Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:59](C1C=C(C=CC=1)C(Cl)=O)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[C:6]([O:59][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(Oc5ccccc5)c4)cc3)cc2C1=O
Yield: 70 %

Procedure:
The compound of example 147 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-phenoxy benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH3:20].CC(C)([O-])C.[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][CH2:18][CH2:19][CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)ethanone (0.150 g, 0.528 mmol), 1-bromopropane (0.24 mL, 2.64 mmol), and potassium tert-butoxide (0.296 g, 2.64 mmol) in N,N-dimethylformamide (3.0 mL) was heated at 80° C. After 24 h, a second portion of 1-bromopropane (0.24 mL, 2.64 mmol) and potassium tert-butoxide (0.296 g, 2.64 mmol) was added and the mixture was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.100 g, 58%) as a colorless oil. MS (ESI, pos. ion) m/z 326, 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[OH:9])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc(Cl)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2O)CC1
Reaction time: 18 h
Yield: 82 %

Procedure:
2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231 mmol) were set stirring in dichloromethane (600 mL). Sodium triacetoxyborohydride (58.0 g, 274 mmol) was added in portions over 10 min. Acetic acid (12 mL, 210 mmol) was then added and the mixture left to stir for 18 h. Saturated NaHCO3 was added and the organics seperated. The organics were dried (MgSO4) and evaporated to give 56 g (82%) of a light beige solid. TLC (silica, 50% EtOAc/hexanes): Rf=0.66. MS (electrospray): exact mass calculated for C16H23ClN2O3, 326.14. m/z found, 349.1 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 6.70 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.55-3.50 (m, 1H), 2.93 (br s, 2H), 1.93 (d, J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35 (d, J=11.2 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na].[N+:7]([C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[O:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]>C(O)C>[NH:4]([C:19]1[O:18][N:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)[N:20]=1)[C:3]([NH2:5])=[NH:2]
Reactant: O=[N+]([O-])c1cccc(-c2noc(C(Cl)(Cl)Cl)n2)c1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N=C(N)Nc1nc(-c2cccc([N+](=O)[O-])c2)no1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
7.3 gm of guanidine hydrochloride were added in portions to a solution of 1.8 gm of sodium in 100 ml of ethanol. After 30 minutes of stirring, 22.5 gm of 3-(3-nitro-phenyl)-5-trichloromethyl-1,2,4-oxadiazole were added. The solid which separated out overnight was filtered off and dried, yielding 15.2 gm of the title compound, m.p. 290°-291° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:29])[C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C.CCOCC>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[O:11][N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:20]=2[CH:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[OH:29])[CH:27]=[CH:26][CH:25]=1
Reactant: OC(C#Cc1cccc(Cl)c1)c1cccnc1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 20 h
Yield: 16.7 %

