Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: Nc1ccccc1O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
A flask with a stirrer was charged with 8.18 g of 2-aminophenol, 7.58 g of triethylamine and 100 ml of tetrahydrofuran, and a solution of 15.50 g of 4-methoxybenzenesulfonyl chloride in 30 ml of tetrahydrofuran was dropwise added with cooling with ice over 10 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethanol/n-hexane mixed solvents, to give 9.8 g of an end product. Melting point 89° C.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])(=O)=O>C(O)(=O)C>[CH2:1]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH2:17][Cl:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=NOCc1ccccc1)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccccc1)C(=O)CCl
Yield: 85.7 %

Procedure:
A solution of ethyl 2-benzyloxyimino-3-oxobutyrate (syn isomer, 56.0 g.), sulfuryl chloride (40.5 g.) and acetic acid (80 ml.) was treated in a similar manner to that of Example A-(2) to give ethyl 2-benzyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 54.6 g.).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14]CC2C=CC=CC=2)=[CH:6][CH:5]=1)=[N+]=[N-].C([O-])=O.[NH4+]>[C].[Pd].CO>[NH2:1][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(N=[N+]=[N-])ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1nc(N)ccc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a methanol (80 ml) suspension of 7 g (24.6 mmol) of methyl 6-azido-3-benzyloxypicolinate in a 200 ml round bottomed flask, 1 g of palladium carbon (10%) was added under a nitrogen gas stream, and 7.8 g (123 mmol) of ammonium formate was further added thereto. The mixture was stirred at room temperature for 12 hours. The catalyst was filtered off, and the filtrate was concentrated and dissolved in chloroform. The solvent was washed with water, dried and concentrated. Crystals thereby formed were collected by filtration and washed with diisopropyl ether to obtain 3.57 g (yield: 86.3%) of methyl 6-amino-3-hydroxypicolinate.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[Br:25])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH3:41][S:42]([CH2:44][S:45][CH3:46])=[O:43]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:26])[C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:44](\[S:42]([CH3:41])=[O:43])/[S:45][CH3:46])=[CH:19][C:18]=3[Br:25])=[CH:14][CH:15]=2)=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1)S(C)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenoxy)benzamide (1.6 g, 3.5 mmol) was diluted with THF (10 mL) followed by the addition of N,N,N-trimethyl(phenyl)methanaminium hydroxide (0.79 ml, 1.7 mmol) and methylsulfinyl(methylthio)methane (0.87 g, 7.0 mmol). The reaction was stirred at 70° C. for 2 hours. The reaction mixture was loaded directly onto a silica gel column and eluted with DCM:MeOH (98:2) to yield (Z)-N-(4-chlorophenethyl)-4-(2-bromo-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)benzamide (1.9 g, 96% yield).
Reaction SMILES: CN([CH:4]([CH3:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O)C.[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:4]=[CH:14][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH3:23])[N:15]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C(=O)c1ccc(F)cc1)N(C)C
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1C

Procedure:
The title compound was prepared from dimethylamino-(4-fluorophenyl)propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. MS (ES): MH+ 260.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([C:12]1[C:13]([NH:19][CH2:20][CH3:21])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11].[Cl:25][CH2:26][C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([C:12]1[C:13]([N:19]([CH2:20][CH3:21])[C:27](=[O:28])[CH2:26][Cl:25])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN(C(=O)CCl)c1nc(C)ccc1C(=O)c1cccc(Cl)c1

Procedure:
To a DMF solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine were added chloroacetyl chloride and pyridine, followed by reaction at room temperature. Thereafter, the whole was worked up and purified in a usual manner to obtain N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]—N-ethylchloroacetamide. To an acetonitrile solution of the compound were added N-tert-butoxycarbonylpiperazine and potassium carbonate, followed by reaction under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-[4-tert-butoxycarbonylpiperazin-1-yl]—N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethylacetamide. The resulting compound was reacted with sodium methoxide in methanol under heating. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 3-(1 -tert-butoxycarbonylpiperazin-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one. NMR1: 4.73 (2H, q, J=7.3 Hz), 3.15-3.35 (2H, m), 1.38 (9H, s).
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH:15]1[C:14]2[N:13]([CH2:10][CH2:11][CH2:12][S:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: C=CCn1c2ccccc2c2ccccc21
Reactant: OC(=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(SCCCn1c2ccccc2c2ccccc21)c1ccccc1

