Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:37]([CH2:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[C:54]1([CH2:53][O:52][C:50](=[O:51])[CH2:49][N:37]([C:25](=[O:26])[C:24]2[CH:28]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=[CH:22][C:23]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: O=C(CNCC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
A mixture of 1.0 g (2.0 mmol) of 5-(octadecyloxy)-2-(phenylmethoxy)benzoic acid in 5 ml of thionyl chloride was heated to reflux for 1 hour and then concentrated at reduced pressure. The resultant acid chloride was dissolved in 30 ml of anhydrous THF and added dropwise to a stirred mixture of 0.785 g (2.5 mmol) of dibenzyl iminodiacetate and 0.85 ml (6.1 mmol) of triethylamine in 10 ml of THF. The reaction mixture was stirred at room temperature for 20 hours and the solvent was removed at reduced pressure. The product was purified by HPLC using 5% ethyl acetate-hexane to give 0.70 g (44% yield) of N-[5-(octadecyloxy)-2-(phenylmethoxy) benzoyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:40](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C)C=O>[C:34]([CH2:33][CH2:32][CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:37])=[O:29])(=[O:36])[NH2:40]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)CC1CN(C(=O)NCCCC(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 85.8 %

Procedure:
To a mixture rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-butyric acid (22.7 mg, 0.041 mmol, Example C11) in N,N-dimethyl formamide (2.5 mL) was added DIPEA (37.1 mg, 0.287 mmol) and HATU (25.1 mg, 0.066 mmol). After it was stirred at rt for 35 min, ground ammonium chloride (5.1 mg, 0.095 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (3-carbamoyl-propyl)-amide (19.4 mg, 85.6%). HRMS (ES+) m/z Calcd for C27H30Cl2F2N4O2+Na [(M+Na): 573.1606; Found: 573.1609.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13]([O:26][CH3:27])=[CH:14][C:15]2[N:20]([CH3:21])[C:19](=[O:22])[C:18]([CH3:24])([CH3:23])[O:17][C:16]=2[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[C:13]([O:26][CH3:27])=[CH:14][C:15]3[N:20]([CH3:21])[C:19](=[O:22])[C:18]([CH3:24])([CH3:23])[O:17][C:16]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CNc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)OC(C)(C)C(=O)N2C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc3c(cc2OC)N(C)C(=O)C(C)(C)O3)ncc1Cl
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 8.4 %

Procedure:
A mixture of 2,5-dichloro-N-methylpyrimidin-4-amine (1 mmol), 7-amino-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (222 mg, 0.94 mmol), cesium carbonate (0.65 g, 2 mmol), XantPhos (17 mg, 0.03 mmol) and Pd2(dba)3 (5 mg, 0.02 mmol) in dioxane (3 mL) was sonnicated in an ultrasonic bath for 1 min. The mixture was then degassed under a stream of nitrogen for 5 min. The tube was sealed and the reaction was heated at 100° C. for 18 h. The reaction mixture was cooled and diluted with ethyl acetate (15 mL). The organic layer was washed with water and the combined aqueous extracts were further washed with ethyl acetate. The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave 7-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (30 mg, 15%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=378 at 2.77 min. 1H NMR δ (ppm)(400 MHz, d6-DMSO): 8.05 (1H, s), 7.98 (1H, s), 7.54 (1H, s), 7.28 (1H, d, J=5.2), 6.85 (1H, s), 3.93 (3H, s), 3.66 (3H, s), 2.91 (3H, d, J=4.6), 1.41 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:14]1[CH2:16][CH2:15]1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].CO>CCOCC>[CH:14]1([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][OH:11])[CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CO)C1CC1
Temperature: 40 °C
Yield: 88.6 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-2-cyclopropylacetate (5.35 g, 23.33 mmol) in Et2O (100 ml) was added LiBH4 (0.762 g, 35.0 mmol), followed by drop wise addition of methanol (1.420 ml, 35.0 mmol). The reaction was refluxed at 40° C. for one hour. The reaction mixture was then cooled to 0° C., and quenched with HCl (1M) until pH=2 for aqueous layer. The phases were separated and the aqueous layer was extracted with DCM (3×100 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (4.16 g). LCMS m/z 224.1 (M+Na)+, Rt 0.62 min.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])C.C(OC(=O)[NH:25][CH2:26][CH:27](O)[CH3:28])(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:28][CH:27]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[C:4](=[O:5])[NH:25][CH2:26]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: CC1CNC(=O)c2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and rac-2-hydroxy-propyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.[CH3:44][S:45](Cl)(=[O:47])=[O:46].BrCC1OC(C(F)(F)F)=CC=1>>[CH3:44][S:45]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21])(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: CS(=O)(=O)N1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and methanesulfonyl chloride to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (51%) as a white solid: mp 215-217° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, 1H), 7.42-7.31 (m, 1H), 7.25-7.17 (m, 2H), 6.52 (s, 1H), 6.20 (s, 1H), 5.93-5.87 (m, 2H), 4.98 (d, 1H), 4.68 (d, 1H), 3.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.8, 149.5, 142.7, 138.1, 130.5, 129.7, 125.9, 124.3, 118.5, 113.8, 102.9, 101.8, 93.8, 80.6, 58.8, 41.8; MS (ES+) m/z 360 (M+1), 382 (M+23).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:7]([NH2:13])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:5][C:6]1[C:7]([N:13]=[C:1]=[S:2])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ncc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: S=C=Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
Thiophosgene (21.9 mL, 288 mmol) was added dropwise to a stirred mixture of 3,5-dichloropyridin-2-amine (23.5 g, 144 mmol) in tetrahydrofuran (150 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (11.4 g, 55.6 mmol, 39%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Reactant: BrCc1ccccc1
Product: CCOC(=O)Cn1c(=O)n(Cc2ccccc2)c2cc(Cl)c(Cl)cc21

