Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>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>[C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=CC=CC=CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
Ethyl diazoacetate (43.4 g, 0.38 mol) was added slowly (syringe pump) over a period of 7 hours to a mixture of benzene (594.32 g, 7.61 mol) and tetrakis (perfluorobenzoato) dirhodium(II) (0.84 g, 0.16 mol). After stirring at room temperature for 6 hours, the solvent was removed and the oily residue distilled in vacuo to give 50.44 g (81%) of ethyl 1,3,5-cycloheptatriene-1-carboxylate: bp 90°-96° C. 2.4-3.0 mm Hg);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[O:14])[CH3:13])[C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(Cl)ccc21
Yield: 94.3 %

Procedure:
A mixture of 7.0 g (42 mmole) of 5-chloro-2-oxindole and 5.9 ml (63 mmole) of acetic anhydride was heated under nitrogen at reflux for 3.5 hours. The cooled reaction mixture was diluted with 300 ml of ethyl acetate, and the resulting solution was washed with aqueous sodium bicarbonate followed by saturated, aqueous sodium chloride solution. The ethyl acetate solution was then dried (Na2SO4) and evaporated in vacuo to give 8.3 g of a purple solid. The latter solid was purified by chromatography on silica gel, eluting with 2.5% ethyl acetate in dichloromethane, to give 6.0 g of crude title compound as a yellow solid. The latter solid was recrystallized from ca. 50 ml of ethanol to give 4.7 g of the title compound as pale yellow needles, m.p. 129°-130° C.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[N+:28]([O-])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Ni].CO>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[C:19]([NH2:28])=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 15 parts of 4-(diphenylmethyl)-N-[2-nitro-4-(trifluoromethyl)phenyl]-1-piperazinepropanamine in 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-4-(trifluoromethyl)-1,2-benzenediamine.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c(-c4ccccc4)n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-phenyl-1H-imidazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20].CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:21][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1)=[O:20]
Reactant: Clc1cncc(Oc2cccnc2)n1
Reactant: NC(=O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cncc(Oc2cccnc2)n1)c1cccc(Cl)c1
Temperature: 110 °C
Yield: 72.6 %

