Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]45[CH2:31][CH2:30][C:27]([CH2:32][C:33]([O:35]C)=[O:34])([CH2:28][CH2:29]4)[CH2:26][O:25]5)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2].O.[OH-].[Li+].O1CCCC1.C(O)C>O>[CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]45[CH2:29][CH2:28][C:27]([CH2:32][C:33]([OH:35])=[O:34])([CH2:30][CH2:31]4)[CH2:26][O:25]5)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)OC)(CC4)CO5)cc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)CO5)cc3)cc2)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A flask was charged with methyl 2-(1-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (0.025 g, 0.020 mmol), lithium hydroxide monohydrate (0.030 g, 0.716 mmol), tetrahydrofuran (1 ml), ethanol (0.3 ml) and water (0.3 ml), and stirred at 50° C. for 2 hours. The mixture was purified by HPLC (0.1% NH4OH, 10-60% acetonitrile/water, 20 minutes run, retention time ˜7 minutes) to afford (1-{4′-[(2-ethyl-4-methyl-oxazole-5-carbonyl)-amino]-biphenyl-4-yl}-2-oxa-bicyclo[2.2.2]oct-4-yl)-acetic acid (4 mg, 41%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.58 Hz, 3H) 1.68-1.90 (m, 6H) 2.02-2.16 (m, 4H) 2.40 (s, 3H) 2.84 (q, J=7.58 Hz, 1H) 3.87 (s, 2H) 7.44 (d, J=8.46 Hz, 2H) 7.58 (d, J=8.59 Hz, 2H) 7.63 (d, J=8.72 Hz, 2H) 7.83 (d, J=8.72 Hz, 2H) 10.13 (s, 1H). LC/MS, [MS+] 474.22, RT: 2.65 (Condition M).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:8][CH:7]=1)[OH:5].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:30])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:8][CH:7]=1)[O:5][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: COC(=O)C(O)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OS(C)(=O)=O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Yield: 105.2 %

Procedure:
To a solution of {4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-hydroxy-acetic acid methyl ester (9.00 g, 21.1 mmol) and triethylamine (3.20 g, 31.6 mmol) in CH2Cl2 (135 mL) cooled to −5 degrees Celcius was added dropwise methanesulfonyl chloride (3.14 g, 27.4 mmol) under N2 atmosphere. The reaction was stirred at 0 degrees Celcius until the starting material had been consumed according to TLC (about 1 hour). The mixture was washed with water (90 mL) and brine (90 mL), dried with MgSO4, filtered, and evaporated in vacuo to obtain 11.2 g (quantitative yield) of light yellow crystal which was used without further purification. MS: calc'd 505 (MH+), exp 505 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1.Cl.N1C=CC=CC=1>>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[C:26]([F:31])[CH:25]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 237 mg (0.97 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 6 mL of 2-ethoxyethanol containing 0.15 mL (1.36 mmol) of 4-chloro-2-fluoroaniline and 112 mg of pyridine hydrochloride is heated at reflux temperature for 30 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration, washing with hexane to give 225 mg (66%) of an off-white solid, mp 250-251° C.
Reaction SMILES: C([N:8]1[C:12]([C:13]([OH:37])([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:25]=2)[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.C(O)C.C([O-])=O.[NH4+]>[Pd].O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH2:14][C:13]([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)([OH:37])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2cncn2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCCc2ccc(F)cc2)c2c[nH]cn2)cc1

Procedure:
12,95 g of 1-benzyl-5-[4-(4-fluorophenyl)-1-hydroxy-1-(4-tert-butylaminocarbonylphenyl)butyl]-1-H-imidazole is dissolved into ethanol (400 ml) and water (130 ml). 8,17 g of ammonium formate and 1,3 g of 10% Pd/C is added to the solution and the mixture is refluxed for three hours. Then the reaction mixture is filtered through siliceous earth and the flitrate is evaporated to dryness. The residue is dissolved into ethyl acetate, washed with 2M aqueous sodium hydroxide and water, dried and evaporated to dryness.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[O:3]1.[ClH:28]>CO.C(Cl)Cl.O1CCOCC1>[ClH:28].[NH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2](=[O:1])[CH:11]=[CH:10]3)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCc2cccc3ccc(=O)oc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(CCc2cccc3ccc(=O)oc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of (1,1-dimethylethyl {1-[2-(2-oxo-2H-chromen-8-yl)ethyl]-4-piperidinyl}carbamate (320 mg, 0.86 mmol) in 20% MeOH/CH2Cl2 (5 mL) at 0° C. was added a solution of HCl in dioxane (4 M, 1.0 mL). The reaction was warmed to RT and stirred for 16 h, then the solvents were removed under reduced pressure to afford the title compound (170 mg, 73%) as a pale yellow solid: MS (ES) m/e 273.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([N:26]=[C:27]=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCCCCC>[CH2:1]([NH:13][C:27](=[O:28])[NH:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCN=C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCCNC(=O)NCCCCCCCCCCCC
Reaction time: 1 h