Procedure:
The procedure described in Example 1 was repeated (using the same molar proportions as before) except that 210 mg. (0.0007 mole) of 5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester (prepared according to the procedure described in Preparation A) and 120 mg. (0.0007 mole) of benzyl bromide were reacted to afford crude 3-benzyl-5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester, which was used as such in the next reaction step (viz., hydrolysis to the corresponding acid as hereinafter described in Example 24) without any further purification being necessary.
Reaction SMILES: [ClH:1].Cl.Cl.[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])CC1.[CH3:37]NC(C1C2C=C(C3C([Cl:56])=CN=C(Cl)N=3)SC=2C=CC=1)=O.C(N1CCN(CCCN)CC1)C>>[ClH:25].[ClH:56].[ClH:1].[CH3:4][NH:7][C:8]([C:10]1[C:18]2[CH:17]=[C:16]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]4)[N:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: CCN1CCN(CCCN)CC1
Agent: Cl
Product: CCN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and 3-(4-ethylpiperazin-1-yl)-propylamine and isolated as a yellow solid. ES+(m/z) 473 (35Cl) and 475 (37Cl) [M(free base)+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NCc1cccnc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCc1cccnc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-(aminomethyl)pyridine (31 mg) according to Method B to give the title compound (14 mg). HRMS m/z 620.2471 (calc. of monoisotopic mass for C32H36N4O9 gives 620.2482).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH:27]1[CH2:36][CH:35]([OH:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: O=C1CC(c2ccc(F)cc2F)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1F)O2

Procedure:
2-(2,4-Difluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1,47 g of 2-(2,4-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (s, 1H), 7.61 (m, 1H), 7.28 (m, 1H), 7.14 (m, 1H), 6.88 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.9 Hz), 6.54 (dd, 1H, J 8.9, 2.7 Hz), 5.46 (s, 1H), 5.32 (dd, 1H, J 11.9, 1.4 Hz), 4.88 (m, 1H), 2.24 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([C@@H:19]1[O:23][C:22](=[O:24])[C@:21]([CH2:26][CH3:27])([CH3:25])[O:20]1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[C:15]([C@@H:19]1[O:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:24])[C@@:21]([CH2:26][CH3:27])([CH3:25])[O:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CSc1ccc(Br)cc1
Reactant: CC[C@@]1(C)O[C@H](C(C)(C)C)OC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@]1(C)O[C@H](C(C)(C)C)OC1(O)c1ccc(SC)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromothioanisole (48.5 g) in THF (600 mL) was cooled to -70° C. and a 2.5M solution of n-butyllithium in hexane (96 mL) was slowly added over 20 min. The resulting suspension was stirred for 1 h allowing the temperature of the cooling bath to raise to -50° C. It was then cooled back to -70° C. and a solution of dioxolanone from Step 2 (29.8 g) in TBF (100 mL) was added dropwise over 30 min. The reaction was allowed to proceed for another 30 min. and then quenched with AcOH (23 mL) always at -70° C. The reaction mixture was allowed to warm to r.t., diluted with a 25% aqueous solution of NH4OAc and extracted with EtOAc (2 L). The organic layer was dried over MgSO4 and concentrated. The resulting crude product was purified by flash chromatography (2→3→5→7% EtOAc in hexane) to give a light yellow solid. 1H NMR(CD3COCD3): mixture of diastereomers δ0.50 (0.5H, m), 0.68 (1.5H, s), 0.72 (1.5H, t), 0.97 (1.5H, t), 0.98 (9H, s), 1.38 (1.5H, s), 1.52 m), 1.68 (0.5H, m), 2.10 (0.5H, m), 2.48 (3H, 2s), 4.85 (1H, s, OH), 5.01 (0.5H, s), 5.32 (0.5H, s), 7.22-7.30 (2H, m), 7.50 (2H, dd).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:21]3[C:16](=[C:17]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]C4C=CC=CC=4)[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Na]>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:21]3[C:16](=[C:17]([NH:22][CH2:23][CH2:24][CH:25]([C:26]4[CH:27]=[CH:5][CH:6]=[CH:2][CH:1]=4)[C:12]4[CH:21]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: Cc1noc(NS(=O)(=O)c2cccc3c(NCCCCCc4ccccc4)cccc23)c1C
Agent: [Na]
Product: Cc1noc(NS(=O)(=O)c2cccc3c(NCCC(c4ccccc4)c4ccccc4)cccc23)c1C