Procedure:
A mixture of 53 mg (0.24 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 1-(3-pyridyl)-3-(3-chlorophenyl)-2-propyn-1-ol, and 26 mg (0.31 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. on a rotary table shaker equipped with a heated sand bath. After 20 hrs, an additional 20 mg of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride and 10 mg of sodium bicarbonate was added, and the reaction mixture was stirred and heated for another 16 hrs. The mixture was then diluted with ether, and the solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 5.92 (br s, 1), 7.04 (d of d, 1), 7.12 (d, 1), 7.72 (m, 1), 8.86 (br s, 1), and 8.29 ppm (br s, 2). MS m/z: 430.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[CH:12][N+:13]([O-:15])=[O:14])[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[N:25]([O-])=[O:26].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:13]([O-:15])=[O:14])=[N:25][OH:26])[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: O=[N+]([O-])C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide* 7 g (0.02 mole), was dissolved by heating in 250 ml of glacial acetic acid. The solution was cooled with tap water and when the temperature reached 70° C. the addition of 1.9 g (0.0275 mole) of sodium nitrite was started. The sodium nitrite was added over a period of 10 min while cooling was continued. Following the addition, the mixture was stirred for 11/2 hr at room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated. Crystallization of the residue from ethyl acetate yielded yellow crystals.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]=[C:13]([Br:15])[Br:14])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[Br:14][C:13]([Br:15])=[CH:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[OH:4]
Reactant: CC(=O)Oc1cc(C)ccc1C=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C=C(Br)Br)c(O)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 2-(2,2-dibromovinyl)-5-methylphenyl acetate (16.5 g, 49.4 mmol) in 100 mL of MeOH was treated with a solution of K2CO3 (10.24 g, 74.1 mmol) dissolved in 5.0 mL of water and stirred at RT. The reaction mixture immediately turned yellow and cloudy. After 30 min the mixture was concentrated under reduced pressure to remove MeOH. The crude material was diluted with water and carefully adjusted to pH˜5-6 via addition of 2M HCl. The crude mixture was extracted with EtOAc×2, dried over MgSO4, filtered, and concentrated under reduced pressure to give an orange oil, 2-(2,2-dibromovinyl)-5-methylphenol (13.5 g). 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 3H), 6.65 (d, J=8.2 Hz, 1H), 6.68 (s, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.57 (s, 1H), 9.83 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:30]OC(N(C)C)(OC)C>>[CH3:30][C:9]1[CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[N:10]=1
Reactant: c1ccc2nc(COc3ccc(-n4nccc4-c4ccncc4)cc3)ccc2c1
Reactant: COC(C)(OC)N(C)C
Product: Cc1cc(-c2ccncc2)n(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline but substituting (1,1-Dimethoxy-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6.2 Hz, 2 H), 8.20 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz,1H), 7.74 (m,1H), 7.64 (d, J=8.3 Hz, 1 H), 7.54 (m, 1H), 7.18 (d, J=8.7 Hz, 2 H), 7.07 (d, J=6.2 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.40 (s, 1H), 5.38 (s, 2H), 2,35 (s, 3H); MS: (M+H m/z=393.4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[OH-].[Na+].CN1CCN(C)C1=O.Cl[CH:23]([F:25])[F:24]>O>[Br:1][C:2]1[C:3]([O:11][CH:23]([F:25])[F:24])=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
Into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 53.0 g (0.24 mol) of 2-bromo-6-nitrophenol, 40.5 g (0.49 mol) of 48% sodium hydroxide, 240 ml of 1,3-dimethylimidazolidine-2-one and 40.5 g of water. The mixture was heated to 80° C. and stirred at the same temperature for 1.5 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. Then, while 20.0 g of 48% sodium hydroxide was added in seven portions, blowing of flon gas was continued at the same temperature for 7.5 hours. The total amount of flon gas blown was 242.3 g (2.80 mol). The reaction mixture was cooled. Thereto were added 26.0 g of 48% sodium hydroxide, 1 liter of water and 500 ml of ether, and extraction and layer separation was conducted. The organic layer was separated, and the water layer was subjected to reextraction using 500 ml of ether. The ether layers were combined and washed with 500 ml of water two times. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to distillation to remove the solvent and obtain 45.4 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 70.6%, purity: 98.1%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C.O>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:21][CH:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[OH:19])[C:7]=2[CH2:6][CH2:5]1
Reactant: c1cncc(C2CO2)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (94 mg, 3.92 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.40 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (254 mg, 1.54 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 200 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])(=[O:13])=[O:12]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc2ccccc2c1
Yield: 95.7 %

Procedure:
Prepared according to the procedure described for Example 121 using 2-napthalenesulfonyl chloride (2.28 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (4.139 g); m.p. 223-225° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:41])[CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH:29][CH2:28][CH2:27][N:26]([CH3:25])[CH3:41])=[O:31])=[CH:33][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CN(C)CCNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)CCNC(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Yield: 18.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(2-(dimethylamino)ethylcarbamoyl)phenylboronic acid (25 mg, 0.104 mmol). The mixture was heated under 120 at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (4.68 mg, 18%). 1H-NMR (MeOD): 2.47 (m, 1H), 2.63 (m, 1H), 3.01 (s, 6H), 3.30 (s, 3H), 3.42 (m, 2H), 3.79 (m, 2H), 5.88 (m, 1H), 7.17 (m, 1H), 7.39 (m, 1H), 7.46 (m, 2H), 7.52 (m, 2H), 7.58 (m, 1H), 7.71 (m, 1H), 7.76 (m, 2H), 7.96 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:18])[N:1]1[C:2]1[CH:3]=[C:4]([OH:12])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(O)cc(N)cc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)O
Temperature: 110 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A mixture of 300 mg 5-amino-3-hydroxy-2-methylbenzoic acid and 265 mg of phtalic anhydride in 12 ml of dimethylformamide was heated to 110° C. for 2 hours, and subsequently to 150° C. for another 2 hours. The solvent was evaporated in vacuo and the residue was crystallized from ethanol/diethylether to give 310 mg of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-2-methylbenzoic acid as white crystals, m.p. >250° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OCC)c1c(F)cc(Oc2ccc(OC)cc2)cc1F
Yield: 64.6 %

