Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>O>[C:10]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(=O)NCC(=O)O
Solvent: O
Product: C=C(C)C(=O)NCC(=O)NCC(=O)O
Yield: 75 %

Procedure:
Using Example 1, glycylglycine was reacted with methacryloyl chloride in water at -10° C. After adjustment to a pH of 3, the white slurry was washed with ethanol to remove sodium chloride and water. The product was dried at 80° C. to obtain a good yield (>75%) product with a melting point of 200°-201° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)[CH3:22]>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOc1cccc(C=O)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(CN2C(=O)C(C)CC2c2c(F)cccc2OCC)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-ethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 372.03 g/mol.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]S(C)=O)[C:6]=1[NH2:7])([CH3:4])[CH3:3].CCCCCC>ClCCCl>[ClH:1].[CH:2]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][Cl:1])[C:6]=1[NH2:7])([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc(CS(C)=O)c1N
Agent: Cl
Solvent: ClCCCl
Solvent: CCCCCC
Product: CC(C)c1cccc(CCl)c1N
Temperature: 50 °C
Yield: 96 %

Procedure:
Hydrogen chloride gas was introduced for 35 minutes into a solution of 7.74 g of 2-isopropyl-6-methylsulfinylmethylaniline [prepared as described in step (ii) above] in 80 ml of 1,2-dichloroethane warmed at 50° C., with the aid of a gas-inlet tube. The reaction mixture was then cooled to room temperature and 50 ml of hexane were added thereto. The crystals which precipitated were collected by filtration and washed with hexane to give 7.78 g (yield 96%) of the title aniline hydrochloride as a powder.
Reaction SMILES: [CH2:1]([NH:5][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:13][C:14](=[O:26])[CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH3:12]>>[CH2:11]([O:13][C:14]([C:15]1[C:16](=[O:17])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[C:21]=1[OH:22])=[O:26])[CH3:12]
Reactant: CCCCNn1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccn21
Temperature: 170 °C

Procedure:
A mixture of butyl-pyrrol-1-yl-amine (943 mg) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.15 mL) in a test tube was heated for 30 min at 170° C. and then 30 min at 200° C.; then cooled, the residue was directly column-purified to give the desired product (778 mg) as brown liquid. ESI (m/z): 279 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:6][NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 51.6 %

Procedure:
A solution of [1-(4-trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (45 g; 126 mmol, prepared in accordance with Example 55) in tetrahydrofuran (450 mL) was added over 7 min to a molar solution of lithium aluminium hydride in tetrahydrofuran (377 mL). The resulting mixture was heated to 100° C., and then maintained at that temperature for 195 min. Afterward, the mixture was allowed to cool to room temperature and then poured onto a mixture of ice (500 g) and of 2 N aqueous HCl (350 mL). The organic solvents were removed by evaporation under reduced pressure, and the aqueous phase was basified to a pH of 11 by adding 2 N aqueous NaOH. This resulting in a precipitate, which was filtered and dried at 40° C. under a pressure of 3 mbar to afford the desired product (17.7 g; 65 mmol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.Br[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C>[CH:21]([C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1)=[O:22]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ccccc2C=O)cn1
Temperature: 100 °C
Yield: 72 %

