Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 84.5 %

Procedure:
In a 250-ml, three-necked, round-bottom flask equipped with a magnetic stirrer, heating mantle, thermometer, and condenser were placed 1.76 g. (9.0 mmol) 4-hydroxy-4'-biphenylcarbonitrile, 3.94 g (28.5 mmol) powdered anhydrous potassium carbonate, 1.18 ml (9.92 mmol) α-bromotoluene, and 150 ml acetonitrile. After stirring the mixture under reflux for two hours, TLC analysis showed that none of the phenolic starting material remained. Two-thirds of the acetonitrile was then distilled off, and 200 ml dichloromethane was added. The mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded white crystals which were purified by recrystallization from methanol. 2.17 g (84.4%) of product was obtained; mp 150°-151.5° C. The following structure was confirmed by infrared, nuclear magnetic resonance, and mass spectral analyses. ##STR34##
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:7][C:8]2[CH:9]=[CH:10][C:11](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:12][C:11]3[CH:17]=[CH:18][C:8]([O:4][CH3:1])=[CH:9][CH:10]=3)=[O:15])=[CH:17][CH:18]=2)=[CH:23][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)/C=C/c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 194.7 %

Procedure:
Potassium carbonate (21 g, 152 mmol) was added to a mixture of 4-hydroxycinnamic acid 40.1 (6.25 g, 38.1 mmol) and p-methoxy benzyl chloride (10.35 mL, 76 mmol) in DMF (100 mL). The mixture was stirred at 80° C. for five hours. After cooling, the mixture was poured into water (700 mL). The solid was collected by filtration, washed with water and dried to give 40.2 (15 g). MS ESI (pos.) m/e: 405 (M+H). 1HNMR (CDCl3) δ 7.68 (d, 1H), 7.47 (d, 2H), 7.38 (m, 4H), 6.95 (m, 6H), 6.35 (d, 1H), 5.20 (s, 2H), 5.03 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC=C1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Yield: 64.3 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.441 g, 1.33 mmol) and 4-butylidenepiperidine (111MF05) (0.204 g, 1.47 mmol) in MeCN (12 mL) were reacted according to GP14 to give the title compound (108LM33-30) (0.293 g, 64%). 1H NMR (CDCl3) δ 7.19 (bd, J=7.0 Hz, 1H), 7.04-6.97 (m, 3H), 5.13 (t, J=7.9 Hz, CH), 4.60 (ABq, J=14.1 Hz, J=16.2 Hz, CH2), 4.00 (d, J=7.0 Hz, CH2), 2.50-2.38 (m, 2H), 2.35-2.05 (m, 9H), 1.95 (dt, J=7.0 Hz, CH2), 1.50-1.40 (m, 2H), 0.94-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.0, 145.8, 136.3, 128.9, 123.8, 122.8, 122.7, 117.3, 115.7, 67.9, 63.7, 56.5, 55.7, 45.5, 36.4, 29.4, 28.6, 23.4, 17.1, 13.9; HPLC-MS (ammonium acetate) [M+H]+=343.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC.CN(C)C=O>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1ccc(CCl)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C#N)cc3)ccc21
Yield: 98.6 %

Procedure:
40.8 g (0.2 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol, 30.4 g (0.2 mol) of 4-cyanobenzyl chloride and 80 g (1.2 mol) of anhydrous potassium carbonate in 400 ml of butanone and 300 ml of dimethylformamide were refluxed for 9 h. The mixture was cooled and then poured into 1.5 l of water, and the solid was filtered off with suction and washed with water. Drying resulted in 63 g of the title compound of melting point 49°-150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH:15][S:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:26])=[O:25])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nc2c(s1)CCc1ccc([N+](=O)[O-])cc1-2
Product: O=[N+]([O-])c1ccc2c(c1)-c1nc(NS(=O)(=O)c3ccccc3)sc1CC2