Procedure:
Thiobenzoic acid (30 g, 0.20 mol) was added to 9-allylcarbazole (11.9 g, 0.057 mol) in 100 mL toluene, and the reaction was carried out at 90° C. with argon purge via radical mechanism using AIBN as the initiator (1.8 g, 11 mmol, in 300 mg increments at 1 hr intervals). After 6 hrs the reaction mixture was poured into a 1 L separatory funnel containing 20 g sodium bicarbonate (NaHCO3, 0.24 mol) in 250 mL water, extracted with 100 mL chloroform, and the organic phase was washed twice with 200 mL water before solvent removal under reduced pressure. The crude product was subsequently washed in 100 mL hot hexane, 150 mL ethanol, and finally 150 mL of 15:1 ethanol:chloroform. Evaporation of leftover solvent at 80° C. under reduced pressure yielded compound 16 in ca. 90% purity as a dark brown, viscous syrup which solidified upon cooling (9.35 g, 0.024 mol, 42% yield, ˜10% wt dibenzoyl disulfide). 1H NMR (300 MHz, CDCl3): δ=8.10 (d, 2 carbazole H, J=8.1 Hz), 8.00-7.95 (m, 2 aromatic H ortho to COS), 7.62-7.41 (m, 3 aromatic H meta and para to COS plus 4 carbazole H), 7.27-7.19 (m, 2 carbazole H), 4.43 (t, NCH2, J=6.9 Hz), 3.06 (t, SCH2, J=6.9 Hz), 2.26 (tt, NCH2CH2CH2S, J=6.9, 6.9 Hz). 13C NMR (300 MHz, CDCl3): δ=191.56, 140.25, 136.88, 133.50, 128.65, 127.23, 125.75, 122.91, 120.41, 119.00, 108.55, 41.65, 28.95, 26.41.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3]1.[OH-].[K+].Br[CH2:15][C:16]#[CH:17]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]=[C:2]1[N:6]([CH2:17][C:16]#[CH:15])[CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3]1
Reactant: CCOC(=O)c1c[nH]c(=O)s1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCn1cc(C(=O)OCC)sc1=O
Reaction time: 3 h

Procedure:
A mixture of 8.65 g of the product of Step A in 130 ml of toluene, 2.8 g of potassium hydroxide, 4.5 ml of 3-bromo-1-propyne and 1.66 g of tetrabutyl ammonium bromide was heated to 95 C and stirred for 3 hours. The mixture was decanted, washed with N sodium hydroxide, with N hydrochloric acid and with water saturated with sodium chloride, dried and brought to dryness. The residue was chromatographed and elution with a hexane-chloroform-acetone mixture (70-15-15) yielded 4.74 g of the expected product melting at 70° to 71° C.
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:2]=1[C:3]1[CH:4]=[C:5]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:20][C:6]3=[C:7]([C:14]#[C:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:8]=1[NH:9]2>[Pd].CO>[CH:1]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:2]=1[C:3]1[CH:4]=[C:5]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:20][C:6]3=[C:7]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:8]=1[NH:9]2
Reactant: CN(C)CC#Cc1c2[nH]c3ccccc3c2cc2c1[nH]c1ccccc12
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1c2[nH]c3ccccc3c2cc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(5,7-dihydroindolo[2,3-b]carbazol-6-yl)-N,N-dimethylprop-2-yn-1-amine (30 mg, 0.08891 mmol), 10% Pd/C (10 mg, 0.0094 mmol) and methanol (20 mL) in a 250-mL hydrogenation bottle was filled with H2 and then degassed via house vacuum. This process was repeated three times. The reaction mixture was shaken at room temperature under H2 (30 psi) for 12 hours. The reaction solution was filtered through celite, and concentrated. The residue was subjected to flash chromatography to provide 3-(5,7-dihydroindolo[2,3-b]carbazol-6-yl)-N,N-dimethylpropan-1-amine. (10.2 mg, 34%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 2 H), 8.64 (s, 1 H), 8.12 (d, J=7.6 Hz, 2 H), 7.46 (d, J=8.0 Hz, 2 H), 7.34-7.27 (m, 2 H), 7.17-7.08 (m, 2 H), 3.18 (t, J=7.4 Hz, 2 H), 2.31 (t, J=7.2 Hz, 2 H), 1.96-1.85 (m, 2 H); MS (ESI) m/z 340.3 (M−H)−; MS (ESI) m/z 342.1 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[Cl:27].[Li+].[OH-]>>[Cl:27][C:7]1[CH:8]=[C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])[CH:10]=[CH:11][C:6]=1[CH2:5][C@H:4]([O:28][CH2:29][CH3:30])[C:3]([OH:31])=[O:2]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1Cl)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1Cl)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-[2-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-[2-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C(OC=C)(=O)C.CC1N=C([C@H](OC(=O)C)C)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>O(C(C)C)C(C)C.CO.O.[Cl-].[Na+].O>[CH3:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(C)O)n1
Agent: CC(=O)O[C@H](C)c1cccc(C)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C=COC(C)=O
Product: Cc1cccc([C@@H](C)O)n1
Yield: 40.6 %