Procedure:
Compound 3 (944 mg, 4.55 mmol, 1.00 eq), 3-chlorobenzamide (1.06 g, 6.81 mmol, 1.50 eq), NaOt-Bu (612 mg, 6.37 mmol, 1.40 eq), Pd(OAc)2 (51 mg, 0.23 mmol, 0.050 eq) and Xantphos (263 mg, 0.455 mmol, 0.100 eq) were dissolved in toluene (9.4 mL) in a flame-dried sealed tube and heated at 110° C. for 18 h. The reaction was cooled to rt, diluted with CH2Cl2 and filtered through a plug of celite. Purification by flash chromatography on silica gel afforded 1.08 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.17 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 8.46 (dd, J=4.7, 1.2 Hz, 1H), 8.33 (s, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.77 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.67-7.64 (m, 1H), 7.54-7.48 (m, 2H); ES-MS [M+1]+: 327.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=O)=O)=[CH:12][CH:11]=1>C(O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:18]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[N:8][C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:1]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccccc1N
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCO
Product: Oc1ccc(-c2nc3ccccc3nc2-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Into a 250 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was placed 1,2-diaminobenzene (2.3275 g, 0.0215 mol), 4,4'-dihydroxybenzil (5.2135 g, 0.0215 mol) and absolute ethanol (30 ml). The solution was stirred for one-half hour at room temperature, and a yellow precipitate formed. The mixture was heated to reflux overnight. The solvent was removed by vacuum distillation and the solid dried at 100° C. for two hours to give 6.6 g (97%) of yellow powder. The material was recrystallized from 1,4-dioxane/water mixture. Yield 6.0 g (89%) m.p. 336° C.-338° C. Anal. Calcd for C20H14N2O2 : C, 76.42%; H, 4.49%; N, 8.91%. Found: C, 76.54%; H, 4.44%; N,8.96%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[S:41]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42]1.[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:46]([C:43]3[CH:44]=[CH:45][S:41][CH:42]=3)(=[O:48])=[O:47])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccsc2)c1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 10 min. After stirring, 15-crown-5 (143 mg) and thiophene-3-sulfonyl chloride (138 mg) were added dropwise and the mixture was further stirred at room temperature for 15 min. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 201 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cccnc1N
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)o1
Temperature: 45 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Manufacturing Example 46-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2-ylamine (4.0 mg, 0.034 mmol) described in Manufacturing Example 1-2-3 and triethylamine (9.4 μL, 0.068 mmol) at room temperature, which was stirred for 3 hours at 45° C. The reaction mixture was cooled to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (5.1 mg, 41%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=1[C:7](OC)=[O:8])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=1[CH2:7][OH:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(OC)cc1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(OC)cc1CO
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
Step AS (2). To a solution of methyl 2-allyloxy-5-methoxybenzoate (12 g, 55 mmol) in 100 mL anhydrous THF was added slowly 55 mL of a 1.0 M solution of lithium aluminum hydride (55 mmol) in THF at −50° C. The resulting solution was stirred at −50° C. for 1.5 h. EtOAc (100 mL) was added, followed by addition of 30 mL of aqueous ammonium chloride. The organic layer was filtered, washed with aqueous ammonium chloride and brine, then dried over magnesium sulfate. After concentration, 2-allyloxy-5-methoxybenzyl alcohol was obtained as a colorless oil (10.5 g, 100%), which was used directly for the next reaction without purification. LC-MS (M+H)+=195; 1H NMR (400 MHz, CDCl3) δ ppm 3.75 (s, 3H) 4.46-4.55 (m, 2H) 4.66 (s, 2H) 5.21-5.29 (m, 1H) 5.34-5.42 (m, 1H) 5.95-6.09 (m, 1H) 6.74 (dd, J=9.05, 3.02 Hz, 1H) 6.78 (d, J=9.05 Hz, 1H) 6.88 (d, J=3.02 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:18]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:10][CH:8]([CH3:9])[CH:7]([CH2:11][S:12]([N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)(=[O:13])=[O:14])[C:6]([OH:5])=[O:16]
Reactant: c1cncc(-c2ccc(N3CCNCC3)cc2)c1
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3cccnc3)cc2)CC1)C(=O)O
Reaction time: 2 h
Yield: 91.9 %

Procedure:
2-Chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester (0.072 g) [preparation described in WO-A-98/05635] was added as a solution in dichloromethane (2 ml) to a stirred mixture of 1-(4-pyridin-3-yl-phenyl)piperazine (0.053 g) and triethylamine (40 μl) and the resultant solution stirred at room temperature for 2 h. Trifluoroacetic acid (4 ml) was then added dropwise, and the mixture stirred for a further 2 h. The solvent were removed under reduced pressure and the residue azeotroped with 1:1 dichloromethane/hexane (2×10 ml). The residue was then diluted with diethyl ether (20 ml) and extracted with 1 M sodium hydroxide (10 ml) followed by 0.5 M sodium hydroxide (10 ml). The combined aqueous extracts were then washed with diethyl ether (20 ml), then cautiously acidified to pH 5 with acetic acid, forming a precipitate. The mixture was then extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with water (2×10 ml), saturated brine (10 ml), dried (Na2SO4) and reduced in vacuo to give the title compound as a pale green solid (0.085 g, 93%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(=O)(O)[O-].[Na+].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=1>CN(C)C=O.O1CCCC1>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:38][CH:39]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Yield: 52.7 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.1 g), sodium bicarbonate (0.6 g) and 4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridine(1.6 g) in dimethylformamide (15 cc) and tetrahydrofuran (15 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 7 hours at this temperature. After purification by crystallization from water (50 cc) then recrystallization from a boiling acetone-ethanol mixture (50-50 vol) (50 cc), 2-{3-[4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.8 g) is obtained, m.p. 224° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 77.1 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[3-(4-pyridine-2-ylbenzoylamino)propoxy]phenyl]propionate (161 mg), which is the product of Example 69, was reacted with aqueous sodium hydroxide solution (1N, 1.20 ml) and the reaction mixture was treated to give the title compound (117 mg) as a white powder.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(CC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 86 %