Procedure:
(RS)-(2,6-Difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (500 mg) was dissolved in CH2Cl2 (20 ml). Cu(OAc)2 (349 mg), 4-methoxyphenylboronic acid (876 mg) and MS4 Å were added followed by pyridine (760 mg). The mixture was stirred over night before filtration and evaporation of the solvent. CC (Hept/CH2Cl2 1:4) afforded 455 mg (65%) of (RS)-[2,6-difluoro-4-(4-methoxy-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester. Yellow oil.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([F:34])[C:32]=1[F:33])[NH2:29]>ClCCCl>[CH2:2]([CH:3]([NH:29][C:28]1[CH:27]=[C:26]([F:25])[C:32]([F:33])=[C:31]([F:34])[CH:30]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCC(CC)Nc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Pentanone, acetic acid and sodium triacetoxyborohydride were added to a 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, for stirring at ambient temperature for 14 hours, to obtain N-(1-ethylpropyl)-3,4,5-trifluoroaniline.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](C(O)=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)[C:16]([Cl:18])=[O:17]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:16]([Cl:18])=[O:17])=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (820 mg, obtained in Example 116, step 5) in CH2Cl2 (10 mL) were added two drops of DMF and oxalylchloride (0.58 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (555 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (49 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (5 mL) was added. The mixture was cooled in an ice bath and a solution of 2-bromomethyl-1-chloro-4-methoxy-benzene (1.0 g, [CAS Reg. No. 3771-13-9]) in 1,2-dimethoxyethane (5 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=6:4) to give the title compound as a colorless solid (510 mg, 36%). MS (neg. ion, m/e)=330.3 [(M−H)−].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:7][C:6]=1C)[CH3:3].N1CC(OC2C=CC(CN(C)C)=C(C)C=2)[CH2:25]1.N1CCC1.OC1C=CC(C=O)=CC=1>>[NH:12]1[CH2:13][CH:10]([O:9][C:8]2[CH:21]=[CH:22][C:5]([CH2:4][N:2]3[CH2:3][CH2:25][CH2:1]3)=[CH:6][CH:7]=2)[CH2:11]1
Reactant: Cc1cc(OC2CNC2)ccc1CN(C)C
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN(C)C
Agent: C1CNC1
Agent: O=Cc1ccc(O)cc1
Product: c1cc(OC2CNC2)ccc1CN1CCC1
Yield: 39 %

Procedure:
Using similar protocols as described in Examples 20A, 20B and 20C employing azetidine and 4-hydroxybenzaldehyde as starting material afforded 0.44 g (39%) of 41A as an oil. 1H NMR (500 MHz, CDCl3): δ 2.06 (m, 2H), 3.18 (m, 4H), 3.35 (t, 1H), 3.48 (s, 2H), 3.66 (t, 1H), 3.8-5.0 (m, 3H), 6.71 (m, 2H), 7.16 (d, 2H).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([O:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O[C:36](=[O:38])[CH3:37])(=O)C>C(Cl)(Cl)Cl>[C:22]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]([O:29][C:36](=[O:38])[CH3:37])[CH2:27][O:28][C:25](=[O:24])[CH3:26])=[O:23])=[CH:30][CH:31]=1)(=[O:23])[CH3:21]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)OCC(COC(C)=O)OC(C)=O)cc1

Procedure:
A solution of 6.53 g of 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate in 100 ml of chloroform is stirred under reflux while 9.0 ml of acetic anhydride is added and for 6 hours thereafter. The solution is extracted with 2% aqueous sodium carbonate solution and water, dried, and evaporated to yield 2,3-diacetoxypropyl N-acetyl-4-(n-hexadecylamino)benzoate as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.CI.[C:16](=O)([O-])O.[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:16])[C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (101.5 mg, 2.33 mmol) (55% in paraffin liquid) was added to a solution of 249 mg (1.16 mmol) of the title compound produced in step (i) of Reference Example 7 in N,N-dimethylformamide (2.5 ml), and the mixture was stirred at room temperature for 30 min. Thereafter, methyl iodide was added, and the mixture was stirred at room temperature for 1 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 239 mg (yield 90%) of the title compound.