Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2].O[N:68]1[C:72](=[O:73])[CH2:71][CH2:70][C:69]1=[O:74].Cl.CN(C)CCCN=C=NCC>ClCCl>[O:74]=[C:69]1[CH2:70][CH2:71][C:72](=[O:73])[N:68]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16 mg (17 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3S)-1-(benzyloxy)-1-oxo-3-phenylbutan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 70) were dissolved in 2 ml of dichloromethane and admixed with 2.6 mg (23 mmol) of 1-hydroxypyrrolidine-2,5-dione and then with 4 mg (21 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring at RT for 2 h, the same amounts of 1-hydroxypyrrolidine-2,5-dione and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added once again. Then stirring at RT overnight, the reaction mixture was concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 10 mg (56% of theory) of the title compound were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]=[O:22]>C1COCC1.CCCCCC>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH:23]=1)[CH:21]([OH:22])[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH3:2])=[CH:5][CH:6]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: BrCCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)ccc2OC)cc1
Reaction time: 2 h

Procedure:
To a stirred −78° solution of p-bromoethylbenzene (2.03 g, 11 mmol) in 10 mL of dry THF under Ar was added 5 mL of 2.5 M n-BuLi (12 mmol) in hexane over 10 min. The temperature was allowed to rise to −10° over 2 hr whereupon the reaction was cooled to −78° before adding solid 5-bromo-2-methoxybenzaldehyde (2.15 g, 10 mmol). After stirring overnight at 20°, the reaction was quenched with saturated aq. NH4Cl and diluted 5 fold with H2O prior to 3 extractions with EtOAc. The combined EtOAc fractions were washed with brine and dried over Na2SO4. After concentration using a rotary evaporator, the residue was chromatographed on silica gel using 10% EtOAc/hexane to elute 1.44 g of 5-bromo-2-methoxy-4′-ethylbenzhydrol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[CH:24][C:23]=1[F:43])=[O:21]>ClCCl>[F:43][C:23]1[CH:24]=[C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:26]=[CH:27][C:22]=1[C:20](=[O:21])[NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:12]
Reactant: O=C(Cl)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Reactant: COC(=O)c1cccc(N)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(C3CCCN3C(=O)OCc3ccccc3)cc2F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-amino-2-hydroxybenzoate (3.4 g, 20.4 mmol) and pyridine in anhydrous dichloromethane (35 mL) was added dropwise a solution of benzyl 2-(4-(chlorocarbonyl)-3-fluorophenyl)pyrrolidine-1-carboxylate (8.87 g, 24.5 mmol) in anhydrous dichloromethane (90 mL). After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water, 1N HCl, brine, dried over anhydrous sodium sulfate, and concentrated, re-crystallized from ethyl acetate to give benzyl 2-(3-fluoro-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamyl)phenyl)pyrrolidine-1-carboxylate as white solid (8.20 g, yield 68%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.77-1.87 (m, 3H), 2.33-2.37 (m, 1H), 3.55-3.58 (m, 1H), 3.64-3.70 (m, 1H), 3.83 (s, 3H), 4.86-5.07 (m, 3H), 6.65 (s, 1H), 6.92 (s, 1H), 7.19-7.39 (m, 6H), 7.48-7.51 (m, 1H), 7.82-7.84 (m, 1H), 8.25-8.30 (m, 1H), 9.86 (br s, 1H), 10.99 (br s, 1H); LC-MS (ESI) m/z: 493 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33]CC)[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([O:38]C)=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl.[O:45]1CCC[CH2:46]1>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][C:31]=4[O:45][CH3:46])[CH2:23][CH2:22][C:21]([C:36]([OH:38])=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (290 mg) in a mixture of tetrahydrofuran (21 ml) and methanol (21 ml) was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (237 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:28]1[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:37]([S:34]([N:31]1[CH2:30][CH2:29][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:10]4[S:11][C:7]([CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:33][CH2:32]1)(=[O:36])=[O:35])[CH3:38]
Reactant: COCCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCOC)s4)cc23)CC1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 42 mg of crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give impure title compound. The impure title compound was repurified using the HPLC and ammonium hydroxide SPE workup shown in preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide to give 15 mg of the title compound (15%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=[CH:17][CH:16]=1>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=[CH:19][C:20]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(CCCCBr)ccc1CCCCBr
Reaction time: 0.17 h

