Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:20][O:19][N:18]([CH3:17])[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a 500 ml round bottom flask, pyrazine-2-carboxylic acid (58 g, 467.37 mmol) was suspended in dry CH2Cl2 (250 ml): oxalyl chloride (50.1 ml, 560.85 mmol) was added along with a few drops of DMF, and the mixture was stirred at room temperature for 12 hours. N,O-Dimethylhydroxylamine hydrochloride (54.7 g, 560.85 mmol) was added, and the resultant mixture was cooled down to 5° C. Triethylamine (195 ml, 1402.12 mmol) was added via a dropping funnel, and the reaction mixture was stirred at room temperature for 30 minutes before being filtered. The filter cake was washed with EtOAc, and the combined filtrate was washed with saturated sodium bicarbonate and brine, concentrated to an oil and dried under high vacuum to give the desired product (72 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([C:57]1[CH:58]=[C:59]([S:63](Cl)(=[O:65])=[O:64])[CH:60]=[CH:61][CH:62]=1)#[N:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([C:55]#[N:56])[CH:58]=2)(=[O:65])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(S(=O)(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 25 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-cyanobenzenesulfonyl chloride as starting materials in 25% yield. LCMS for C31H30ClN8O3S (M+H)+: m/z=629.2.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)=[O:30])=[CH:19][CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: CCCCCC(C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 76.7 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoylamino]-benzoic acid methyl ester (0.15 g, 0.35 mmole) in 10 mL of a 4:1 THF/methanol mixture was treated with a solution of 0.1 g of lithium hydroxide monohydrate in 2.5 mL of water and stirred at 40° C. for 6 hours. The mixture was diluted with 10 mL of water and the pH adjusted to 2.0 with 2N HCl solution. The mixture was extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% methanol in dichloromethane) to yield 0.11 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptanoylamino]-benzoic acid as a white powder. MS (ESI): (M−): 408.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3Cl)[CH:23]=2)=[O:21])=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]2[S:30][C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:23]=2)=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCc1ccncc1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (pyridin-4-ylmethyl)-amide by a procedure analogous to Example 1C. MS: 414 (MH+), HPLC Rf: 3.97 min.; HPLC purity 94%.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C@H:9]([CH3:12])[CH2:10][OH:11].[CH3:13][Si:14]([CH3:17])([CH3:16])Cl>C1C=CC=CC=1>[CH3:13][Si:14]([CH3:17])([CH3:16])[O:11][CH2:10][C@H:9]([SH:8])[CH3:12]
Reactant: C[C@@H](S)CO
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[C@@H](S)CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.53 ml of triethylamine are added, while stirring, at 0° and within a period of 15 minutes to a mixture of 920 mg of the (2R)-2-mercaptopropan-1-ol manufactured according to Example 2 under 2.3 and 1.36 ml of trimethylchlorosilane in 10 ml of dry benzene. The mixture is stirred for a further 15 minutes at room temperature and for 15 minutes at 60° and is then cooled and the precipitate formed is filtered off. The filter residue is washed with 10 ml of benzene and the combined filtrates are removed in a rotary evaporator at 11 mm and 25°. Bulb tube distillation of the residue at 11 mm and 100° yields a pure liquid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][CH2:18][C:19](OCCCC)=[O:20])=[CH:13][C:12](=[O:26])[NH:11]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[OH:20][CH2:19][CH2:18][CH2:17][C:14]1[C:15](=[O:16])[N:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:11][C:12](=[O:26])[CH:13]=1
Reactant: CCCCOC(=O)CCc1cc(=O)[nH]n(Cc2ccc(OC)cc2)c1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2[nH]c(=O)cc(CCCO)c2=O)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Butyl 3-(2-{[4-(methyloxy)phenyl]methyl}-3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)propanoate (0.56 g, 1.56 mmol) was dissolved in dry THF (30 ml). The solution under argon was cooled to −30° C., treated dropwise with a 1M solution of lithium aluminium hydride in THF (1.8 ml, 1.8 mmol), allowed to warm gradually to 0° C. and stirred in an ice bath for 30 minutes. 2M Hydrochloric acid was added until pH 3 was obtained, and the mixture was partitioned between water and ethyl acetate. The aqueous was re-extracted with ethyl acetate and the combined organic solution dried and evaporated. Chromatography of the residue on silica, eluting with ethyl acetate, gave the product as a white solid (300 mg, 67%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[C:11]1([C:9]2[O:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A solution of the above-prepared 2,4-diphenyl-oxazole-5-carboxylic acid ethyl ester (500 mg, 1.70 mmole, 1.0 eq) in dioxane (6 ml) was treated with 2N NaOH (1.7 ml, 3.4 mmole, 2.0 eq) and the mixture stirred at room temperature overnight under nitrogen. The mixture was then partitioned between ethyl acetate and 2.0N HCl. The organic phase washed with 0.5N HCl and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 426 mg of the title compound as a crude yellow solid. The product was used directly in the next step, without purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(O)c2)C1