Procedure:
Stir a mixture of 1-(6-methyl-pyridin-2-yl)-ethanol (2.9 g, 21 mmol), 4 A molecular sieves powder (3 g), vinyl acetate (6 mL) and lipase Candida Antarctica acrylic resin (0.87 g) in i-Pr2O (40 mL) at ambient temperature overnight (J. Org. Chem. 1998, 63, 2481-2487; Synlett 1999, 41-44). Remove the solid residue by filtration. Evaporate the volatile substances and purify by chromatography eluting with hexane/EtOAc (7:3 to 1:1) to give the faster eluting (R)-acetic acid 1-(6-methyl-pyridin-2-yl)-ethyl ester as colorless oil (1.9 g, 50%), and the slower eluting (S)-alcohol as light yellow oil (1.258 g, 43%). Dissolve (R)-acetic acid 1-(6-methyl-pyridin-2-yl)-ethyl ester (1.72 g, 9.62 mmol) in methanol (50 mL) and add potassium carbonate (5.3 g, 38.5 mmol) in water (10 mL). Stir the mixture at ambient temperature for 4 h. Dilute with brine, extract three times with EtOAc, dry over anhydrous Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a colorless oil (1.17 g, 89%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:61][C:62]1[C:67]([CH3:68])=[CH:66][CH:65]=[CH:64][N:63]=1>C1(C[C@H](CN(C=O)OCC2C=CC=CC=2)C(N2[C@H](C(O)=O)CCN2C(OCC2C=CC=CC=2)=O)=O)CCCC1.O1CCCC1.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:61][C:62]3[C:67]([CH3:68])=[CH:66][CH:65]=[CH:64][N:63]=3)=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccnc1N
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1NC(=O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (as a mixture of diastereomers enriched in (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid) (250 mg, 0.465 mmol) in tetrahydrofuran (3 ml) was added N,N-diisopropylethylamine (405 μl, 2.325 mmol) and 2,4,6-trichlorobenzoyl chloride (0.087 mL, 0.558 mmol). The mixture was stirred for 2 h and then the solvent was evaporated. The residue was then diluted with toluene (3 mL). The resulting suspension was treated with 2-amino-3-methylpyridine (61 mg, 0.56 mmol) followed by DMAP (11.3 mg, 0.093 mmol). After 2 h, 15 minutes, the solvent mixture was removed. The residue was diluted with MeOH and purified by reverse-phase HPLC to afford 179 mg (61%) of the title compound as a white solid. LC/MS: (M+H)+: 628.5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:21]([O-])([N+]([O-])=O)=[O:22]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CC1)C1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 64.9 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-xylopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.2 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-xylopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C:4]#[C:5][C:6]1[NH:32][C:9]2=[N:10][CH:11]=[C:12]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:13]=[C:8]2[CH:7]=1.[H][H]>CO.[Pd]>[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[NH:32][C:9]2=[N:10][CH:11]=[C:12]([NH:14][C:15](=[O:31])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:17]=3[F:30])[CH:13]=[C:8]2[CH:7]=1
Reactant: [H][H]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#CCN(C)C)cc3c2)c1F
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(CCCN(C)C)cc3c2)c1F
Yield: 42.9 %