Procedure:
The title compound was prepared from 8-nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 7-nitrotetralone) and benzenesulfonyl chloride (85 mg) as described in the synthetic METHOD A to give a yellow powder (12 mg) with a purity of >90%: MS-ES (neg) m/z 386.3.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.I[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:3][C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: O=C(O)c1ccccc1I
Reactant: CCn1nc(C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of 5-amino-1-ethyl-3-methylpyrazole (7.5 g, 0.06 mol), 2-iodobenzoic acid (14.88 g, 0.06 mol), DMF (50 ml) Cu(OAc)2.H2O (0.5 g) and K2CO3 (8.3 g, 0.06 mol) is refluxed under a nitrogen atmosphere for 20 hours. The reaction mixture is cooled to room temperature and then is poured into ice water. The mixture is neutralized with acetic acid, and the resulting solid is collected by filtration, washed with water and dried to afford 7.1 g (48%) of N-(1-ethyl-3-methylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][C:33]#[N:34])=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-:36].[K+].[K+].OO.C(OCC)(=O)C>CS(C)=O.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][C:33](=[O:36])[NH2:34])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(N)=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 528.3 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-cyanomethyl-4-(triphenylmethylthio) pyrrolidine (1.17 g) in dimethyl sulfoxide (3.75 ml) were added potassium carbonate (50 mg) and 30% hydrogen peroxide (313 μl). After stirring at 60° C. for 2 hours, the mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with aqueous sodium chloride solution twice, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel (eluent; n-hexane:ethyl acetate=1:1) to give (2R,4S)-1-allyloxycarbonyl-2-carbamoylmethyl-4-(triphenylmethylthio)pyrrolidine (0.93 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:14]([CH:16]1[CH2:18][CH2:17]1)=O)[C:6](=O)[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[CH3:2].Cl.[NH2:21][NH2:22]>>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)=[N:21][NH:22][C:14]=1[CH:16]1[CH2:18][CH2:17]1)=[O:19])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)c1cncnc1)C(=O)C1CC1
Agent: Cl
Product: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Yield: 39 %

Procedure:
In analogy to the procedure described in Example 162B], 2-cyclopropanecarbonyl-3-oxo-3-pyrimidin-5-yl-propionic acid ethyl ester and hydrazine.hydrochloride gave the title compound as white solid (39%). MS: 259.1 (MH+).
Reaction SMILES: [N:1]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19](=O)[CH3:20].C(O)(=O)C.C([BH3-])#N.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[CH2:19]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:2][CH2:3]1)[CH3:20]
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc(N2CCCN(CC)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol), acetaldehyde (0.701 mL, 12.50 mmol) and acetic acid (0.286 mL, 5.00 mmol) in tetrahydrofuran (30 mL), methanol (3 mL) was treated with sodium cyanoborohydride (0.393 g, 6.25 mmol) at 20° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was cooled and extra amount of acetaldehyde (2.146 mL, 38 mmol) and sodium triacetoxyborohydride (1.060 g, 5.00 mmol) were added. The reaction was stirred at room temperature for 18 h. The reaction mixture was filtered and evaporated to dryness. The residue was dissolved in 2N HCl (5 ml) and methanol (20 ml). The solution of crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford ethyl 4-(4-ethyl-1,4-diazepan-1-yl)benzoate (0.526 g, 76%)
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH3:21])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH3:21])[N:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1cc2ccccc2c(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccccc3c(O)n2)cc1
Yield: 69.8 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.36 g), 4-[N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (2.00 g), anhydrous potassium carbonate (1.04 g) and methyl ethyl ketone (20 ml) was heated under reflux for a period of 3 hours. The mixture was cooled, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil, which was purified by column chromatography over silica gel (eluant dichloromethane to yield ethyl 2-{4-[N-(1-hydroxyisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (1.92 g) as a brown solid mp 96° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].CO[C:39]1O[C:41](OC)=[CH:42][CH:43]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.CCOC(C)=O>[F:31][C:2]([F:30])([F:1])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([N:17]4[CH:39]=[CH:43][CH:42]=[CH:41]4)[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: COc1ccc(OC)o1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)[C@@]2(Cc3ccc(OC(F)(F)F)cc3)C[C@H](n3cccc3)CN12

