Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:44])[C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:44])[C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCOCc1ccccc1)c1ncc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cn1
Agent: [Br-]
Agent: [Zn+2]
Product: CN(CCCOCc1ccccc1)c1ncc(C2CCNCC2OCc2ccc3ccccc3c2)cn1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3RS,4RS)-4-[2-[(3-benzyloxy-propyl)-methyl-amino]-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of BOC group by means of anhydrous zinc bromide there was obtained (3-benzyloxy-propyl)-methyl-[5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidin-2-yl]-amine in the form of an amorphous colourless solid; MS: 498 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([NH:22][C@H:23]([B:40]3[O:48]C4C(C)(C5CC(C4)C5(C)C)[O:41]3)[CH2:24][C:25]3[C:26](OC)=[C:27]([CH:35]=[CH:36][CH:37]=3)[C:28]([O:30]C(C)(C)C)=[O:29])=[O:21])[CH:17]=2)[CH2:12]1)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:8][CH2:9][CH2:10][N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([NH:22][C@H:23]3[CH2:24][C:25]4[CH:37]=[CH:36][CH:35]=[C:27]([C:28]([OH:30])=[O:29])[C:26]=4[O:48][B:40]3[OH:41])=[O:21])[CH:17]=2)[CH2:12]1
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCCN1Cc2ccc(C(=O)N[C@H]3Cc4cccc(C(=O)O)c4OB3O)cc2C1

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2-(2-(tert-butoxycarbonylamino)ethyl)isoindoline-5-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 396 (MH)+.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([B:43]2[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:51])([CH3:50])[O:44]2)=[CH:39][CH:38]=1>O1CCCC1>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[N:16]2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([B:43]3[O:44][C:45]([CH3:51])([CH3:50])[C:46]([CH3:49])([CH3:48])[O:47]3)=[CH:41][CH:42]=2)=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: c1ccc(-c2ccc(CC(c3ccccc3)n3nnc4ccccc43)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(CC(Cc3ccc(-c4ccccc4)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
A solution of 4.26-A of Step 1 (450 mg, 1.2 mmol) in tetrahydrofuran (14 mL) was cooled to −78° C. and treated with n-butyllithium (0.62 mL, 2.5 M in hexanes) dropwise. The reaction mixture was stirred at −78° C. for 10 min and 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (410 mg, 1.4 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, quenched with sat. ammonium chloride (2 mL), and extracted with ethyl acetate (15 mL). The organic layer was separated and washed with brine (5 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue which was purified by flash column chromatography to yield the desired product (350 mg, 50%). LCMS found for C39H38BN3O2Na (M+Na)+: m/z=614.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]2[C:17]3[C:7]([C:8]4[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][C:9]=42)=[CH:6][CH:5]=[CH:4][C:3]1=3.Br[C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:39]3[C:34]2=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=1>>[CH:35]1[C:34]2[N:33]([C:30]3[CH:31]=[CH:32][C:27]([C:20]4[CH:19]=[CH:18][C:9]5[N:10]6[C:17]7[C:7]([C:8]=5[CH:21]=4)=[CH:6][CH:5]=[CH:4][C:3]=7[C:2]([CH3:25])([CH3:1])[C:16]4[C:11]6=[CH:12][CH:13]=[N:14][CH:15]=4)=[CH:28][CH:29]=3)[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Reactant: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Product: CC1(C)c2cnccc2-n2c3ccc(-c4ccc(-n5c6ccccc6c6ccccc65)cc4)cc3c3cccc1c32