Procedure:
Didodecylurea was prepared as follows: Dodecylamine (37 mmol, 6.84 g, commercially available from Sigma Aldrich Fine Chemicals, Milwaukee, Wis.) was dissolved in hexane (100 ml) in a 250 ml single neck, round bottomed flask. A solution of dodecyl isocyanate (37 mmol, 7.8 g, commercially available from Sigma Aldrich Fine Chemicals) in hexane (100 ml) was slowly added to the amine solution through an addition funnel. The mixture was stirred for 1 hr during which a white precipitate was formed. IR was used to confirm completion of reaction. The white precipitate was filtered and dried under vacuum overnight to give 14.64 g of a white solid (99.7% yield). The product is believed to be of the formula
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].O[Li].O>O1CCCC1.CO.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1cccc([N+](=O)[O-])c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
The mixture of ethyl 2-methyl-2-(3-nitrophenoxy)propanoate (3.5 g, 13.82 mmol) and LiOH.H2O (2.320 g, 55.3 mmol) in Tetrahydrofuran (7 ml), MeOH (7 ml) and Water (7 ml) was stirred at room temperature for 4 hr. The reaction mixture was concentrated under vacuum and the residue was neutralised with 1N HCl, solid separated was filtered and treated with pentane to afford the title product (2.68 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[O:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:16][CH2:17][C:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)=[CH:13][CH2:14]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Reactant: Fc1ccc2cc(C3=CCNCC3)ccc2c1
Solvent: CO
Product: O[C@H](COc1cccc2occc12)CN1CC=C(c2ccc3cc(F)ccc3c2)CC1
Yield: 37.8 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)-1,2,5,6-tetrahydropyridine (0.101 g, 0.444 mmol) and (S)-(+)-4-(oxiranylmethoxy)-benzo[b]furan (0.085 g, 0.444 mmol) in methanol (5 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified by silica gel chromatography (dichloromethane/2% methanol in dichloromethane gradient elution) to give the title compound as a clear colorless oil (0.070 g, 38%). FDMS m/e=418 (M++1). C26H24FNO3.0.5H2O.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Br)(Br)[Br:15]>CN(C=O)C>[Br:15][C:5]1[C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Oc1ccnc2c(F)cc(F)cc12
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: Fc1cc(F)c2nccc(Br)c2c1

Procedure:
6,8-Difluoro-quinolin-4-ol (commercially available) (7.43 g) in DMF (200 mL) was treated with phosphorus tribromide (4.24 mL) by the method of Example (28a) to give a solid (9.03 g).
Reaction SMILES: [OH-].[K+].[CH:3]([C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])([CH3:5])[CH3:4]>CO.O>[CH:3]([C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([O:16][CH3:17])=[C:10]([CH:15]=1)[C:11]([OH:13])=[O:12])([CH3:5])[CH3:4]
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.2 ml) was added to a suspension of methyl 5-isopropyl-2,4-dimethoxybenzoate (330 mg, 1.39 mmol) in methanol (5 ml) and water (2 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were evaporated in vacuo to afford 5-isopropyl-2,4-dimethoxybenzoic acid (305 mg, 98%) as an off-white solid. 1H NMR (DMSO-d6) 12.07 (1H, br s), 7.57 (1H, s), 6.64 (1H, s), 3.90 (3H, s), 3.85 (3H, s), 3.13 (1H, m), 1.14 (6H, d). MS: [M+H]+ 225.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30]>C1(C)C(C)=CC=CC=1>[CH3:35][O:34][C:32]1[CH:31]=[C:29]([NH:30][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:28]=[C:27]([O:26][CH3:25])[CH:33]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Solvent: Cc1ccccc1C
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(OC)c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A flask was charged with N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (5 g, 13.7 mmol), prepared using procedures similar to those in Example 1, 3,5-dimethoxyaniline (4.2 g, 27.4 mmol), and 80 mL of xylene. The reaction mixture was stirred under an N2 atmosphere at 150° C. for 3 hours, after which time, solvent was removed on a rotary evaporator, and 10 mL of Dichloromethane and 50 mL of methanol were added. The slurry was heated to reflux and filtered while hot, resulting in 4.6 g (69.7%) of N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide MS (EI) m/z for C22H19N5O6S: 482.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[S:25]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:27])=[O:26])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 102.4 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-aminoquinoline (500 mg, 3 mmol) and 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (990 mg, 3 mmol) gave the title compound (1.22 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]OS(C)(=O)=O)=[CH:4][CH:3]=1.BrC1C=CC(CCO)=CC=1.CS(Cl)(=O)=O.[O-:30][S:31]([O-:33])=[O:32].[Na+:34].[Na+]>C(O)C.O>[Na+:34].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][S:31]([O-:33])(=[O:32])=[O:30])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCc1ccc(Br)cc1
Reactant: O=S([O-])[O-]
Agent: CS(=O)(=O)Cl
Agent: OCCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCc1ccc(Br)cc1