Procedure:
A solution of N-(2-(3-(dimethylamino)prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (30 mg, 63 mmol) in MeOH (10 mL) was treated with 10% Pd/C and allowed to stir under a balloon atmosphere of hydrogen for 4 hours. The mixture was filtered through GF/F paper, rinsing with MeOH. The filtrate was purified by silica gel chromatography (eluting with 10% MeOH/DCM containing 1% NH4OH) to afford N-(2-(3-(dimethylamino)propyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (13 mg, 27 mmol, 43%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.50 (s, 1H), 10.77 (s, 1H), 9.80 (br s, 1H), 8.27-8.18 (m, 2H), 7.56-7.49 (m, 1H), 7.26-7.20 (m, 1H), 6.19-6.17 (m, 1H), 3.12-3.08 (m, 2H), 2.76-2.71 (m, 2H), 2.32-2.27 (m, 2H), 2.17 (s, 6H), 1.87-1.72 (m, 2H), 1.01-0.97 (m, 3H); m/z (APCI-pos) M+1=480.1.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[CH:12]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=2)[CH:17]=1
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: Brc1ccc2cc(-c3ccccc3)ccc2c1
Temperature: 78 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
Under an argon gas atmosphere, 128.0 g (1.049 mol) of phenylboronic acid, 300.0 g (1.163 mol) of 2.6-dibromonaphthalene, 24.2 g (21.0 mmol) of tetrakis(triphenylphosphine)palladium(0), 4.3 L of dimethoxyethane and 1.60 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 78 degrees C. The reaction mixture was further added with toluene and water, and then aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. By refining residue thereof by silica-gel column chromatography and by recrystallizing the residue by hexane, 108 g of 2-bromo-6-phenyl naphthalene was obtained with an yield of 36%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH2:15]2
Reactant: C#CCN1CCN(C)CC1
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.061 mL, 0.4 mmol), 5-bromo-7-methyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.105 g, 0.3 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropylamine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-methyl-2-(4-chloro-benzyl)-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.100 g, 81%).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCC[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A 4M hydrochloric acid-dioxane solution (15 ml) was added to tert-butyl 3-(R)-benzyloxycarbonyloctanoate (983 mg), prepared in Referential Example 6, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 30:1 mixture of chloroform and methanol as an eluent, to give 838 mg of the desired compound as a colorless oil.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12]2.[I:22]N1C(=O)CCC1=O>ClCCl>[I:22][C:12]1[C:11]2[C:15](=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])[CH:8]=[CH:9][CH:10]=2)[NH:14][C:13]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc2cccc(-c3ccccc3C)c2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 564A (944 mg, 3.38 mmol) in dichloromethane (10 mL) was added 1-iodopyrrolidine-2,5-dione (798 mg, 3.55 9 mmol). The reaction mixture was stirred at room temperature for 3 hours and directly loaded on a flash column, eluting with hexane first and then with 0-50% hexane in dichloromethane. The title compound was obtained as a white solid.
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.[CH3:59][C:60]1[CH:61]=[C:62]([NH2:67])[CH:63]=[C:64]([CH3:66])[CH:65]=1>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:67][C:62]2[CH:63]=[C:64]([CH3:66])[CH:65]=[C:60]([CH3:59])[CH:61]=2)[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[CH3:57])=[O:42]
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Cc1cc(C)cc(N)c1
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(C)cc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 471 (0.13 mmol) and 3,5-dimethyl-phenylamine (0.13 mmol). The crude product was purified by flash chromatography using MeOH/DCM 1:20 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.8, 149.2, 146.3, 141.2, 139.6, 139.4, 137.9, 135.6, 134.7, 134.1, 132.5, 126.9, 126.0, 122.1, 120.5, 120.0, 119.3, 116.3, 112.7, 67.1, 61.5, 28.8, 21.3, 19.8