Procedure:
N-(3,4-Dimethyl-5-isoxazolyl)-5-[(5-phenylpentyl)amino]-1-naphthalenesufonamide, sodium salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COC=COC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[CH:7]=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)[CH:9]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: COC=COC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Temperature: 130 °C
Yield: 56.3 %

Procedure:
To a solution of 3-Nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (100 mg, 0.326 mmol), 2-bromo-5 methyl-pyridine (56 mg, 0.326 mmol), K3PO4 (138 mg, 0.652 mmol) in dimethoxy ethylene (3 mL) and water (1 mL) was added Pd(Pph3)4 (11.3 mg, 0.001 mmol). The mixture was flushed with N2 and heated under microwave at 130° C. for 30 minutes. The reaction mixture was cooled, solvent was removed under reduced pressure, and the residue was purified by column chromatography (EtOAc/hexane=1:3) to afford 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester as a white solid (50 mg, 56%). MS (M+H)=273.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[N+:8]([C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[CH2:13][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][NH:16][C:15]1=[O:20])([O-:10])=[O:9].[CH2:30](I)[CH2:31][CH3:32]>O>[N+:8]([C:11]1[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=1[CH2:13][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][N:16]([CH2:30][CH2:31][CH3:32])[C:15]1=[O:20])([O-:10])=[O:9]
Reactant: CCOC(=O)C1(Cc2ccccc2[N+](=O)[O-])CCCNC1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCCC(Cc2ccccc2[N+](=O)[O-])(C(=O)OCC)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.59 g) was added to a DMF solution (100 ml) of ethyl 3-(2-nitrobenzyl)-2-oxo-3-piperidinecarboxylate (11.0 g) and propyl iodide (5.79 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with a mixture of ethyl acetate and diethyl ether. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4 to 1/2) to obtain the entitled compound (10.6 g).
Reaction SMILES: [CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=2)[C:19](O)=[O:20])=[CH:13][CH:12]=1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1.C(OC1C=C(C=C(C(=O)NC2SC=CN=2)C=1)OC1C=CC(P(=O)(O)O)=CC=1)(C)C>>[CH:8]([O:7][P:5]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:17]=[C:18]([C:19](=[O:20])[NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH:22]=[C:23]([O:25][CH:26]([CH3:27])[CH3:28])[CH:24]=2)=[CH:29][CH:30]=1)(=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])([CH3:10])[CH3:9]
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)O)c1
Reactant: Nc1nccs1
Agent: CC(C)Oc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)Nc2nccs2)c1
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)Nc2nccs2)c1

Procedure:
Starting from 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (7.64 g, 17.6 mmol) and 2-aminothiazole (1.84 g, 18.4 mmol), {4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonic acid was synthesized as yellow gum (8.80 g, 17.0 mmol) according to Step D in Example 1. 1H NMR (300 MHz, CDCl3): δ 7.78 (dd, J=9, 13 Hz, 2H), 7.29-7.30 (m, 1H), 7.18-7.20 (m, 2H), 7.04 (dd, J=4, 9 Hz, 2H), 6.94 (d J=4 Hz, 1H), 6.78 (dd, J=2, 2 Hz, 1H), 4.63-4.74 (m, 2H), 4.51-4.59 (m, 1H), 1.36 (d, J=6 Hz, 6H), 1.33 (d, J=6 Hz, 6H) 1.24 (d, J=6 Hz, 6H).
Reaction SMILES: O[CH:2]1[CH2:5][C:4]([CH2:20][C:21]#[N:22])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.COCCN(CCOC)S(F)(F)[F:29].C(O)C>ClCCl>[F:29][CH:2]1[CH2:5][C:4]([CH2:20][C:21]#[N:22])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1
Reactant: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(F)C1

Procedure:
A solution of 3-hydroxy-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.01 g, 0.00003 mol) (a mixture of cis/trans isomers) in dichloromethane (3 mL), contained in a Teflon bottle equipped with a nitrogen inlet tube and stirring bar, was treated with 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (0.03 mL, 0.0002 mol) at rt. Ethanol (0.002 mL, 0.00003 mol) was added, and the mixture was stirred at rt over weekend. The reaction was evaporated to dry and the residue was purified with prep. HPLC (pH=10) to give a mixture of two isomers. LCMS calculated for C15H14FN6(M+H)+: 297.1. Found: 297.3.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[CH:23]=2)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,1-dimethylethyl((1R)-1-{[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 69, 1.28 g) was dissolved in 18 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (7.15 mL, 93 mmol). The reaction was stirred during 3 hours at 0° C. The reaction mixture was evaporated. The residue obtained was purified by SCX on a 50 g cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). After evaporation of the volatiles, the title compound was obtained (932 mg).