Procedure:
A suspension of N-(4-neopentyl-2-nitrophenyl)acetamide (Preparation 87, 3.0 g, 12.0 mmol) in aqueous sodium hydroxide (6.0 M, 20 mL, 120 mmol) was heated at 90° C. for 36 hours. After cooling, a small amount of water was added and the mixture extracted with dichloromethane (5×). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo to provide the title compound (2.15 g, 90%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:27]=[CH:26][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:20][CH2:19][N:18]([CH2:21][C:22](=[NH:24])[NH2:23])[C:17]3=[O:25])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1.O=[C:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34](OC)=[O:35].[O-]CC.[Na+]>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[NH:23][C:34](=[O:35])[C:30]5[CH2:31][CH2:32][CH2:33][C:29]=5[N:24]=4)[C:17]3=[O:25])[CH2:12][CH2:11]2)=[O:9])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCN(CC(=N)N)C3=O)CC2)cc1
Reactant: COC(=O)C1CCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)C2CCN(C3CCN(Cc4nc5c(c(=O)[nH]4)CCC5)C3=O)CC2)cc1
Temperature: 100 °C
Yield: 19.8 %

Procedure:
To a solution of 2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetimidamide hydrochloride (140 mg, 0.37 mmol) and methyl 2-oxocyclopentanecarboxylate (0.060 mL, 0.47 mmol) in ethanol (4 mL) was added sodium ethoxide (0.160 mL, 0.44 mmol, 21%). The mixture was heated at 100° C. for 24 h. The resulting mixture was purified via flash column chromatography (methanol: dichloromethane, 1:99 to 10:90) and then crystalized out from methanol to provide slightly yellow solid (33 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 10.85 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 4.32-4.47 (m, 2H), 3.89 (s, 3H), 3.60-3.73 (m, 1H), 3.40-3.56 (m, 2H), 3.23-3.37 (br. s, 1H), 3.00-3.20 (br. s, 3H), 2.84 (ddd, 4H, J=14.7, 7.5, 7.4 Hz), 2.46-2.62 (br. s, 1H), 2.38 (d, 1H, J=7.0 Hz), 2.15-2.25 (br. s, 1H), 2.10 (dq, 2H, J=7.8, 7.6 Hz), 1.82-2.01 (br. s, 4H) HRMS calculated for C25H30N4O4 451.2345. found (ESI, [M+H]+), 451.2362.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.Cl>O>[CH3:10][C:11]1([CH3:13])[O:7][CH2:6][C:3]([CH2:8][Br:9])([CH2:2][Br:1])[CH2:4][O:5]1
Reactant: CC(C)=O
Reactant: OCC(CO)(CBr)CBr
Agent: Cl
Solvent: O
Product: CC1(C)OCC(CBr)(CBr)CO1

Procedure:
The reactant 2,2-dimethyl-5,5-bis(bromomethyl)-1,3-dioxane was prepared by contacting 2,2-bis(bromomethyl) 1,3-propane diol with an excess of acetone in the presence of a catalytic amount of hydrochloric acid. Water produced in the reaction was removed with anhydrous calcium chloride and any residual acid was neutralized with sodium carbonate, the mixture filtered and the filtrate evaporated to dryness. The residue was extracted with carbon tetrachloride, filtered and the filtrate evaporated to give the desired 2,2-dimethyl-5,5-bis(bromomethyl)-1,3-dioxane reactant.
Reaction SMILES: C(OC([N:8]1[CH:13]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:28]=2[NH:27][C:26]2[CH:25]=[N:24][CH:23]=[CH:22][C:21]3=2)[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO.O1CCOCC1>[Cl:29][C:18]1[CH:19]=[C:20]2[C:28](=[C:16]([NH:15][C:14]([CH:13]3[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9][NH:8]3)=[O:30])[CH:17]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: CC1(C)CNC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.2 %

