]([C:3]1[C:4]([O:23][CH3:24])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:42][CH2:41][CH2:40][CH2:39][N:38]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[CH3:32])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1OC
Reactant: CC1CCCCN1CCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCN2CCCC[C@H]2C)c(C(=O)O)c1OC

Procedure:
A mixture of Example 318E (50 mg, 0.14 mmol), triethylamine (0.1 mL, 0.71 mmol), acetonitrile (1 mL) and 1-(3-aminopropyl)-2-pipecoline (177 mg, 1.1 mmol) was purged with argon, sealed in a vial and microwaved at 150° C. for 55 minutes. Purification by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min provided the desired product. MS (ESI(+)) m/e 490 (M+H)+; (ESI(−)) m/e 488 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.24 (br s, 1H), 9.71 (br s, 1H), 7.58 (dd, 1H), 7.42 (t, 1H), 7.13 (d, 1H), 6.87 (dd, 1H), 6.67 (m, 2H), 6.05 (m, 1H), 3.69 (s, 3H), 3.36 (m, 2H), 3.12 (m, 2H), 3.05 (m, 2H), 2.88 (m, 1H), 2.54 (q, 2H), 1.86 (m, 4H), 1.64 (m, 2H), 1.43 (m, 2H), 1.20 (d, 3H), 1.10 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21](=[O:58])[C:22]([CH3:57])([CH3:56])[CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:55])=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]5[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[C@@H:43]([CH3:54])[CH2:42]5)[CH:35]=4)[CH:33]=3)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl>O1CCOCC1.CO>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21](=[O:58])[C:22]([CH3:57])([CH3:56])[CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]5[CH2:46][CH2:45][NH:44][C@@H:43]([CH3:54])[CH2:42]5)[CH:35]=4)[C:31]([F:55])=[CH:30][CH:29]=3)=[O:25])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 60 °C
Yield: 3.5 %

Procedure:
174(d) 1,1-Dimethylethyl (2S)-4-{[5′-({[4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3,3-dimethyl-4-oxobutanoyl]amino}methyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate was dissolved in 2 mL of dioxane and 0.5 mL of MeOH. HCl (concentrated, 101 mg, 2.78 mmol) was added to the resultant solution and heated at 60° C. for 1 h. The solution was applied to an amine column, rinsed with 4 mL of MeOH to afford 7 mg of the title compound (3.5%). LC-MS m/z 727 (M+H)+, 1.23 min (ret time). The structure of the title compound was confirmed by gCOSY45, gHMQC, gHMBC and 13C gaspe spectra.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13]CC)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>C(OCC)(=O)C>[CH2:16]([O:23][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C1(c2ccc(OCc3ccccc3)nc2)CC1

Procedure:
A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (45.1 mg, 0.000200 mol), benzyl alcohol (0.50 mL, 0.0048 mol) and sodium hydride (9.50 mg, 0.000238 mol) was irradiated by microwave at 150° C. for 15 minutes. After cooling, additional sodium hydride (9.5 mg) was added to the mixture. The mixture then was irradiated by microwave at 150° C. for 15 minutes. Ethyl acetate (5 mL) was added and the resulting mixture was washed with water and brine successively. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash with ethyl acetate/hexane to give the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([SH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([S:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)S
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
2-(tert-butoxycarbonylamino)-3-mercapto-3-methylbutanoic acid (2.96 g, 11.87 mmol) was suspended in water (33 ml) and cooled with an ice/water bath. KOH (1.67 g, 29.7 mmol) dissolved in water (16 ml) followed by acetic anhydride (1.41 ml, 14.9 mmol) were added to the reaction flask and stirred at 0-5° C. for 4 hours (a white precipitated appears after ca. 30 minutes of stirring). The reaction mixture was partitioned between EtOAc and HCl 1M. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and solvent removed under vacuum. Crude compound was used in the next step without further purification. (3.45 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([C@H:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH2:58][CH3:59])=[CH:55][CH:56]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of compound 81 (2.0 g, 2.46 mmol) and Pd/C (10% wt., 200 mg) in THF (12 mL) and MeOH (12 mL) was stirred at room temperature under an atmosphere of H2 for 16 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E024 (514 mg, 46%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:5]1)[CH3:2]
Reactant: COc1ccc(C2CCCN(C(C)=O)C2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1CCCC(c2ccc(OC)c(OC)c2)C1
Temperature: 5 °C
Yield: 93.2 %

