Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.C([Li])CCC>C1COCC1>[CH2:12]([O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:21])[OH:19])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COS(=O)(=O)c1ccc(B(O)O)cc1
Temperature: 20 °C
Yield: 92 %

Procedure:
To a solution of isobutyl 4-bromobenzenesulfonate (56 g, 200 mmol) in 280 ml of THF was added triisopropylborate (84 ml, 1.82 eq) and the reaction mixture was cooled to less than −65° C. To the cooled solution, n-butyllithium (144 ml, 0.9 eq, 1.07 M in hexanes) was slowly added while maintaining the temperature below −65° C. The reaction mixture was stirred for at least 0.5 hours and then was quenched with 1M sulfuric acid (200 ml). The reaction mixture was allowed to warm to ca. 20° C. The layers were separated and the rich organic layer containing 35 g (92% yield) of 4-(isobutoxysulfonyl)phenylboronic acid was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH2:29][CH3:30].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1.C(NCC)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH3:26][C:25]([O:24][C:22](=[O:23])[C@H:10]([CH2:9][NH:8][C:4]1[C:3]([CH2:29][CH3:30])=[C:2]([N:31]2[CH2:36][CH2:35][CH:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]2)[N:7]=[CH:6][N:5]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([CH3:28])[CH3:27]
Reactant: COC(=O)C1CCNCC1
Reactant: CCc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCNC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(C(=O)OC)CC1
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 1.2 g (2.8 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-ethyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy)carbonyl]alaninate, 5 ml of methyl 4-piperidinylcarboxylate and 1 ml of isopropylethylamine is heated between 110 and 120° C. for 4 hours. After cooling down to ambient temperature, the reaction medium is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate then concentrated to dryness under vacuum. The residue is chromatographed on silicagel with a gradient of pure heptane to pure ethyl acetate. 260 mg (Yield=17%) of expected product is obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.P(OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Agent: CCOP(OCC)OCC
Product: Clc1ccc2c(c1)[nH]c1ccccc12
Temperature: 150 °C
Yield: 69.2 %

Procedure:
A mixture of 4′-Chloro-2-nitrobiphenyl (640 mg) and triethyl phosphite (1.9 ml) was heated at 150° C. for 3 hrs. The mixture was then allowed to cool and purified by flash chromatography (5–10% ethyl acetate/hexane) to afford the sub-title compound as a white solid (382 mg): 1H NMR (400 MHz, d6-DMSO) δ 7.12–7.23 (2H, m), 2.40 (1H, m), 7.46–7.54 (2H, m), 8.12 (2H, d).
Reaction SMILES: [F:1][C:2]1([F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[C:3]1([CH3:13])[CH3:12].[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([F:14])([F:1])[C:3]2([CH3:13])[CH3:12])[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)C(O)c2ccccc2C1(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2C(F)(F)C1(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 3,3-difluoro-2,2-dimethyl-indan-1-ol (388 mg, 1.96 mmol) in THF (16 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 370 mg, 2.94 mmol), and triphenylphosphine (770 mg, 2.94 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (670 mg, 2.94 mmol) is added. The reaction is placed at room temperature and permitted to stir for six hours and then is heated to 40° C. overnight. The next day the reaction mixture is cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4 filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:5) to furnish 3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester. MS: (ESI) m/z 307.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.87 (d, J=2.5 Hz, 3 H), 1.33 (d, J=3.0 Hz, 3 H), 3.96 (s, 3 H), 6.43 (d, J=2.8 Hz, 1 H), 7.17 (s, 1 H), 7.30-7.37 (m, 1 H), 7.56-7.64 (m, 2 H), 7.69-7.76 (m, 1 H), 7.85 (s, 1 H)
Reaction SMILES: NC1C=CC(C)=C([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.ClC1C=C(C2(N)C=C(Cl)N=CN2)C=CC=1F.[CH3:41][C:42]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:43]=1N.Cl>C(O)CCC.CCOC(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([N:15]([C:48]2[CH:47]=[C:46]([N+:49]([O-:51])=[O:50])[CH:45]=[CH:43][C:42]=2[CH3:41])[C:13]2[CH:14]=[C:9]([NH2:8])[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: Cl
Agent: NC1(c2ccc(F)c(Cl)c2)C=C(Cl)N=CN1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Temperature: 120 °C