Procedure:
The compound is synthesised by the same procedure as Example 7 by reaction of 36 g (110 mmol) of 8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene-3-boronic acid with 35.4 g (110 mmol) of 9-(4-bromophenyl)-9H-carbazole. The residue is recrystallised from toluene and from CH2Cl2/isopropanol and finally sublimed in a high vacuum. Yield: 47 g (99 mmol), 82% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:17])[N:10]([CH2:22][CH:21]=[CH2:20])[C@H:11]([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@@H](C)NC(=O)OCc1ccccc1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC[C@@H](C)N(CC=C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
((R)-1-Methyl-pent-4-enyl)-carbamic acid benzyl ester (790 mg, 3.39 mmol) was dissolved in DMF (8 ml) and was cooled to 0 degrees C. Sodium hydride (60% dispersion, 271 mg, 6.78 mmol) was added and the reaction was stirred for 15 minutes. Allyl bromide (1.23 g, 0.88 ml, 10.17 mmol) was added and the reaction mixture was stirred for 3 h at 0 degrees C. H2O (10 ml) was added, then 2N HCl was added dropwise adjusting the pH to 1. The reaction mixture was extracted with Et2O (2×50 ml). The combined organics were washed with aq. 2N HCl, then aq. NaHCO3, then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then chromatographed on silica gel (5% EtOAc/hexanes) to yield the title compound as a colorless oil (883 mg, 95%).
Reaction SMILES: [H-].[Na+].I[CH3:4].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]2[C:19]([CH:20]=[CH:21][C:22]=1[CH2:23][OH:24])=[C:18]([C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])[C:17](=[O:33])[CH:16]=[CH:15]2>C1COCC1>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[N:14]2[C:19]([CH:20]=[CH:21][C:22]=1[CH2:23][O:24][CH3:4])=[C:18]([C:25]1[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=1[F:31])[C:17](=[O:33])[CH:16]=[CH:15]2
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)c(CO)ccc2c1-c1c(F)cccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2c1-c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
Oil free sodium hydride suspended in THF was added iodomethane (0.06 mL) and 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-7-(hydroxymethyl)-2H-quinolizin-2-one (Example 50, 40 mg) at 0° C. The mixture was warmed to room temperature and stirred for a couple of hours until reaction complete. The mixture was quenched with water, extracted with ethyl acetate, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% acetone) to give the title compound (22 mg).
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.CN(C)CCCN.C[O:33][C:34]1[CH:35]=[C:36]([C:40]2[C:41]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH2:57][N:58]([CH3:60])[CH3:59])[C:42]=3[N:43]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:45]=2)[CH:37]=[CH:38][CH:39]=1>>[CH3:60][N:58]([CH3:59])[CH2:57][CH2:56][CH2:55][N:52]1[C:42]2[N:43]=[C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:45]=[C:40]([C:36]3[CH:35]=[C:34]([OH:33])[CH:39]=[CH:38][CH:37]=3)[C:41]=2[CH2:54][CH2:53]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3CCCN(C)C)c1
Agent: CN(C)CCCN
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: CN(C)CCCN1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and N,N-dimethyl-1,3-propanediamine, {3-[4-(3-methoxy-phenyl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-propyl}-dimethyl-amine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][Si:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][C:9](O)=[O:10]>ClCCCl>[CH3:5][Si:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][C:9]([Cl:3])=[O:10]
Reactant: C[Si](C)(C)CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: C[Si](C)(C)CCC(=O)Cl
Temperature: 40 °C

Procedure:
13.5 g (0.11 mol) of thionyl chloride are added dropwise with stirring to a mixture of 10 g (0.068 mol) of 3-trimethylsilylpropanoic acid in 30 ml of 1,2-dichloroethane. The reaction mixture is heated at 40° C. for 2 hours. The excess thionyl chloride is removed by distillation under reduced pressure. The solution obtained is used without further purification for the following step.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.[NH2:26][C:27]1[CH:28]=[C:29]([CH2:33][CH2:34][OH:35])[CH:30]=[CH:31][CH:32]=1>>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][OH:35])[CH:28]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: Nc1cccc(CCO)c1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Product: CC(C)(N)c1ccc(-c2nc(Nc3cccc(CCO)c3)ncc2Cl)cc1
Yield: 23.9 %