Procedure:
To 1 ml of 60% nitric acid was added 1 ml of 97% sulfuric acid under ice-cooling, and the mixture was stirred for 10 minutes. After adding 0.42 g of 1,4-bis(4-bromobutyl)benzene, the whole was stirred at a room temperature for an hour. The reaction mixture was poured onto ice, and extracted with total 60 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. The residue was applied to a silica gel column and eluted with chloroform/hexane (1:1). From the first fraction, 0.43 g of the title compound was obtained as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[OH:27])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[O:27][CH2:35][CH3:36])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
In a 4 mL screw cap vial fitted with a small egg-shaped stir bar, were combined 5-fluoro-2-(4-fluoro-2-hydroxybenzoylamino)-N-(5-chloropyridin-2-yl)benzamide (200 mg, 0.49 mmol) and powdered anhydrous K2CO3 (103 mg, 0.74 mmol, 1.5 eq) in 0.5 mL of dry dimethylformamide (DMF). Ethyl iodide (115 mg, 0.74 mmol) was then added, the vial was capped, and the slurry heated to 50° C. with vigorous stirring overnight. The slurry was diluted with 20 mL water and extracted into 15 mL of dichloromethane. The organic layer was then washed with 20 mL portions of saturated NaHCO3, water, and brine; then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a few mL of dichloromethane and purified by radial chromatography, eluting using hexanes, then 4:1 hexanes:EtOAc, to provide 135 mg (63%) of the title compound as pinkish-white crystals.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:11]([C@H:12]3[C@H:19]4[C@H:15]([O:16]C(C)(C)[O:18]4)[C@@H:14]([CH3:22])[CH2:13]3)[CH:10]=[N:9][C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.Cl>CO>[NH2:8][C:5]1[CH:4]2[N:9]=[CH:10][N:11]([C@@H:12]3[CH2:13][C@H:14]([CH3:22])[C@@H:15]([OH:16])[C@H:19]3[OH:18])[CH:3]2[C:2]([F:1])=[CH:7][N:6]=1
Reactant: C[C@H]1C[C@@H](n2cnc3c(N)ncc(F)c32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Solvent: CO
Product: C[C@H]1C[C@@H](N2C=NC3C(N)=NC=C(F)C32)[C@H](O)[C@@H]1O

Procedure:
7-fluoro-1-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (6-5) was dissolved in MeOH (1 mL) and concentrated HCl (200 uL) was added. After disappearance of the starting material, the mixture was concentrated to afford (1R,2S,3R,5S)-3-(4-amino-7-fluoro-3a,7a-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-5-methylcyclopentane-1,2-diol (6-7) as a brown solid. 1H NMR (500 MHz, CD3OD): δ 8.54 (s, 1H); 7.77 (d, J=5.6 Hz, 1H); 4.95 (q, J=8.5 Hz, 1H); 4.33 (t, J=6.5 Hz, 1H); 3.76 (t, J=6.0 Hz, 1H); 2.54 (m, 1H); 2.11 (m, 1H); 1.60 (q, J=11.0 Hz, 1H); 1.21 (d, J=7.5 Hz, 3H). LRMS m/z (M+H) 267.0 found, 267.1 required.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[CH2:28])[CH2:12][C@@H:11]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:46].[Na+].OO>CO>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:46])[CH2:12][C@@H:11]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: C=C1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17-methyleneandrost-5-ene (30.3 g), was added 9-borabicyclo[3,3,1]nonane (0.5M solution in tetrahydrofuran, 228 ml) and reacted by stirring at room temperature for 4 hours. Under cooling with ice, a 3M sodium hydroxide solution (150 ml) and then a 30% hydrogen peroxide solution (150 ml) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent, giving crude crystals (37.3 g). The crude crystals were mixed with methanol, stirred while under suspension, filtered and the thus obtained crystals were dried to give the titled compound (24.3 g).
Reaction SMILES: C(OC(=O)[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)(C)(C)C.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([NH:7][C:8]2[CH:13]=[N:12][CH:11]=[C:10]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[N:24]3)[N:9]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: c1ccc2[nH]ncc2c1
Product: Clc1ccc(Nc2cncc(-n3ncc4ccccc43)n2)cc1