Procedure:
To a solution of the compound from Example 63 (0.25 g) in acetic acid (5 mL) was added sodium acetate (0.26 g) and 2,5-dimethoxyfuran (0.14 mL). After 20 minutes at reflux, the reaction was cooled, diluted with EtOAc, neutralized with solid NaHCO3. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel; 95:5 CH2Cl2/methanol, Chromatotron) to afford the titled compound (0.145 g): MS (m/z) 525 [MH+]. mp 129.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].C[CH2:21][N:22]=C=NCCCN(C)C.Cl.CN1CCOCC1.CN>C(Cl)Cl>[CH3:21][NH:22][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0M in THF; 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
Reaction SMILES: [C:1]([C:4]([CH3:24])([CH3:23])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[CH:8][CH:7]=1)([OH:3])=[O:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[O:15]=[C:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([CH3:24])([CH3:23])[C:1]([OH:3])=[O:2])=[CH:22][C:21]1=2
Reactant: CC(C)(Cc1ccc(OCc2ccccc2C(=O)O)cc1)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Cc1ccc2c(c1)C(=O)c1ccccc1CO2)C(=O)O
Yield: 19.6 %

Procedure:
A slurry of 2-[4-(2-carboxy-2-methylpropyl)phenoxymethyl]benzoic acid (15.9 g) in 200 ml dry dichloromethane was treated dropwise with 12.5 ml trifluoroacetic anhydride then heated to reflux for 5 hours. Evaporation left an oil which was purified by HPLC (20:1 dichloromethane-methanol) to give 2.95 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-2,2-dimethyl-propanoic acid a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[Li])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20]([CH2:33][CH3:34])[C:21]([C:23]1[C:24]([O:31][CH3:32])=[N:25][CH:26]=[CH:27][C:28]=1[CH:29]=[O:30])=[O:22])[CH3:19].CN(C)CCN(C)C.CC1(C)CCCC(C)(C)N1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:29]([C:28]1[CH:27]=[CH:26][N:25]=[C:24]([O:31][CH3:32])[C:23]=1[C:21]([N:20]([CH2:18][CH3:19])[CH2:33][CH3:34])=[O:22])[OH:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)C(=O)c1c(C=O)ccnc1OC
Reactant: [Li]c1cc2cnccc2n1C(=O)OC(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN(C)CCN(C)C
Product: CCN(CC)C(=O)c1c(C(O)c2cc3cnccc3n2C(=O)OC(C)(C)C)ccnc1OC

Procedure:
Starting from 1-tert.butoxycarbonyl 2-lithio 5-aza indole and 3-diethylaminocarbonyl 4-formyl 2-methoxy pyridine as reagent with electrophilic character, prepared according to paragraph b (stabilization reagent: tetramethylethylenediamine; amine: 2,2,6,6-tetramethylpiperidine).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.O>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: CC(C)(N)CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(N)COc1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (0.5 ml, 5.60 mmol), in DMF (20 mL) was added NaH 60% (0.67 g, 16.80 mmol) and then 6-chloronicotinonitrile (2.03 g, 11.22 mmol). The mixture heated to 70° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was taken up in H2O and extracted with EtOAc. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 235 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].Br[CH2:16][CH2:17]Br>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]2[O:12][CH2:16][CH2:17][O:13][C:7]=2[CH:6]=1)=[O:14])[CH3:2]
Reactant: BrCCBr
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3,4,5-trihydroxy-benzoic acid ethyl ester (5.00 g, 24.2 mmol) in DMF (70 mL) are added 1,2-dibromoethane (2.13 mL, 24.2 mmol) and CsCO3 (16.9 g, 50.9 mmol) and the mixture is stirred overnight at room temperature and for 5 hrs at 60° C. Extractive work-up with diethyl ether, washing of the organic phase with brine and evaporation gives the crude product as brown oil which is purified by silica gel chromatography (hexane/AcOEt 3:2). The title compound is obtained as a white solid. TLC, Rf (hexane/AcOEt 1:1)=0.27. MS: 223.0 [M−H]+. 1H-NMR (CDCl3): δ 1.40 (t, 3H), 4.3-4.42 (m, 6H), 5.45 (s, 1H), 7.23 (s, 1H), 7.29 (s, 1H) ppm.
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:8]([CH3:18])[N:7]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=O>C(O)C>[CH3:38][N:37]([CH3:39])[C:34]1[CH:35]=[CH:36][C:31]([C:29](=[N:5][NH:4][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[C:8]([CH3:18])[N:7]=2)[CH3:28])=[CH:32][CH:33]=1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=NNc1cc(-c2ccccc2)nc(C)n1)c1ccc(N(C)C)cc1
Yield: 17.9 %