Procedure:
Methanesulfonic acid 2-(4-bromo-phenyl)-ethyl ester (1.39 g) prepared from 2-(4-bromo-phenyl)-ethanol and methanesulfonyl chloride, and Na2SO3 (816 mg) were reacted in ethanol/water (1/1), to obtain a crude product of 2-(4-bromo-phenyl)-ethanesulfonic acid sodium salt as a colorless plate-like crystal. Then, thionyl chloride (3 ml) was left to react in the presence of DMF (500 μl), to obtain 2-(4-bromo-phenyl)-ethanesulfonyl chloride, and further N-methylpiperazine (73 μl) was left to react in dichloromethane (2 ml) in the presence of triethylamine (54 μl), to obtain 1-[2-(4-bromo-phenyl)-ethanesulfonyl]-4-methyl-piperazine as a yellow solid (94 mg, 24%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:17]([C:18](=O)[CH:19]=1)=[CH:16][CH:15]=[C:14]1[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]1)=[O:5])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[O:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(=O)c2ccc3ncccc3c2o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCc2ccc3c(c2O1)CCCN3
Yield: 41.4 %

Procedure:
8-Oxo-8H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester (2.0 g, 7.4 mmole) was dissolved in 200 mL of ethanol and 0.50 g of 20% palladium hydroxide on carbon added. The mixture was treated with 60 psi of hydrogen on a Parr apparatus for 48 hours, then filtered through celite and concentrated in vacuum. Thin layer chromatography on silica gel vs. a starting material standard indicated that the reaction was incomplete. The material was redissolved in 150 mL of acetic acid, 0.50 g of 20% palladium hydroxide on carbon added, and the mixture again treated with 60 psi of hydrogen for 48 hours. It was then filtered through celite, concentrated in vacuum and column chromatographed on silica gel with 2% ethanol in chloroform as eluant to give 0.80 g of 1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester. 1H-NMR (CDCl3): doublet 6.65 δ (1 H); doublet 6.1 δ (1 H); multiplet 4.7 δ (1 H); quartet 4.25 δ (2 H); broad singlet 3.65 δ (1 H); multiplet 3.2 δ (2 H); multiplet 2.65 δ (4 H); multiplet 2.2 δ (2 H); multiplet 1.95 δ (2 H); triplet 1.25 δ (3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[H-].[Na+].CCOCC>CN(C=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])=[C:7]2[CH3:12])=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(-c2c(C)[nH]c3ccc(OC)cc23)c1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. mixture of the indole from Step 3 (285 mg, 0.96 mmol) and 4-bromobenzyl bromide (310 mg, 1.05 mmol) in DMF (5 mL) was added NaH (44 mg, 1.1 mmol). The mixture was warmed up to r.t. and stirred for 1.5 h after which time it was poured on a mixture of ice water and Et2O. The organic layer was washed with brine, dried with MgSO4 and the solvent removed to yield a residue which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[S:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH:39][C:18]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[N:15][S:16][C:17]=3[C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[O:20])[CH2:34][O:33]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3cnsc3c2Nc2ccc(Br)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (584 mg, 1.59 mmol) and diisopropylethylamine (0.82 mL, 4.77 mmol) in DMF (6 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (468 mg, 3.18 mmol), EDCI (611 mg, 3.18 mmol) and HOBt (430 mg, 3.18 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 50% to 100%, TBME in cyclohexane) to afford the title compound as a yellow oil (370 mg, 47%). LCMS (method B): RT=3.96 min, [M+H]+=496/498.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28](B(O)O)=[CH:29][C:24]=2[CH:23]=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)=[CH:29][C:24]=2[CH:23]=[CH:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2occc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4occc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in dioxane (5.0 mL) was added (1-benzofuran-5-yl)boronic acid (215.6 mg, 1.33 mmol), K3PO4 (280.6 mg, 1.33 mmol), Pd(PPh3)4 (25.56 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(1-benzofuran-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (105 mg, crude). LC/MS (ES, m/z): 376.0
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:11][N:12]3CCC#N)=[CH:7][C:6]=2[C:25]#[N:26])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][NH:12]3)=[CH:7][C:6]=2[C:25]#[N:26])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(C#N)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1cc2c(=O)c(C(=O)O)c[nH]c2nc1N1CCC1
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 83A (0.38 g) in methanol (100 mL) was treated with 1M LiOH (50 mL), stirred for 18 hours, treated with 10% citric acid, and filtered. NMR (300 MHz, DMSO-d6) δ 14.83 (s, 1H), 13.27 (br s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 4.43 (br s, 4H), 2.40 (m, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[CH:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH2:29].C([O-])(=O)C.[Tl+].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:31]([O:30][C:28]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1)=[CH2:29])[CH2:32][CH2:33][CH3:34]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Tl+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To 215 ml of N,N-dimethylformamide solution containing 10.1 g (21.2 mmol) of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 20-(a) were added 13.9 ml (108 mmol) of butyl vinyl ether, 5.59 g (21.2 mmol) of thallium acetate, 6.24 ml (36.7 mmol) of N,N-diisopropylethylamine, 482 mg (2.15 mmol) of palladium acetate and 1.86 g (4.51 mmol) of 1,3-bis(diphenylphosphino)propane in this order, and after degassing under reduced pressure, the atmosphere was replaced by a nitrogen gas, and the mixture was stirred at 100° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 8.80 g of the title compound as a pale brownish oil. (Yield: 84%)