Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:17][CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH2:20]3)=[O:16])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:17][CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH2:20]3)=[O:16])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)[C:34]([CH3:35])=[O:36]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the resultant product (262 mg) of Example 9 in pyridine (2 mL) was added dropwise acetic anhydride (57 μL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (279 mg) as a white amorphous solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.[C:25]1(B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.C1COCC1>[C:25]1([C:7]2[C:11]3[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=3[N:9]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nccc2c1c(C1=CCCCC1)nn2C1CCCC1
Reaction time: 0.08 h

Procedure:
To a solution (1.0 mL) of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (29.2 mg) obtained in Step C of Example 12, 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.7 mg) and tetrakistriphenylphosphine palladium (18.5 mg) in DME was added 2N sodium carbonate (120 μl), and the mixture was reacted at 100° C. for 6 hr. To the reaction mixture were added ethyl acetate (4 mL), THF (1 mL) and water (1 mL), the mixture was stirred for 5 min, and the organic layer was separated, and concentrated by air-blowing. The residue was purified by preparative high-performance liquid chromatography (C18, mobile phase: acetonitrile/10 mM aqueous ammonium bicarbonate solution) to give 3-(cyclohex-1-en-1-yl)-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridine. A solution (1.0 mL) of chloro(trimethyl)silane (10.2 μl) and sodium iodide (12.0 mg) in acetonitrile was added to 3-(cyclohex-1-en-1-yl)-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridine, and the mixture was reacted at 60° C. for 1 hr. To the reaction mixture were added ethyl acetate (4 mL), THF (1 mL) and water (1 mL), the mixture was stirred for 5 min, and the organic layer was separated, and concentrated by air-blowing. The residue was purified by preparative high-performance liquid chromatography (C18, mobile phase: acetonitrile/10 mM aqueous ammonium bicarbonate solution) to give the title compound (13.0 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+].[Cl-].[Na+]>O>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(C)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CO)nc1
Yield: 83.4 %

Procedure:
14.0 g of 2-acetoxymethyl-5-methylpyridine were heated under reflux for 90 minutes in a solution of 4.5 g of sodium hydroxide in 150 ml of water. The cooled solution was saturated with sodium chloride and extracted with a total amount of 100 ml of chloroform. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and concentrated by evaporation at 40°/16 mm Hg. The oil obtained distilled at 12°/8 mm Hg. 8.7 g of 2 -hydroxymethyl-5-methylpyridine were obtained.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]2[N:23]([CH2:33][CH3:34])[C:24](=[O:32])[C:25]([CH3:31])([CH3:30])[C:26](=[O:29])[N:27]([CH3:28])[C:21]=2[CH:20]=1>CO>[NH2:6][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:36]=[CH:35][C:22]2[N:23]([CH2:33][CH3:34])[C:24](=[O:32])[C:25]([CH3:30])([CH3:31])[C:26](=[O:29])[N:27]([CH3:28])[C:21]=2[CH:20]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Solvent: CO
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Yield: 77.2 %

Procedure:
Hydrazine hydrate (1.17 ml, 24 mmol) was added to a methanol solution (60 ml) of 7-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.70 g, 6.0 mmol), and stirred while heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. A 1N-sodium hydroxide aqueous solution was added to the residue, and stirred for 30 minutes, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to thereby obtain 1.48 g (yield: 77%) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:23]([F:25])[F:24].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:23]([F:25])[F:24])[N:11]([CH3:15])[N:10]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2Cl)cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1nc(-c2ccc(Cl)cc2Cl)cc1OC(F)F
Temperature: 90 °C
Yield: 94 %