Procedure:
A solution of 680 mg of N-acetyl-3-(3',4'-dimethoxyphenyl)-piperidine in 10 ml of tetrahydrofouran was slowly added with stirring at 20° C to 200 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran and the mixture was stirred for an hour and then cooled to 5° C. 10 ml of ethyl acetate were slowly added thereto and the mixture was poured into water and filtered. The aqueous phase was recovered by decanting and was extracted again with ethyl acetate. The combined organic phases were washed with water, dried and evaporated to dryness to obtain 600 mg of N-ethyl-3-(3',4'-dimethoxyphenyl)-piperidine melting at about 50° C.
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[CH3:7][O:8][C:9](=[O:25])[C:10](=[N:22][O:23][CH3:24])[C:11]#[C:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[O:14]>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9](=[O:25])[C:10]([C:11]1[CH2:5][C:4]([CH3:6])=[C:2]([CH3:3])[CH2:1][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)=[N:22][O:23][CH3:24]
Reactant: C=C(C)C(=C)C
Reactant: CON=C(C#CC(=O)c1cccc(Br)c1)C(=O)OC
Solvent: Cc1ccccc1
Product: CON=C(C(=O)OC)C1=C(C(=O)c2cccc(Br)c2)CC(C)=C(C)C1

Procedure:
1.5 ml of 2,3-dimethylbuta-1,3-diene are added to the solution of 300 mg 5-(3-bromo-phenyl)-2-methoxyimino-5-oxo-pent-3-ynoic acid methyl ester in 1 ml toluene. The reaction mixture is heated for 24 hours at 130° in an autoclave. It is subsequently evaporated, stirred with petrol ether and filtered with suction. The filtrate is evaporated to give 300 mg of [2-(3- bromo-benzoyl)-4,5-dimethyl-cyclohexa-1,4-dienyl]-methoxyimino-acetic acid methyl ester as a resinous oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][Si](C)(C)C>C(#N)C>[Cl:21][CH2:12][C:11](=[O:13])[C:3](=[N:2][OH:1])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=NO)C(=O)CCl
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
In 15 ml of acetonitrile was dissolved 1.07 g of tert-butyl 2-hydroxyimino-3-oxobutyrate, followed by addition of 2.8 ml of triethylamine. Then, 2.5 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1.5 hours, after which it was concentrated under reduced pressure. The residue was suspended in 15 ml of tetrahydrofuran and the suspension was filtered in a nitrogen gas stream to remove insolubles. This filtrate containing tert-butyl 2-trimethylsilyloxyimino-3-trimethylsilyloxy-3-butenoate was cooled to -30° C. and 0.46 ml of sulfuryl chloride was added dropwise. After the temperature of the system was increased to 20° C., the reaction mixture was concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (1:1, v/v). The eluate was concentrated under reduced pressure to give 1.08 g of tert-butyl 4-chloro-2-hydroxyimino-3-oxobutyrate. Yield 85.2%.
Reaction SMILES: [S:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27][CH2:26]2)[N:19]=1)(=[O:4])(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.NC>C1COCC1.O>[CH3:45][NH:41][C:31]([CH:28]1[CH2:27][CH2:26][CH:25]([NH:24][C:20]2[N:19]=[C:18]([N:13]3[C:14]4[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:1](=[O:3])(=[O:4])[NH2:2])[CH:17]=[CH:16][CH:15]=4)[CH:11]=[CH:12]3)[CH:23]=[CH:22][N:21]=2)[CH2:30][CH2:29]1)=[O:33]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(N)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
4-{4-[4-(3-Sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexane-carboxylic acid (75 mg, 0.158 mmol), BOP (105.08 mg, 0.238 mmol), DIEA (55 μL, 0.317 mmol), and H2NMe (0.120 μL, 20% soln. in THF, 0.238 mmol) were combined in THF and allowed to stir at RT overnight. Water was then added to the reaction mixture and the mixture sonicated, and the solid filtered, washed with water, dried and recrystallized to yield 4-{4-[4-(3-sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methylamide (Compound 319, 53.3 mg, 69.3%).
