Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:29](=[O:30])[N:4]2[C:5]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[C:6]([C@H:9]3[CH2:13][CH2:12][C@@H:11]([CH2:14][O:15][CH3:16])[O:10]3)[CH2:7][S:8][C@H:3]12>C(Cl)(Cl)Cl>[NH2:1][C@@H:2]1[C:29](=[O:30])[N:4]2[C:5]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]3[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH3:16])[O:10]3)[CH2:7][S:8][C@H:3]12
Reactant: COC[C@@H]1CC[C@H](C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1
Solvent: ClC(Cl)Cl
Product: COCC1CCC(C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1

Procedure:
A solution of 4-methoxybenzyl (6R,7R)-3-[(2RS,5SR)-5-methoxymethyltetrahydrofuran-2-yl]-7-phenoxyacetamidoceph-3-em-4-carboxylate (1.93g) in dichloromethane (25ml) was cooled to -15 to -20° C., N-methylmorpholine (0.75ml) was added followed by a solution of phosphorus pentachloride in dichloromethane (26.5ml of a solution containing 40mg.ml-1). The mixture was stirred at the same temperature for 0.5h and then methanol (6.8ml) was added and the mixture stirred at room temperature for 0.5h. Water (10ml) was then added and the mixture vigorously stirred for 0.5h. The dichloromethane was then removed on a rotary evaporator and the residue was partitioned between ether and water. The aqueous phase was stirred with ethyl acetate and the pH was adjusted to 6.2 with 1N aqueous ammonia. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The products were separated by column chromatography of the residue using gradient elution is (silica gel, 1:1 hexane : ethyl acetate going to neat ethyl acetate). The following were obtained in order of elution 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxymethyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (388mg); vmax (CHCl3) 3410, 1776 and 1725cm-1 ; δH (CDCl3) 1.59-1.78 (2H,m), 1.93-2.08 (1H,m), 2.18-2.32 (1H,m), 2.54 (2H, br s), 3.33-3.54 (3H,m), 3.38 (3H,s), 3.80 (3H,s), 4.00-4.11 (1H,m), 4.76 (1H,d, J 4.99Hz), 4.90 (1H,d, J 4.97Hz) 4.96 (1H,t, J 8.23Hz) 5.17 (2H,s), 6.88 (2H,d, J 8.60Hz) and 7.33 (2H,d, J 8.61Hz). [Mass spectrum: M+ (434)]; 4-methoxybenzyl (6R,7R)-7-amino-3-[(2R,5S)-5-methoxymethyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (305mg); vmax (CHCl3) 3409, 1776 and 1725cm-1 ; δH (CDCl3) 1.60-1.81 (2H, m), 1.85-2.01 (2H, m), 3.30-3.50 (2H, m), 3.38 (3H, s), 3.44 (1H,d, J 17.78Hz), 3.69 (1H, d, J 17.75Hz), 3.80 (3H, s), 4.00-4.17 (1H,m), 4.70 (1H, d, J 4.92Hz), 4.93 (1H, d, J 4.95Hz), 5.10-5.20 (1H, m), 5.18 (1H, d, J 11.88Hz), 5.24 (1H, d, J 11.89Hz), 6.88 (1H,d, J 8.65Hz) and 7.35 (1H, d, J 8.64Hz). [Mass spectrum: M+ (434)].
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([NH:41][C:42](=[O:46])[CH:43]([OH:45])[CH3:44])[C:36]([O:39][CH3:40])=[N:37][CH:38]=1.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[OH:45][CH:43]([CH3:44])[C:42]([NH:41][C:35]1[CH:34]=[C:33]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:38]=[N:37][C:36]=1[O:39][CH3:40])=[O:46]
Reactant: COc1ncc(Br)cc1NC(=O)C(C)O
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NC(=O)C(C)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (150 mg, 0.267 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2-hydroxypropanamide (88 mg, 0.321 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 mins, then again at 120° C. for a further for 30 mins. The reaction mixture was passed through a 1 g silica cartridge, pre-conditioned with methanol, washing with methanol. The solvent was evaporated in the blow down. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (Method E). Pure fraction was evaporated to dryness. The residue was dissolved in IPA and 2M NaOH (aq) and left overnight. The reaction was concentrated in vacuo, then neutralised using 2M HCl (aq) and the resultant precipitate was collected by filtration. The material was dissolved in DMSO:methanol (0.7 ml, 1:1, v/v) and purified by MDAP (Method E). Pure fractions were combined and evaporated to dryness to afford the title compound (10 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35].C(O)C(N)(CO)CO.CCN(CC)CC>C1COCC1>[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:35]
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Agent: NC(CO)(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1cc(F)ccc1Cl
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine (80 mg, 0.20 mmol) in 2 mL THF was added 2-chloro-5-fluorobenzoyl chloride (26 μL, 0.22 mmol). When LC/MS indicated the reaction was complete, several equivalents of PS-trisamine were added and the mixture was stirred for 16 h. Et3N was added if necessary to get the reaction into solution. The mixture was filtered and the resin washed well with THF. The filtrate was concentrated and triturated with DCM to give the title compound (51 mg, 46%). 1H NMR (400 MHz, d6-DMSO) δ 10.66 (s, 1H), 9.78 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 8.45 (d, J=8.8 Hz, 1H), 8.30 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.80-7.74 (m, 2H), 7.61-7.42 (m, 5H), 7.39-7.32 (m, 2H), 7.26-7.20 (m, 1H), 7.11 (t, J=6.4 Hz, 1H), 6.72-6.67 (m, 1H), 6.57 (d, J=5.2 Hz, 1H) ppm. MS (ESI) m/z=553 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH:29]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:37][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:28]2[CH:29]=[N:25][N:26]=[CH:27]2)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: NCc1ccccc1-n1cnnc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1-n1cnnc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-proline (Example 16, Step B, 0.06 g, 0.19 mmol) in DMF (1 mL) was added 1-[2-(4H-1,2,4triazol-4-yl) phenyl]methanamine (Example 5, Step A, 0.05 g, 0.31 mmol), BOP Reagent (0.11 g, 0.24 mmol) and N-methylmorpholine to pH=8. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, filtered and purified on a Gilson Preparative HPLC to give the solid 1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-N-[2-(4H-1,2,4-triazol-4-yl)benzyl]-L-prolinamide (0.065 g, HPLC RT=2.77 min, Method A; LCMS m/z=480). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 2H), 7.67–7.64 (m, 3H), 7.62–7.52 (m, 1H), 7.44–7.37 (m, 2H), 7.35–7.29 (m, 3H), 7.23–719 (m, 1H), 7.15 (s, 1H), 7.04 (d, 1H), 4.55–4.53 (m, 1H), 4.31–4.11 (m, 2H), 2.34–2.26 (m, 1H), 2.24–1.95 (m, 1H), 1.72–1.55 (m, 2H), 1.46–1.43 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:26])[CH:3]=1.[C:27](=O)([O-])O.[Na+]>COS(OC)(=O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:27])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=2[Cl:26])[CH:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOC(=O)CN(C)c1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 15 step ii). (0.70 g) which was dissolved in dimethylsulphate (3 ml). Sodium hydrogen carbonate (0.355 g) was added and heated to 90 C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated under reduced pressure to give an oil. The residue was purified by chromatography on silica eluting with diethyl ether, yield 0.70 g.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[C:5]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:12][C:11]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:13]2[C:18](=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:2]([CH3:4])([CH3:3])[CH2:1]1
Reactant: C=C(C)C
Reactant: CC(c1ccccc1)c1ccc(O)cc1
Product: CC1(C)CC(C)(c2ccccc2)c2ccc(O)cc21
Reaction time: 5 h
Yield: 13.5 %