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stifling, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.N1(C2C3CCCCC=3N=CC=2)CCNCC1>C(#N)C>[N:26]1[C:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C:32]=2[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Agent: c1cc(N2CCNCC2)c2c(n1)CCCC2
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a similar manner to Example 1, methyl 4-bromoacetylphenoxyacetate (1.23 g), a 1:1 mixture containing 4-(1-piperazinyl)quinoline and 4-(1-piperazinyl)-5,6,7,8-tetrahydroquinoline (1.84 g) and acetonitrile (56 ml) yielded, after stirring at room temperature overnight, filtration and evaporation of the filtrate, an orange/brown oily residue which was purified by flash chromatography, first on neutral alumina by elution with 5% v/v methanol/dichloromethane, then on silica by elution with methanol/dichloromethane (0.5% v/v to 5% v/v), and finally by crystallisation of the lower Rf material from methanol/water, to yield the title compound (298 mg) as a cream solid: NMR (CDCl3) δ 1.76(2H,m), 1.89(2H,m), 2.64(2H,m), 2.76(4H,m), 2.95(2H,m), 3.07(4H,m), 3.80(2H,s), 3.81(3H,s), 4.71(2H,s), 6.68(1H,d), 6.95(2H,d), 8.03(2H,d), 8.28(1H,d); m/Z 424 (M+H)+ ; calculated for C24H29N3O4.1.0 H2O: C, 65.3%; H, 7.08%; N, 9.52%; found: C, 65.6%; H, 6.7%; N, 9.3%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:70])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][CH:52]=[C:53]([C:55]2[CH:60]=[CH:59][C:58](B3OC(C)(C)C(C)(C)O3)=[CH:57][CH:56]=2)[N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:58]4[CH:59]=[CH:60][C:55]([C:53]5[NH:54][C:50]([CH:46]6[CH2:47][CH2:48][CH2:49][N:45]6[C:43](=[O:44])[CH:39]([NH:38][C:37]([O:36][CH3:35])=[O:70])[CH:40]([CH3:42])[CH3:41])=[N:51][CH:52]=5)=[CH:56][CH:57]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(c6ccccc6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 8.7 %

Procedure:
{1-[4-(4-Bromo-phenyl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (40 mg, 0.076 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (37.6 mg, 0.076 mmol) under an argon atmosphere. Potassium carbonate (20.9 mg, 0.152 mmol) and Pd(PPh3)4 (8.7 mg, 0.0076 mmol) were added, followed by DME (1.8 mL) and water (0.3 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (5.4 mg): LCMS-ESI+: calc'd for C45H53N9O6: 815.9 (M+). Found: 816.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.89-7.86 (m, 10H), 7.35 (m, 2H), 7.18 (m, 1H), 6.94 (m, 2H), 5.67 (m, 1H), 5.37 (m, 1H), 5.25 (m, 1H), 5.12 (m, 1H), 4.31-4.08 (m, 3H), 4.01-3.79 (m, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 2.58 (m, 1H), 2.29-1.99 (m, 5H), 0.99-0.89 (m, 12H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:50][CH3:51])[C:34]([NH:39][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42][CH2:41]2)=[N:35][C:36]=1[CH2:37][CH3:38].[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][C:54]=1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]([NH:39][C:34]2[C:33]([CH2:50][CH3:51])=[N:32][C:31]([C:54]3[CH:55]=[CH:56][C:57]([CH3:59])=[CH:58][C:53]=3[CH3:52])=[C:36]([CH2:37][CH3:38])[N:35]=2)[CH2:41][CH2:42]1
Reactant: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: [Pd]
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(C)cc2C)c(CC)nc1NC1CCOc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine, ethylene glycol dimethyl ether, 2,4-dimethyl phenyl boronic acid and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.38, 7.22, 7.11–6.90, 5.38, 4.58, 4.31, 2.68, 2.53, 2.37, 2.26, 2.14, 1.25–1.15; HRMS (FAB) calcd for C25H29N3O+H 388.2389, found 388.2383.
Reaction SMILES: CC(C)N=C=NC(C)C.O[CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14].[CH3:20][CH2:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:45][CH2:44][N:43]([C:46]4[CH:51]=[CH:50][C:49]([NH:52][S:53]([C:56]5[CH:61]=[CH:60][C:59]([NH:62][C@@H:63]([CH2:73][S:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH2:64][CH2:65][N:66]6[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68][CH2:67]6)=[C:58]([S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH:57]=5)(=[O:55])=[O:54])=[CH:48][CH:47]=4)[CH2:42][CH2:41]3)[CH:35]=2)[C:24]([C:88]([OH:90])=[O:89])=[C:23]1[CH3:91]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:22]([CH2:21][CH3:20])[C:23]([CH3:91])=[C:24]([C:88]([O:90][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:89])[C:25]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][N:43]([C:46]4[CH:47]=[CH:48][C:49]([NH:52][S:53]([C:56]5[CH:61]=[CH:60][C:59]([NH:62][C@H:63]([CH2:64][CH2:65][N:66]6[CH2:67][CH2:68][CH:69]([OH:72])[CH2:70][CH2:71]6)[CH2:73][S:74][C:75]6[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=6)=[C:58]([S:81]([C:84]([F:85])([F:86])[F:87])(=[O:82])=[O:83])[CH:57]=5)(=[O:55])=[O:54])=[CH:50][CH:51]=4)[CH2:44][CH2:45]3)[CH:35]=2)=[CH:28][CH:29]=1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CCO
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCn1c(C)c(C(=O)OCCC(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added tert-butyl 3-hydroxypropanoate (41 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TFA (2.5 mL). The solution was stirred at room temperature for 3 h until no starting material was observed by TLC. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 5 (salt with TFA, 75 mg, yield 70% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. MS (ESI): m/z 1238.17 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12](=[CH2:31])[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[N-]>ClCCl.O.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:55]([O:54][C:52]([CH:51]1[C:12]2([C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:10]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=4)[CH:33]=3)[O:11]2)[CH2:31]1)=[O:53])[CH3:56]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CC12O[C@@H](c1ccc(Cl)c(Cc3ccc(OCC)cc3)c1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of (2S,3S,4R,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran (See Ex. 1, step III, 100 mg, 0.15 mmole) and rhodium acetate dimmer (0.13 mg, 0.002 mmole) in dry dichloromehane (5 mL), ethyl diazoacetate in dichloromethane (2 mL) was added during 3 hours at room temperature and stirred for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to furnish 50 mg of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(I)cc1
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(I)cc2c1O
Temperature: 25 °C