Procedure:
The title compound was prepared from 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.50 g, 6.55 mmol) and 2-(3-aminophenyl)ethanol (942 mg, 6.87 mmol) following the method of Example 1. The crude product was purified by chromatography (Silica, 10% methanol in CH2Cl2) to give the title compound as a brown solid (600 mg) m.p. 184-185°. δH (d6DMSO) 9.77 (1H, s), 8.57 (1H, s), 7.79 (2H, d, J 8.4 Hz), 7.68 (2H, d, J 8.4 Hz), 7.61-7.58 (2H, m), 7.17 (1H, t, J 7.7 Hz), 6.82 (1H, d, J 7.4 Hz), 4.62 (1H, bs), 3.60 (2H, t, J 7.0 Hz), 2.68 (2H, t, J 7.1 Hz), 2.07 (2H, bs), 1.41 (6H, s); MS (ESI) 383 (MH+, 35Cl).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=[NH:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:21](=[N:34][C:17]1[CH:18]=[CH:19][C:14]([CH:12]2[O:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13]2)=[CH:15][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCOC(c3ccc(N=C(c4ccccc4)c4ccccc4)cc3)C2)cc1
Temperature: 100 °C
Yield: 63.4 %

Procedure:
To a degassed solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (4.00 g; 12.04 mmol) in toluene (50 mL) was added benzophenone imine (2.42 mL; 14.45 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.60 g; 0.96 mmol), tris-(dibenzylideneacetone)-dipalladium(0) (0.22 g; 0.24 mmol) and NaOtBu (1.62 g; 16.86 mmol). The resulting mixture was heated to 100° C. for 16 hours. After cooling to RT a 5% aqueous NaHCO3 solution was added, and the product was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford benzhydrylidene-[4-(4-benzyl-morpholin-2-yl)-phenyl]-amine (3.30 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:11]([OH:30])[CH2:12][N:13]1[C@H:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14]1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:38](O)(=[O:49])[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:26]([NH:25][C:23]([C@@H:22]1[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][N:13]1[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:6])[NH2:5])[NH:1][C:38]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1)=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 25 %

Procedure:
A solution of 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 50 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H]+, NMR: δ (d4CH3OH, 400 MHz):
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:41][N:42]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)[CH3:43])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=2)[CH:31]=1.CCN(C(C)C)C(C)C.Cl.[CH2:67]([O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73])[CH3:68]>CCOC(C)=O.C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:41][N:42]([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=3)=[CH:46][CH:45]=2)[CH3:43])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH2:67][CH3:68])=[O:74])=[O:39])=[N:36][CH:37]=2)[CH:31]=1
Reactant: CN(Cc1ccc(Cl)cc1-c1ccc(C(=O)O)nc1)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 45 °C

Procedure:
Solid HATU (127 mg, 0.34 mmol) was added to a THF solution (3 mL) of 5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinic acid (155 mg, 0.34 mmol), i-Pr2NEt (0.29 mL, 1.67 mmol), and β-alanine ethyl ester hydrochloride (54 mg, 0.35) and the resulting mixture was warmed to 45° C. After 16 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[C:25]([C:28]1[C:34](O)=[CH:33][C:32]([CH3:36])=[CH:31][C:29]=1[OH:30])(=[O:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][C@H:6]1[O:7][C:34]1[CH:33]=[C:32]([CH3:36])[CH:31]=[C:29]([OH:30])[C:28]=1[C:25](=[O:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)c1c(O)cc(C)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1S[C@@H](Oc2cc(C)cc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
2,3,4,6-Tetra-O-acetyl-5-thio-D-glucopyranose (200 mg, 0.55 mmol), 2-acetyl-5-methylresorcinol (182 mg, 1.10 mmol), triphenylphosphine (288 mg, 1.10 mmol) and toluene (2 mL) were mixed, and to the resulting mixture, diisopropyl azodicarboxylate (40% in toluene, 555 mg) was then slowly added dropwise in ice. After stirring at room temperature for 18 hours, the reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-50:50) to give 2-acetyl-3-hydroxy-5-methylphenyl 2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranoside (82 mg, 28%) as a light-yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:24][CH2:25]O>>[CH2:24]([O:16][C:15](=[O:17])[C@H:14]([OH:18])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:25]
Reactant: CCO
Reactant: O=C(NCC[C@@H](O)C(=O)O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](O)CCNC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
A solution of (R)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid (2.42 g, 9.56 mmol) and sulfuric acid (94 mg, 0.96 mmol) in EtOH (6 mL) was heated at reflux for 18 h, then partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (2.18 g, 81%). Light yellow liquid, MS: 304.2 (M+Na)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[O:1]=[CH:2][CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10]
Reactant: O=C(NCCC1OCCO1)c1ccc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=CCCNC(=O)c1ccc[nH]1
Yield: 80.1 %