Procedure:
112 g of isobutylene were introduced with stirring into 198 g of 1-phenyl-1-(4-hydroxy-phenyl)-ethane and 30 g of an acid activated Fuller's earth at 150°C and the reaction mixture was then stirred at this temperature for 5 hours. 34 g of 1,3,3-trimethyl-1-phenyl-5-hydroxy-indane could be obtained by distillation followed by recrystallisation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(C(Cc2ccccc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCc1ccc(C(Cc2ccccc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a suspension of 2.00 g of methyl 4-[4-[1-(4-chlorophenylsulfonylamino)-2-phenylethyl]phenyl]butyrate in 17 ml of methanol, 7.7 ml of 2N aqueous sodium hydroxide was added and stirring was continued at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was added with water, acidified with dilute hydrochloric acid, and then extracted with methylene chloride. After the methylene chloride layer was washed with water and dried, the solvent was removed under reduced pressure to yield 1.87 g of colorless crystals. Recrystallization from a mixture of isopropyl ether and ethyl acetate gave colorless needles, mp 152°~153° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1.N1C=CC=CC=1>C(Cl)Cl>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([NH:22][C:34](=[O:35])[C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([OH:37])=[O:26])[CH2:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:24])[CH3:23])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 29: 70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60° C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition F); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][CH2:31][CH2:30]2)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[CH2:32][CH2:31][CH2:30]4)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=Nc1ccc2c(c1)CCC2
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)CCC4)c(=O)n(C3CCCC3)c12
Yield: 49.1 %

Procedure:
1-Cyclopentyl-3-indan-5-yl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 5-isocyanato-indan (0.5 mmol) following general procedure C. LCMS: m/z 428 [M+1]+.
Reaction SMILES: [OH2:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21][CH2:20]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][S:21](=[O:1])[CH2:20]3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O
Reactant: O=C1CSCN1CCCCN1CCN(c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=C1CS(=O)CN1CCCCN1CCN(c2ccc(F)cc2)CC1