Procedure:
In a microwave vial, 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile (279 mg, 1.51 mmol), 2-bromo-benzaldehyde (230 mg, 1 mmol) and 2 ml of actonitrile were mixed. Then, 2 ml of 1N aqueous sodium carbonate was added, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 100° C. for 10 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water and dried over sodium sulfate. The organic solvent was evaporated to give crude product which was purified by ISCO to give 150 mg of 5-(2-formyl-phenyl)-pyridine-2-carbonitrile, yield 72%.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:38]1[C:46]2[N:45]=N[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:43][C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:46]=3[NH2:45])=[O:23])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)CCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
5-(2-(9H-fluoren-9-ylidene)acetamido)pentanoic acid (321 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (292 mg, 71% yield) as a brown solid. LC-MS (m/z) 412 (M+1).
Reaction SMILES: CC1(C)CCC2C(=CC([N+:12]([O-:14])=[O:13])=CC=2)N1.[CH2:16]([C:18]1([CH2:28][CH3:29])[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1)[CH3:17].[N+]([O-])(O)=O.CCOC(C)=O>S(=O)(=O)(O)O>[CH2:28]([C:18]1([CH2:16][CH3:17])[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([N+:12]([O-:14])=[O:13])=[CH:23][CH:24]=2)[NH:19]1)[CH3:29]
Reactant: CC1(C)CCc2ccc([N+](=O)[O-])cc2N1
Reactant: CCC1(CC)CCc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: CCC1(CC)CCc2ccc([N+](=O)[O-])cc2N1
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that described for 1,2,3,4-tetrahydro-2,2-dimethyl-7-nitroquinoline (Scheme III) from for 2,2-diethyl-1,2,3,4-tetrahydroquinoline (0.955 g, 5.04 mmol) and fuming HNO3 (0.32 g, 5.0 mmol) in concentrated sulfuric acid (10 mL) to afford 0.811 g (69%) of 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline after chromatography (hexanes:EtOAc, 24:1). Data for 2,2-diethyl-1,2,3,4-tetrahydro-7-nitroquinoline: Rf 0.43 (24:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) 7.38 (dd, J=8.3, 2.3, 1H), 7.29 (d, J=2.3, 1H), 7.04 (d, J=8.3, 1H), 4.00 (broad s, 1H), 2.78 (t, J=6.7 2H), 1.71 (t, J=6.7, 2H), 1.38-1.58 (m, 4H), 0.88 (t, J=7.4, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[CH:18]=O.Cl>CO>[CH3:24][O:23][C:21]1[CH:20]=[C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:16]=[C:15]([O:14][CH3:13])[CH:22]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2CCc3cc(O)ccc3C2=O)cc(OC)c1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,5-dimethoxybenzaldehyde 1.23 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 1.276 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[C:9](/N(C)C)\[CH3:10])=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[F:25])=[O:17].[Cl-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CC(=O)OCC.O.CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:15]2[N:6]3[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]3=[N:8][C:9]=2[CH3:10])=[O:17])=[C:19]([F:25])[CH:20]=1
Reactant: C/C(=N\c1ccc(Cl)nn1)N(C)C
Reactant: O=C(CCl)c1ccc(Cl)cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(Cl)nn2c1C(=O)c1ccc(Cl)cc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
In a round bottom flask combine (E)-N′-(6-chloropyridazin-3-yl)-N,N-dimethylacetimidamide (36.61 g, 184.3 mmol), 2-chloro-1-(4-chloro-2-fluorophenyl)ethanone (38.15 g, 1 equiv.), and dimethylformamide (150 mL). Place under nitrogen then heat at 120° C. for 4 h. Let cool to RT and stir overnight. Dilute with EA (1 L) and water (500 mL). Extract organics three times with water followed by aqueous saturated sodium chloride aqueous. Dry organics over anhydrous magnesium sulfate. Filter and concentrate in vacuo. Purify by silica plug (hexane→4:1 hexane:EA→3:1 hexane:EA→2:1 hexane:EA→1:1 hexane:EA) and isolate the title compound (33.8 g, 57%) as a light green solid. LCMS (4 min=324.0, 326.0, M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]([CH3:43])[N:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]([CH3:43])[N:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K7) (150 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow foam (90 mg).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].CCCCCC>O1CCCC1>[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][OH:16]
Reactant: O=C(O)c1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: OCc1ccccc1Br
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A 5-liter, 3-necked glass reaction vessel equipped as described in Example 1 was charged with 62.4 grams (1.65 moles) of sodium borohydride, 1 liter of tetrahydrofuran, and 0.26 liter (2.1 moles) of boron trifluoride diethyl etherate at 0°-5°C using essentially the same procedure as described in Example 1. After stirring the reaction mixture for an additional 15 minutes, a solution of 400 grams (2 moles) of 2-bromobenzoic acid in 1 liter of tetrahydrofuran was added dropwise over a 1.5 hour period while maintaining a temperature of 0°-10°C. When the addition was complete, the reaction mixture was stirred for 6 hours at room temperature. Hydrolysis of the reaction mixture and recrystallization of the product from hexane gave 293 grams (78.5% yield) of 2-bromobenzyl alcohol as light-orange crystals, mp 78°-80°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3cccc(C(=O)OCc4ccccc4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (3.00 g) in N,N-dimethylformamide (16.8 mL) were added potassium carbonate (1.39 g) and benzyl bromide (0.996 mL) successively, and this mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (3.06 g). 1H-NMR (CDCl3) δ ppm: 3.85 (3H, s), 4.54 (2H, s), 5.48 (2H, s), 6.72 (1H, dd, J=2.2, 8.5 Hz), 6.91 (1H, d, J=2.2 Hz), 7.16-7.23 (1H, m), 7.27-7.44 (7H, m), 7.47-7.57 (4H, m), 7.60 (1H, t, J=7.8 Hz), 7.90-7.97 (1H, m), 8.10 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[CH3:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[CH:34]=1>CN(C)C=O.CN(C)C(=O)C>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][C:46]([CH3:47])=[C:25]([NH:24][C:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:26]=4)=[CH:34][N:33]3[N:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)n(CC(F)(F)F)n1
Yield: 81.2 %