Procedure:
Were prepared according to Example 3 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and indazole.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH2:23][OH:24])[CH:17]=[CH:16]2.C(OCC)C>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]2
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a suspension of pyridinium chlorochromate (2.4 gr, 11 mmol) in anhydrous CH2Cl2 (60 mL) was added a solution of the above alcohol in anh. CH2Cl2 and the reaction was heated under reflux for 5 hours. Upon completion, it was cooled to room temperature and poured into diethyl ether. The solution was then filtered through a pad of silica and concentrated under reduced pressure to yield 21 (2.4 gr, 95%). 20: white solid; 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.31 (bs, 1H), 8.08 (bs, 1H), 7.98 (dd, 1H, J=1.5 Hz, J=8.5 Hz), 7.86 (m, 2H), 7.67 (dd, 1H, J=1.5 Hz, J=8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 191.8, 137.3, 134.3, 134.1, 131.0, 131.0, 130.6, 130.2, 128.2, 124.0, 123.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[C:11]([C:16]#[C:17][Si](C)(C)C)=[N:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>CO.[OH-].[Na+]>[C:16]([C:11]1[C:12](=[O:15])[CH:13]=[CH:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=2)[N:10]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A mixture of 1-[3-(trifluoromethyl)phenyl]-3-[(trimethylsilyl)ethynyl]pyridazin-4(1H)-one (148 mg, 0.439 mmol) in MeOH (3 mL) and 1 M NaOH aqueous solution (5 mL) was stirred at 0° C. for 5 min and at room temperature for 2 h. The mixture was neutralized with 1 M HCl aqueous solution at 0° C. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (69 mg, 59% yield) as a pale red solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 4.70 (1H, s), 6.65 (1H, d, J=7.9 Hz), 7.76-7.92 (2H, m), 7.99-8.17 (2H, m), 8.93 (1H, d, J=7.9 Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6](=[O:20])[N:7]2NC(OC(C)(C)C)=O.O.[NH2:28][NH2:29]>O1CCOCC1>[NH:28]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6](=[O:20])[NH:7]2)[NH2:29]
Reactant: CC(C)(C)OC(=O)Nn1c(=O)c(-c2ccccc2)cc2c(Cl)nccc21
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1nccc2[nH]c(=O)c(-c3ccccc3)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 5-chloro-2-oxo-3-phenyl-1,6-naphthyridine-1(2H)-carbamate (2-2) (2.0 g, 5.6 mmol) and hydrazine hydrate (7.2 g, 112 mmol) in 1,4-dioxane (28 mL) was heated under microwave irradiation at 120° C. for 20 minutes. The solvent was removed under reduced pressure, and water was added to the residue. The resulting solid was collected by filtration to give 5-hydrazino-3-phenyl-1,6-naphthyridine-2(1H)-one (2-3) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[N:13]([C@H:14]2[O:26][C@@H:25]([CH2:27][O:28]C(=O)C)[C@H:20]([O:21]C(=O)C)[C@@H:15]2[O:16]C(=O)C)[C:12]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:11]=2[N:10]=1.C(O)C>ClCCl>[NH:1]([C:9]1[N:13]([C@H:14]2[O:26][C@@H:25]([CH2:27][OH:28])[C@H:20]([OH:21])[C@@H:15]2[OH:16])[C:12]2[CH:32]=[C:33]([Cl:37])[C:34]([Cl:36])=[CH:35][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: OC[C@@H]1O[C@H](n2c(Nc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 336 h
Yield: 5 %

Procedure:
Aniline (5 ml) and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.6 g, 1.1 mmol) were combined with absolute ethanol (35 mL) and stirred at 80 ° C. for 14 days. The reaction mixture was concentrated and the aniline was distilled off under high vacuum at 80° C. The brown residue was dissolved in methanol (50 mL) and K2CO3 was added. This solution was stirred for 18 h. The solution was filtered, concentrated and purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:15 methanol:dichloromethane to give a white solid (0.024 g, 0.06 mmol, 5%). MS (AP+): m/z (rel. intensity) 410 (19.39, M+1); 1H NMR (DMSO-d6) d 9.09 (s, 1H, NH), 7.83 (s, 1H, Ar-H), 7.78 (d, 1H, Ar-H, J=7.9 Hz), 7.58 (s, 2H, Ar-H), 7.31 (t, 2H, Ar-H, J=7.9 Hz), 6.99 (t, 1H, Ar-H, J=7.5 Hz), 5.95 (d, 1H, H-1', J=7.8 Hz), 5.86 (t, 1H, OH, J=4.4 Hz), 5.38 (d, 1H, OH, J=7.6 Hz), 5.30 (d, 1H, OH, J=4.2 Hz), 4.33 (apparent dd, 1H, H-4', J=13.4 Hz, J=7.8 Hz), 4.11 (apparent t, 1H, H-2', J=4.8 Hz), 4.05 (s, 1H, H-4'), 3.79-3.71 (m, 2H, H-5').
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.[I:39]I>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[I:39])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: II
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1OC
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(cc(I)n2S(=O)(=O)c2ccccc2)c1OC
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To 541 mg (1.71 mmol) of the protected indole from step 1 in 20 mL dry THF at −20° C. was added 269 μL (1.8 mmol, 1.05 eq) TMEDA, then LDA (1.1 mL, 2.22 mmol, 1.3 eq) dropwise. The reaction was stirred for 45 minutes and iodine (879 mg, 3.42 mmol, 2 eq) in 4 mL THF was added slowly, and stirred an additional 45 minutes at −20° C. The reaction was then quenched with H2O, concentrated and partitioned with EtOAc and 2N Na2CO3 solution. The EtOAc layer was washed with H2O, aqueous NaCl, dried (MgSO4), and concentrated under vacuum to yield 750 mg of 1-benzenesulfonyl-2-iodo-4,5-dimethoxy-1H-indole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52](OC(C)=O)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:52](=[O:53])[CH3:51])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) and DMAP (cat) in DCM (5 mL) was cooled to 0° C., followed by the addition of Ac2O (50 mg, 0.48 mmol). After 1 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford crude 38 which was used without further purification. Mass spectrum, m/z [615.1] (M+H)+.