Procedure:
A second run using NaIO4 (1.41 g), H2O (13 ml), 1 (2.02 g) and THF (20 ml) was conducted in a similar manner yielding 0.910 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@H:10]2[C:21]([O:23]C)=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[OH-].Cl>CO>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:11]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Boc anhydride (3.0 g, 13.7 mmol) was added to a solution of (3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (3.10 g, 11.3 mmol) in THF (100 mL) and TEA (4 mL). The mixture was stirred at room temperature overnight. The solvent was removed, and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (8:1) to give (3S,4R)-1-tert-butyl 3-methyl 4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate (LCMS (APCI+) [M−Boc+H]+ 274.1; Rt: 4.17 min). The (3S,4R)-1-tert-butyl 3-methyl 4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate was redissolved in MeOH (50 mL), and LiOH (3M, 10 mL) was added. The mixture was stirred at room temperature for 6 hours. 2N HCl (15 mL) was added to the mixture. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (40:1-10:1) to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (1.95 g). (LCMS (APCI+) [M−Boc+H]+ 260.1; Rt: 3.67 min.)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1>>[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[C:12]=2[CH:11]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: COCCOCCBr
Product: COCCOCCC1(CCOCCOC)c2ccccc2-c2ccc(Br)cc21

Procedure:
2-Bromo-9,9-bis(3,6-dioxaheptyl)-fluorene (14) was synthesized from bromo-2-(2-methoxyethoxy)ethane and 2-bromofluorene following the general procedure outlined in Example 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][N:7]([C:23]1[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][N:26]=[C:21]([Cl:20])[N:22]=1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CN[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.3 %

Procedure:
A solution of 7.8 g (0.029 mole) of 2,2-difluoro-3-(trans-2-phenyl-cyclopropylamino)-propionic acid ethyl ester in 20 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 5.6 g (0.029 mole) of 2,4-dichloro-5-nitro-pyrimidine, 9.7 g (0.12 mole) of sodium bicarbonate and 80 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 11.8 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(trans-2-phenyl-cyclopropyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-287) as a yellow thick oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)[C:2]#[CH:3].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[CH:12][CH:13]=1)[C:2]#[CH:3]
Reactant: O=C(Cl)C1CC1
Reactant: C#CCOCc1ccc(CO)cc1
Product: C#CCOCc1ccc(COC(=O)C2CC2)cc1

Procedure:
In an analogous manner to that described in Example 1, from 4-(hydroxymethyl)benzyl alcohol and propargyl bromide there is obtained 4-[(2-propynyloxy)methyl]benzyl alcohol. This alcohol is reacted in an analogous manner to that described in Example 2 with cyclopropane carboxylic acid chloride to give cyclopropane carboxylic acid p-[(2-propynyloxy)methyl]benzyl ester.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:45]=[C:46]([NH2:53])[C:47]2[CH:48]=[N:49][NH:50][C:51]=2[CH:52]=1>CN(C=O)C>[Br:43][C:44]1[CH:52]=[C:51]2[C:47]([CH:48]=[N:49][NH:50]2)=[C:46]([NH:53][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[O:9])[CH:45]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Temperature: 20 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
2-Methyl-1,3-thiazole-4-carboxylic acid (4.59 g, 32.1 mmol), HATU (13.4 g, 35.3 mmol) and DIPEA (16.8 ml, 96 mmol) were stirred in DMF (140 ml) for 30 mins at 20° C. 6-Bromo-1H-indazol-4-amine (3.40 g, 16.03 mmol) was added and the reaction stirred at 20° C. for 2 days. The solvent was reduced to ˜40 ml and the reaction mixture applied to 5×70 g aminopropyl SPE cartridges and left to stand for 3 h. The cartridges were eluted with DCM:MeOH (1:1, v/v) and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-15% MeOH (containing 1% Et3N) in DCM. Appropriate fractions were evaporated to give the title compound 1.02 g.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)[CH3:3].[H][H]>CO.[Ni]>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)Oc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)Oc1ccccc1N
Yield: 94.4 %

Procedure:
1-(1-methylethoxy)-2-nitrobenzene, 45.26 g (0.25 mol) is dissolved in 500 ml of methanol, 4 g Raney nickel is added and the mixture is exposed to hydrogen gas until the required amount of hydrogen is absorbed. The methanol solution is filtered and concentrated in vacuo and the residue distilled to give 35.7 g (94.4%) of 2-(1-methylethoxy)benzenamine; bp 100-102 (at 4 mm).
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][C@H:5]([N:7]([C@@H](C2C=CC=CC=2)C)C(=O)OCC2C=CC=CC=2)[C@@H:4]([NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH2:3]1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:7][C@H:5]1[CH2:6][C:2]([F:1])([F:34])[CH2:3][C@@H:4]1[NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)[C@H]1CC(F)(F)C[C@@H]1NS(=O)(=O)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC(F)(F)C[C@@H]1N

Procedure:
A solution of benzyl N-[(1S,2S)-4,4-difluoro-2-(2-methylpropane-2-sulfonamido)cyclopentyl]-N-[(1R)-1-phenylethyl]carbamate (2.24 g, 4.53 mmol) and palladium hydroxide on carbon (20%, 1.59 g, 2.26 mmol) in methanol (65 ml) was stirred under a balloon of hydrogen gas for 17 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.