Procedure:
In the same manner as in Example 55 and using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (82.8 mg, 0.398=mol), tetrahydrofuran (5 mL), thionyl chloride (69.1 μL, 0.796 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (117 mg, 0.362 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (151 mg, 81%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.[CH:34]12[O:40][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[OH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@@H:34]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(O[C@H]3CCCC[C@@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and cyclohexene oxide (1.20 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.25 g), and the mixture was stirred at 100° C. for 20 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.93 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.N1CCCN2CCCCCC=12>CO>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=N[C@](CF)(c2cccc(Br)c2)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](CF)(c2cccc(Br)c2)C[C@@H](C(F)(F)F)O1
Temperature: 65 °C
Yield: 54 %

Procedure:
To a solution of N-((4S,6S)-4-(3-bromophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.15 g, 2.504 mmol) in MeOH 8 mL was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.449 ml, 3.01 mmol) and the resulting mixture was heated at 65° C. for 9 h. The mixture was concentrated, and then diluted with EtOAc. The resulting solution was washed with water, saturated NH4Cl solution, dried over sodium sulfate, filtered, concentrated. The crude material was purified by column chromatographed on silica gel using 0-40% EtOAc/Hexane to give (4S,6S)-4-(3-bromophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.480 g, 1.352 mmol, 54.0% yield). MS m/z=356.9 [M+H]+. Calculated for C12H11BrF4NO2: 355.1
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)(C)C>[CH2:24]([O:23][CH2:22][CH2:21][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:13]1)[CH3:25]
Reactant: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOCCn1cc(C2CCNCC2)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 16 g (0.054 mol) of 4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester in 10 ml of iso-propanol, a solution of 32 g of potassium hydroxide in 270 ml of iso-propanol was added. The crude mixture was refluxed for 16 hours. After cooling at room temperature, the solvent was removed at reduced pressure and the crude mixture was extracted between ethyl acetate and water. The organic layer was dried with sodium sulphate and after filtration, the solvent was removed under reduced pressure affording 9.6 g (71% of yield) of an oil which corresponds to the expected product.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[C:3]1=[S:17].[CH3:18][C:19]1[CH:20]=[C:21]([N:26]2[C:30]([OH:31])=[C:29]([CH:32]=O)[C:28]([CH3:34])=[N:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25]>C(O)C.CO>[C:14]([C:10]1[CH:9]=[C:8]([N:4]2[C:5](=[O:7])[CH2:6][N:2]([N:1]=[CH:32][C:29]3[C:28]([CH3:34])=[N:27][N:26]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([CH3:18])[CH:20]=4)[C:30]=3[OH:31])[C:3]2=[S:17])[CH:13]=[CH:12][CH:11]=1)([OH:16])=[O:15]
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Reactant: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-n2nc(C)c(C=NN3CC(=O)N(c4cccc(C(=O)O)c4)C3=S)c2O)cc1C
Reaction time: 96 h
Yield: 45.5 %

Procedure:
Ethyl hydrazinoacetate hydrochloride (155 mg, 1.00 mmol) was added to a stirred solution of 3-isothiocyanatobenzoic acid (179 mg, 1.00 mmol) and di-isopropylethylamine (523 uL, 3.00 mmol) in dichloromethane (4 mL). The mixture was stirred for 96 h, evaporated under reduced pressure and partitioned between aqueous acetic acid and ethyl acetate. The organic extracts were washed with water, saturated aqueous sodium chloride, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was chromatographed (silica gel, 5-15% methanol/ethyl acetate, then 20% methanol/ethyl acetate ±0.5% acetic acid) to give 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 51%) contaminated with 6% uncyclised by-product, suitable for the next step. A solution of 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 0.199 mmol) and 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde (55 mg, 0.239 mmol) in ethanol/methanol (2:1, 15 mL) was allowed to stand a room temperature for 96 h. The solid was filtered off, washed with ether and dried to give the title compound (42 mg, 46%) as a powder. LCMS, m/e 464 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]1([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:22]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:24][CH:23]=4)[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc2cc3ccccc3cc2c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 14.5 g of phenylboronic acid, 25.7 g of 2-bromoanthracene, 4.62 g of tetrakis(triphenylphosphine)palladium(0), 400 mL of toluene and 200 mL of a 2M aqueous solution of sodium carbonate were charged, and the mixture was refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were separated by filtration. The resulting solids were recrystallized with toluene-hexane and washed repeatedly, whereby 19.1 g (yield: 75%) of 2-phenylanthracene was obtained.