Agent: B
Solvent: C1CCOC1
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 47.8 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxyphenyl)piperidin-1-yl]-methanone (17.8 g, 54.7 mmol) was treated with BH3THF according to the above general procedure. Crystallisation from hot EtOH gave 8.5 g of the title compound as almost white crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[N:15]2)(=O)=O)=CC=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[I:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][CH2:12][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cn2)cc1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(CCn2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (Preparation 58, 377 mg, 0.961 mmol) in acetonitrile (6 mL) was treated with 1-methylpiperazine (1.1 mL, 9.88 mmol). The resulting mixture was stirred at room temperature for 3 days. The majority of the solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc twice and the combined organic layers washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 15% MeOH in DCM to give the title compound (208 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[N:7]([CH2:8][CH2:9][OH:10])[C:6]([CH3:12])([CH3:11])[CH2:5][C:4]2([O:34][CH2:33][C:15]3([CH2:32][O:31][C:18]4([CH2:23][C:22]([CH3:25])([CH3:24])[N:21]([CH2:26]CO)[C:20]([CH3:30])([CH3:29])[CH2:19]4)[O:17][CH2:16]3)[CH2:14][O:13]2)[CH2:3]1.[C:36]([C:40]1[CH:41]=[C:42]([CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:43]=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:45]=1[OH:46])([CH3:39])([CH3:38])[CH3:37].[NH2-].[Li+]>C1(C)C=CC=CC=1>[CH3:24][C:22]1([CH3:25])[N:21]([CH2:26][CH2:56][O:55][C:53](=[O:54])[CH2:52][CH2:51][C:42]2[CH:43]=[C:44]([C:47]([CH3:48])([CH3:49])[CH3:50])[C:45]([OH:46])=[C:40]([C:36]([CH3:37])([CH3:38])[CH3:39])[CH:41]=2)[C:20]([CH3:29])([CH3:30])[CH2:19][C:18]2([O:17][CH2:16][C:15]3([CH2:14][O:13][C:4]4([CH2:5][C:6]([CH3:11])([CH3:12])[N:7]([CH2:8][CH2:9][O:10][C:53](=[O:54])[CH2:52][CH2:51][C:42]5[CH:43]=[C:44]([C:47]([CH3:48])([CH3:50])[CH3:49])[C:45]([OH:46])=[C:40]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:41]=5)[C:2]([CH3:1])([CH3:35])[CH2:3]4)[O:34][CH2:33]3)[CH2:32][O:31]2)[CH2:23]1
Reactant: CC1(C)CC2(CC(C)(C)N1CCO)OCC1(CO2)COC2(CC(C)(C)N(CCO)C(C)(C)C2)OC1
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)OCCN2C(C)(C)CC3(CC2(C)C)OCC2(CO3)COC3(CC(C)(C)N(CCOC(=O)CCc4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)C(C)(C)C3)OC2)cc(C(C)(C)C)c1O

Procedure:
A mixture of 20 g of 2,2,4,4,14,14,16,16-octamethyl-3,15-bis(2-hydroxyethyl)-7,11,18,21-tetraoxa-3,15-diazatrispiro[5.2.2.5.2.2]heneicosane, 26 g of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and 2 g of lithium amide was refluxed for 8 hours in 400 ml of toluene under argon stream. Following the procedures in Example 1, the residue was purified first by column chromatography through silica gel with a 9:1 by volume mixture of benzene and ethyl acetate, then by recrystallization from a 4:1 by volume mixture of n-hexane and benzene, giving the desired compound in the form of pale yellow crystals melting at 176°-178° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([S:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.O>CO>[CH2:13]([O:12][CH2:11][CH2:10][SH:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)SCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: SCCOCc1ccccc1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
Potassium carbonate (11.20 g) was added to S-2-(benzyloxy)ethyl ethanethioate (8.52 g) in methanol (170 mL)/water (85 mL) and the reaction was stirred for 20 min. Water was added and the mixture extracted with ethyl acetate. The organic layers were combined, washed with aqueous ammonium chloride and dried (MgSO4) and concentrated in vacuo to give the subtitle compound (6.64 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:12]([C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Na+].[Cl-]>CN(C=O)C>[N:3]1([CH2:28][CH:26]([OH:27])[CH2:25][O:24][C:23]2[CH:29]=[CH:30][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.048 g (1.20 mmol) sodium hydride as 60% dispersion in mineral oil are suspended in 10 ml absolute DMF, stirred at room temperature for 10 min and mixed with a solution of 0.134 g (1.14 mmol) indole in 10 ml absolute DMF. Having stirred for 1½ hours, a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml absolute DMF is added drop-wise. The mixture is stirred for 16 hours, hydrolyzed with a semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator and washed three times with saturated NaCl solution. Drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product an orange oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([OH:17])[CH:9]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([N:32]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>COCCOC.O.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>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([S:29]([N:32]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[C:33]4[S:34][CH:35]=[CH:36][N:37]=4)(=[O:30])=[O:31])=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[C:10]([OH:17])[CH:9]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: OB(O)c1ccc(F)cc1O