Reaction SMILES: [Na].Br[C:3]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]2[C:9](=[O:20])[N:8]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:7](=[O:32])[N:6]([CH3:33])[C:5]=2[N:4]=1.[O:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1>O>[Si:25]([O:24][CH2:23][CH2:22][CH2:21][N:8]1[C:9](=[O:20])[C:10]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:3]([O:42][CH2:41][CH2:40][N:37]3[CH2:38][CH2:39][O:34][CH2:35][CH2:36]3)=[N:4][C:5]=2[N:6]([CH3:33])[C:7]1=[O:32])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: OCCN1CCOCC1
Agent: [Na]
Solvent: O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OCCN1CCOCC1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Step 1 Sodium (0.053 g, 2.31 mmol) was dissolved in 2-morpholinoethanol (5 mL) and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was added. The reaction was stirred at room temperature for 24 h. The reaction was diluted with water (75 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-8-(2-morpholinoethoxy)-1H-purine-2,6(3H,7H)-dione (0.27 g, 100% yield) as a clear oil. LCMS retention time=2.990 min and 96% purity, LCMS MH+ 592.
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C@H:9]([OH:17])[CH2:8][CH2:7]1)=O.[OH-].[Na+]>CO.O>[NH2:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C@H:9]([OH:17])[CH2:8][CH2:7]1
Reactant: O=C(N[C@H]1CC[C@@H](O)c2ccc(F)cc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N[C@H]1CC[C@@H](O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 65 h
Yield: 86 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1S,4R)-7-fluoro-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide (synthesised in an analogous manner to that described in WO 2009/048474, which is incorporated herein by reference in its entirety) (2.31 g, 8.34 mmol) in MeOH (22.5 mL), was added a solution of sodium hydroxide (0.834 g, 20.8 mmol) in water (15 mL) and the mixture was stirred at RT for 65 h. The mixture was concentrated in vacuo, then applied to an SCX-2 cartridge (50 g), washing with methanol then eluting basic components with 0.2-1 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.29 g, 86%). 1H NMR (300 MHz, d6-DMSO): 1.60-2.15 (6H, m), 3.62-3.71 (1H, m), 4.49 (1H, t, J 4.7), 5.15 (1H, br s), 6.98 (1H, dt, J 8.6, 2.8), 7.28 (1H, dd, J 10.7, 2.8), 7.36 (1H, dd, J 8.6, 6.2).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23](O)=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(Br)ccn1N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
Methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (2.83 g, 12.92 mmol) was treated with (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (4 g, 12.93 mmol), N,N-diisopropylethylamine (7.4 mL, 42.6 mmol) and T3P® (50% in ethyl acetate, 10.8 mL, 18.14 mmol) according to the method of Preparation 5a to give 6.77 g (84% yield) of the desired compound. Purity 81%.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9])=C.Cl.[OH-].[Na+]>CCO.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc12
Yield: 96 %

Procedure:
A solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (2-vinyloxyethoxy) amide (11a) (55.4 mg, 0.114 mmol) and aqueous HCl (1 M, 0.23 mL) in EtOH (3 mL) was stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 6-7 with aqueous NaOH (2 M). The reaction was diluted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 50.2 mg (96% yield) of the desired product (12a). MS APCI (−) m/z 456, 458 (M+, Br, Cl pattern) detected. 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 4.01 (t, 2H), 3.74 (t, 2H), 2.60 (s, 3H): 19F NMR (376 MHz, CD3OD)−140.85 (s).
Reaction SMILES: [PH4+].[CH:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>>[C:2]([O:12][CH2:2][CH3:3])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC=O
Agent: [PH4+]
Product: CCCCCCCCC/C=C\CCCCC(=O)OCC

Procedure:
Reaction of the phosphonium salt with decanal to give ethyl cis-6-hexadecenoate