Procedure:
Method A. A mixture of 6 (2.85 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (1.3 g, 6.84 mmol) in 80 mL of acetone/water (1:1, v/v) was refluxed for 6 h. After cooling, the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was recrystallized from acetone/CH2Cl2 to afford 7 (1.81 g, 80%) as a colorless solid: mp 88-90° C.; 1H NMR (CDCl3) d 2.77 (t, 2H, J=5.8), 3.66 (q, 2H, J=5.8), 6.16 (m, 1H), 6.38 (br, 1H), 6.50 (m, 1H), 6.87 (m, 1H), 9.69 (br, 1H), 9.78 (bs, 1H); 13C NMR (CD3COCD3) d 33.7 (e), 44.6 (e), 109.6 (o), 110.0 (o), 122.1 (o), 127.1 (e), 162.0 (e), 201.9 (o); IR (nujol) 1715, 1622, 1565, 1409, 1328 cm−1; MS m/z (relative intensity) 167 (M++1, 100), 138 (15) , 123 (28), 94 (50); Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86; Found: C, 57.68; H, 5.17; N, 16.79. Method B. To a stirred solution of oxalyl chloride (0.12 mL, 1.31 mmol) in 3 mL of CH2Cl2 at −78° C. was added DMSO (0.21 mL, 2.9 mmol) in 0.6 mL of CH2Cl2 under argon. After 2 min, a solution of 5 (0.2 g, 1.19 mmol) in 40 mL of CH2Cl2 was added to the mixture and allowed to stir for 15 min. Next, triethylamine (830 mL, 5.92 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 15 min, the mixture was poured into 10 mL of water and the organic layer was separated and washed successively with 10% citric acid (20 mL), saturated NaHCO3 (20 mL), and saturated NaCl (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (CH2Cl2/MeOH 19:1) to afford 7 (0.14 g, 70%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.[C:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([Cl:38])[CH:30]=1)([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].COCCOC.O>[Cl:38][C:31]1[CH:30]=[C:29]([C:26]([OH:28])=[O:27])[CH:34]=[CH:33][C:32]=1[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(COc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)c1cc(COc2ccc(-c3ccc(C(=O)O)cc3Cl)cc2)n(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C

Procedure:
Into a 8 mL flask was added 200 mg (0.454 mmol) of 5-(4-bromophenoxymethyl)-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole, 108 mg (0.54 mmol) of (4-carboxy-2-chlorophenyl)boronic acid, 186 mg of potassium carbonate (1.36 mmol) and 2 mL of 9:1 DME-water. The solution was sparged under argon and 6.5 mg (0.01 mmol) of palladium dppf was added. The reaction mixture was heated to 80° C. for 4 h. After cooling, the crude reaction was filtered through a pad of celite, concentrated in vacuo, and purified directly on a reverse phase HPLC-MS to afford 2-chloro-4′-[2-(2,6-dichlorophenyl)-5-isopropyl-2H-pyrazol-3-ylmethoxy]-biphenyl-4-carboxylic acid as an off white solid, yield (80.1 mg, 34%); 1H NMR (400 MHz, DMSO-d6): δ 13.37 (s, 1H), 8.04 (m, 1H), 7.96 (dd, J=8.1 (1.77) Hz, 1H), 7.73 (d J=8.1 Hz, 2H) 7.61 (m, 1H), 7.55 (d, J=7.83 Hz, 1H), 7.41 (d, J=8.84 Hz, 2H), 6.98 (d, J=9.09 Hz, 2H), 6.61 (s, 1H), 5.01 (s, 1H), 4.83 (s, 2H), 3.02 (m 1H), 2.52 (s, 1H), 1.31 (d J=6.82 Hz 6H), MS (ES): 515 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:15]([OH:16])[CH:14]=[C:13]([CH2:12][Cl:11])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc(O)cc(CCl)n2)nc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 4-chloroacetoacetate (0.387 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform to obtain the title compound.