Procedure:
4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 60 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid is filtered, washed with hexanes, and dried to yield 11.20 g of ethyl 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g) and 4-chlorobenzylamine (4.0 mL) are heated at 180° C. for 1.5 hours. The reaction is cooled and poured into 50 mL diethyl ether. The resulting solid is filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).
Reaction SMILES: C(OC1C=C(C=CC=1)CN(C1C=CC(C#N)=CC=1)N1C=NN=C1)C1C=CC=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][N:41]2[CH:45]=[N:44][N:43]=[CH:42]2)=[CH:36][CH:35]=1)#[N:33].[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[F:63])[CH2:58]Br)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.CCOC(C)=O>[C:46]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[F:63])[CH2:58][N:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][CH:38]=1)[N:41]1[CH:42]=[N:43][N:44]=[CH:45]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(Oc1cc(CBr)ccc1F)c1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(F)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Yield: 56.1 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using NaH (60% dispersion in oil, 0.20 g, 5.0 mmol), 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (0.926 g, 5.0 mmol) and 3-benzoyloxy-4-fluorobenzyl bromide (1.55 g, 5.0 mmol) in anhydrous DMF (20 mL) to give 4-[(3-benzoyloxy-4-fluorobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as a white solid (1.16 g, 56%) after chromatography [SiO2, EtOAc (100%)]; δH (400 MHz, CDCl3) 4.91 (s, 2H), 6.67 (AA′BB′, 2H), 7.07 (ddd, J=8.2, 4.3, 2.0, 1H), 7.18 (dd, J=9.4, 8.6, 1H), 7.24 (dd, J=7.0, 2.3, 1H), 7.49-7.56 (m, 2H), 7.58 (AA′BB′, 2H), 7.62-7.70 (m, 1H), 8.15-8.20 (m, 2H), 8.21 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 414.2 (100, [M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:45])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:27][N:28]([CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:45]
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
The title compound was prepared from 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (500 mg, 1.14 mmol) and N,N-dimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (300 mg, 1.14 mmol) in the same manner as described for example 73 wherein the contents were heated at 120° C. for 2 h. The product was collected as a pale red solid (120 mg, 21%). 1H NMR (CDCl3, 400 MHz): δ 1.568 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.41 (s, 8H), 2.55 (s, 3H), 3.67 (s, 2H), 4.614 (d, J=5.2 Hz, 2H), 4.899-4.834 (m, 1H), 5.90 (s, 1H), 7.326-7.308 (m, 1H), 7.408-7.368 (m, 3H), 7.558 (d, J=7.6 Hz, 1H,), 7.639 (s, 1H), 7.699 (s, 1H), 11.193 (brs, 1H). LCMS (ES+) m/z: 486.31.