Procedure:
To a solution of 4-hydrazino-2-methyl-6-phenylpyrimidine trihydrochloride (300 mg, 0.97 mmol) and diisopropylethylamine (0.17 mL, 0.97 mmol) in ethanol (10 mL) was added 4-dimethylaminoacetophenone (158 mg, 0.97 mmol). The resultant reaction mixture was heated at reflux overnight. The reaction mixture was diluted with dIH2O and the pH was adjusted to 1-2 and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 and was extracted with ethyl acetate. The combined extracts were concentrated in vacuo and the residue crystallized from ethyl acetate:hexanes. 60 mg (18%) of the title compound was isolated as a yellow solid. HPLC Purity: 98%.
Reaction SMILES: [C:1]([Cu])#[N:2].[CH2:4]([NH:6][C:7](=[O:9])[O-:8])[CH3:5].[CH3:10][O:11][C:12]1[C:13](Br)=[CH:14][C:15]2[CH:16]([CH3:24])[CH:17]3[CH2:21][NH:20][CH2:19][CH:18]3[C:22]=2[CH:23]=1>CN(C=O)C.O>[CH2:4]([NH:6][C:7](=[O:8])[O-:9])[CH3:5].[CH3:10][O:11][C:12]1[C:13]([C:1]#[N:2])=[CH:14][C:15]2[CH:16]([CH3:24])[CH:17]3[CH2:21][NH:20][CH2:19][CH:18]3[C:22]=2[CH:23]=1
Reactant: COc1cc2c(cc1Br)C(C)C1CNCC21
Reactant: N#C[Cu]
Agent: CCNC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C#N)C(C)C1CNCC21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
CuCN (68 mg, 0.85 mmol) was added to a solution of N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (60 mg, 0.17 mmol) in DMF (1.7 mL), and stirred overnight at 100° C. The reaction mixture was diluted with EtOAC and H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via a silica plug eluting with Hexanes/EtOAc (2/1, v/v). MS calculated for C17H20N2O3+H: 301, observed: 301.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][C:3]=1[CH3:24].C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([CH3:23])[CH:17]=2)=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:30]=[O:31])=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(C(=Cc2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=C(C=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
A solution of 1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyltetrazol-5-yl)ethene (3.58 g, 11.0 mmoles)) in dry tetrahydrofuran (20 mL) at -78° C. was treated with n-butyllithium (5.3 ml of 2.5M solution in hexane; 13.25 mmoles) and the mixture stirred at -78° C. for 0.5 hours. Ethyl formate (1.33 ml; 1.22 g, 16.5 mmoles) was added and the mixture was allowed to warm up to 23° C. over 1 hour, then quenched with 2N HCl (250 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 20% EtOAc-Hexane as eluent to afford 2.2 g (57%) of the title compound as a foam. MS (CI): m/e=355 for (M+H)+.
Reaction SMILES: [C:1]([O:4]C(C)(C)C)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O1CCCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH2:2][C:1]([OH:4])=[O:3])=[CH:20][CH:19]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(Br)cc1
Reaction time: 4 h

Procedure:
t-Butyl acetate (159 mL, 1180 mmol) was added to lithium diisopropylamide (941 mmol) in tetrahydrofuran at -78° C. followed by 4-bromobenzylbromide (200 g, 784 mmol). The bath temperature was kept at -15° C. for 4 hours whereupon the reaction was quenched with ammonium chloride. The mixture was extracted with diethyl ether and the organic layer was washed with dilute hydrochloric acid, water, and brine, drying with sodium sulfate to yield a pale oil. This was refluxed with trifluoroacetic acid (150 mL, 1960 mmol) for 1 hour. The trifluoroacetic acid was removed under vacuum and the residue was partitioned between diethyl ether and aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid at 0° C. and extracted with diethyl ether. This organic layer was washed with water and brine and was dried over sodium sulfate to obtain a white solid after removing solvent under vacuum, (167 g, 93%), 132-134° C. m.p.