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Temperature: 125 °C
Yield: 92.4 %

Procedure:
A vial containing a suspension of Cs2CO3 (0.292 g, 0.897 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (0.045 g, 0.292 mmol) and 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.1 g, 0.224 mmol) in DME (2.5 ml) and water (0.375 ml) was degassed with nitrogen and tetrakis(triphenylphosphine)palladium (0.026 g, 0.022 mmol) was added. The vial was sealed and heated under microwave irradiation at 125° C. for 30 min. The aqueous layer was discarded using a pipette and the organic layer was concentrated and purified by silica gel chromatography (25 g column, eluting with Hex:EtOAc (0 to 50%)). Pure fractions were combined and concentrated to obtain 1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.108 g, 0.207 mmol, 92% yield) as light yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][CH2:14][CH:15]([OH:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[C:29]1([CH2:35][CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[Na+].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH:15]([OH:28])[CH2:14][CH2:13][CH:2]([NH:1][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(CCC(O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCC(O)CCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Compound VI and 4-phenyl-2-oxobutanoic acid (5 eq) were mixed with water (10 ml) and concentrated NaOH was added to raise the pH to 7.5. Ethanol was added (10 ml) and a solution of sodium cyanoborohydride (3 eq) in ethanol (4 ml) was added dropwise over 15 hours. Dowex 50W-2X (H+) (25 cc) was added with stirring. After 1 hour, the slurry was added to a column of Dowex (50 cc), the column was washed with ethanol and water and the product was eluted with 3% pyridine in water. After concentration and purfication over an LH-20 column, freeze drying gave V.
Reaction SMILES: C(OCC)C.O[CH:7]([CH2:16][C:17]([CH2:20][Si](C)(C)C)=[C:18]=[CH2:19])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:20]=[C:17]1[C:18](=[CH2:19])[C:10]23[O:15][CH:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16]1
Reactant: C=C=C(CC(O)CC1CCCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1CC2CC3CCCCC3(O2)C1=C
Temperature: -78 °C
Yield: 77.4 %

Procedure:
1.5 mL of diethyl ether was added to 2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cyclohexanone (100 mg, 0.36 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (64.5 μL, 0.36 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/6) to obtain 53 mg of the product (78%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.O>ClCCl>[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:24][CH2:25][N:26]([S:4]([CH2:3][CH:2]([CH3:8])[CH3:1])(=[O:6])=[O:5])[CH2:27][CH2:28]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(=O)(=O)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
479 mg (3.0 mmol) of 2-methylpropane-1-sulfonyl chloride are added to a solution of 800 mg (2.8 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared as described in example 23.1) and 775 μl (5.5 mmol) of triethylamine in 8 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is stirred at ambient temperature for 18 h and then water is added and the medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[N:34][NH2:35])[NH:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH3:59][N:60]1[CH:64]=[C:63]([C:65](O)=O)[N:62]=[CH:61]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:65]([C:63]6[N:62]=[CH:61][N:60]([CH3:59])[CH:64]=6)[N:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=NN)NCC4)cc2)CCC1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc(-c2nnc3n2CCc2nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc2-3)c1
Temperature: 60 °C
Yield: 4.4 %

Procedure:
To a solution of tert-butyl(1-(4-(5-hydrazono-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (22 mg, 0.04 mmol) in dry DMF (1 mL) was added EDCI (11 mg, 0.06 mmol), HOBt.H2O (8 mg, 0.06 mmol) and 1-methyl-1H-imidazole-4-carboxylic acid (8 mg, 0.06 mmol) under nitrogen. The reaction mixture was heated at 60° C. overnight. After cooled down to room temperature, the mixture was partitioned between saturated NaHCO3 solution and ethyl acetate. The layers were separated and the organic phase washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O) to give the title compound (1 mg, 5%). 1H NMR (500 MHz, CDCl3): 8.49 (1H, s), 7.74 (1H, s), 7.54 (1H, s), 7.38 (2H, d), 7.31 (2H, d), 7.28-7.23 (5H, m), 5.01 (1H, br s), 4.94 (2H, t), 3.81 (3H, s), 3.49 (2H, t), 2.60-2.30 (4H, m), 2.10-2.01 (1H, m), 1.85-1.76 (1H, m), 1.45-1.20 (9H, br).