Procedure:
9 g of 3-(2,4-dichlorophenyl)-5-hydroxy-1-methyl-1H-pyrazole from Example 4.1 were initially charged in 50 ml of dimethylacetamide, and 5.4 g of potassium carbonate were added. The mixture was heated at 90° C., and 48 g of gaseous chlorodifluoromethane were introduced over a period of 1 h. The mixture was poured into 800 ml of water and extracted twice with 300 ml of MTBE, and the combined organic phases were extracted once with 100 ml of water and once with 100 ml of saturated sodium chloride solution. Drying and concentration of the organic phase gave 10.2 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole of a purity of 56% (yield 50.2%, based on the title compound), which was purified further by vacuum distillation.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+:9]([C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([CH2:16][C:17](OCC)=[O:18])=O)([O-:11])=[O:10].Cl>CO>[N+:9]([C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:17](=[O:18])[CH:16]=1)([O-:11])=[O:10]
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: O=c1cc(-c2ccccc2[N+](=O)[O-])c2ccc(O)cc2o1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
0.1 mole resorcinol is reacted with 0.1 mole ethyl o-nitrobenzoylacetate in methanol at 0° C. while passing through for one hour gaseous hydrochloric acid, and then maintaining at ambient temperature for 24 hours. After recrystallisation from an acetone-water mixture, there are obtained 18 grams 4-o-nitrophenyl-7-hydroxy-coumarin. This compound melts at 230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](I)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2c(I)ccnc2c1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a degassed solution of 7-chloro-4-iodo-quinoline (5.33 g, 18.42 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.43 g, 22.11 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.17 g, 46.06 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.18 g, 0.37 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone) dipalladium(0) (1.53 g, 1.47 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with dichloromethane/methanol (20:1+0.5% triethylamine) and then recrystallized from heptane/ethyl acetate to provide 2.20 g (33%) of the title compound in 80% purity according to 1H NMR. 1H NMR (250 MHz, DMSO): δ 1.42 (s, 9H), 1.46-1.61 (m, 2H), 1.94 (d, J=10.3 Hz, 2H), 2.75-3.03 (m, 2H), 3.88 (br s, 1H), 3.94-4.14 (m, 2H), 6.75 (d, J=6.1 Hz, 1H), 7.56 (d, J=6.9 Hz, 2H), 7.82 (s, 1H), 8.31-8.55 (m, 2H). MS (ESI): 362.2 [M+H]+.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:55])[C:36]([CH3:54])([O:47]C1C=CC=CC=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([O:45][CH3:46])[CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:44][C:41]3[CH:42]=[CH:43][C:38]([CH2:37][C:36]([CH3:54])([O:47][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:35]([OH:34])=[O:55])=[CH:39][C:40]=3[O:45][CH3:46])[N:11]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)c(OC)c1)Oc1ccccc1
Solvent: CCO
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 2, Part F) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-methoxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (see Ex. 7, Part D) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a steam of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to provide analytically pure material. MS (EI) 564.4 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>[OH-].[K+].CCO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:25][C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccsc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 77.2 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.250 g, 0.98 mmol) was reacted with 3-thiophene carboxaldehyde (0.166 g, 1.48 mmol) in 5.0 mL of 4% KOH in EtOH at room temperature to afford 0.265 g (77%) of the title compound as a cream-colored solid, mp 61-62° C.: CI-MS m/e 350 (M+), 351 (M+ +1);
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:16]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)#[N:17]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]1([N:22]2[CH:23]=[C:19]([CH2:18][C:16]#[N:17])[N:20]=[CH:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1c[nH]cn1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CCc1cn(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Molecular sieve 4A (4.88 g), copper (II) sulfate (7.71 g), phenylboronic acid (6.76 g), and pyridine (4.49 mL) were added to a solution of 4-cyanomethylimidazole (3.00 g) in methylene chloride (120 mL), and the mixture was stirred overnight at room temperature under an air atmosphere at normal pressure. The reaction solution was filtered through celite and washed with methylene chloride. Then, a saturated aqueous solution of sodium bicarbonate (200 mL) and disodium dihydrogen ethylenediaminetetraacetate dihydrate (15.5 g) were added to the filtrate, and the mixture was stirred at room temperature for 20 minutes. After separation into aqueous and organic layers, the organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (2.34 g).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([NH:30][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-N-(trans-4-aminocyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f56) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[CH:3]=1.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[N:5]=[C:6]([NH:36][C@H:33]2[CH2:34][CH2:35][C@H:30]([NH2:37])[CH2:31][CH2:32]2)[N:7]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)CC1

Procedure:
A mixture of Example 42b (5 g, 11.14 mmol), trans-cyclohexane-1,4-diamine (2.54 g, 22.28 mmol), triethylamine (3.10 mL, 22.28 mmol) and dioxane (120 mL) in a 250 mL of flask was heated at 60° C. for 90 minutes. The reaction mixture was concentrated and used directly for the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:15][C:14]([CH2:16][NH2:17])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[NH:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:23]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:24].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:15][C:14]([CH2:16][NH:17][C:25](=[O:26])[C@@H:23]([NH:22][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:24])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:18]([F:20])([F:21])[F:19])[CH:7]=1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a stirred solution of 23 (crude) (0.588 mmol) in CH2Cl2 (2.9 mL) at 0 degrees were added Boc-Ala-OSu (185 mg, 0.647 mmol) and triethylamine (0.18 mL, 1.3 mmol). The mixture was allowed to reach 21° C. slowly, stirring for 16 h at room temperature. The solvent was then evaporated. The mixture was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 24 (140 mg, 49%) as a white solid. LRMS (ESI): calc. 484.1; found 507.2 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[C@@H:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:23]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC1(C)C(C)(C)OB([C:77]2[CH2:78][CH2:79][O:80][CH2:81][CH:82]=2)O1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:40]([O:39][C:37]([NH:36][C@H:23]1[C@H:24]([O:28][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:30])[CH3:31])[C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:77]4[CH2:82][CH2:81][O:80][CH2:79][CH:78]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 90 °C
Yield: 65 %

Procedure:
A pressure vial was charged with benzyl [7-bromo-2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)quinolin-3-yl]carbamate (0.035 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.013 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap then heated at 90° C. for 1.5 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.023 g, 65%). LCMS calc. for C45H59N6O7Si [M+H]+: m/z=823.4. found: 823.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[Cu](C#N)[C:27]#[N:28]>ClC(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[C:27]#[N:28]
Reactant: N#C[Cu]C#N
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#CC(c1ccc(Cl)cc1Cl)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 180 °C

Procedure:
A mixture of 12 parts of 2-[3-chloro-4-[chloro(2,4-dichlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 5.4 parts of copper cyanide is stirred and heated first for 3 hours at 130° C. and for 3 hours at 180° C. After cooling, the precipitated product is dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The inorganic precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is purified by column chromatography over silica gel using first a mixture of trichloromethane and acetonitrile (93:7 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dissolved in 20 parts of N,N-dimethylformamide and 25 parts of 1,1'-oxybisethane. The product is allowed to crystallize, filtered off and dried, yielding 2-chloro-α-(2,4-dichloro- phenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile (intermediate 1).