Procedure:
To a clear brown solution of 5-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholine-4-carboxylic acid tert-butyl ester (10.4 g, 22.7 mmol) in methanol (41 mL) was added HCl in dioxane (4M, 91 mL). The reaction was stirred for 30 minutes at room temperature, during which time a pale brown precipitate began to form. The mixture was poured into a 250-mL volume of vigorously stirring Et2O. The resulting slurry was stirred at room temperature for 15 minutes, then filtered to yield a pale orange solid. The solid was placed on the high-vacuum pump overnight, after which 9.71 g of 6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide was obtained (99% yield). 1H-NMR (DMSO-d6, 300 MHz) δ 13.47 (s, 1); 11.77 (s, 1); 9.42 (s, 1); 8.86 (d, 1); 8.66 (d, 1); 8.58 (d, 1); 8.25 (d, 1); 4.41-4.37 (m, 2); 4.05 (dd, 1); 3.32-3.28 (m, 1); 3.04-3.00 (m, 1); 1.34 (s, 3); 1.30 (s, 3). NH4OAc standard conditions. DAD Rf=1.48 min. M+H=359.
Reaction SMILES: B([O:6][CH3:7])(OC)OC.[C-]#N.[K+].[Si:11]([C:15]#[N:16])([CH3:14])([CH3:13])[CH3:12]>>[Si:11]([C:15]#[N:16])([CH3:14])([CH3:13])[CH3:12].[Si:11]([O:6][CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: COB(OC)OC
Agent: C[Si](C)(C)C#N
Agent: [C-]#N
Agent: [K+]
Product: CO[Si](C)(C)C
Temperature: 70 °C

Procedure:
B(OCH3)3 (20.0 g, 0.19 mol) and KCN (12.5 g, 0.19 mol) were dissolved in TMSCN (66.8 g, 0.67 mol) and heated at a reflux temperature of 70° C. under protective gas for 18 hours. After cooling, all volatile components (unreacted TMSCN, formed TMSOMe) were distilled off to give powdery K[B(CN)3(OCH3)] in a yield of 27.8 g (92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][OH:12]
Reactant: Oc1ccccc1Br
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1Br
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
In a nitrogen atmosphere, 2-bromophenol 5.0 g, 2-bromoethanol 5.42 g, and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30 ml, and the mixture was stirred at 100° C. After about 2.5 hours, the reaction mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 5.09 g, 81% was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.B(F)(F)F.CCOCC>O>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([O:11][C:12]3[C:13]([F:20])=[CH:14][C:15]([O:18][CH3:19])=[CH:16][C:17]=3[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser and temperature probe was charged with 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (2340 g, 6.9 mol). TFA (11.7 L) was carefully added to the solution followed by TFAA (1144 mL). Boron trifluoride diethyl etherate (85 mL, 0.68 mol) was then carefully added to the reaction mixture. The mixture was stirred for 4 hours at which point the reaction was transferred to another 100 L glass reactor containing 35.1 L of water cooled to 0° C. The resulting slurry was allowed to warm to RT and stir for 1 hour. The solids were filtered and washed with water (4.7 L) and 3 N NaOH (2×3.5 L) and water (7 L). The solids were transferred into a 22 L reactor and acetone (4.7 L) was added. The solids were slurried for 1.5 hour and the filtered, washing well with acetone (4.7 L). An additional slurry with acetone (6.4 L@ 45° C.) provided 1310 g of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one as an off white solid.