Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[H-].[Na+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>CN(C=O)C.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:3])=[O:18])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Clc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.5 g, 2.0 mmol) in anhydrous DMF (10 mL) were added NaH (0.240 g, 6.0 mmol, 60% in mineral oil) and 2-chloro-pyrimidine (0.275 g, 2.4 mmol) at 0° C. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0° C., diluted with water (20 mL) and acidified to pH 2 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extract washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and aqueous LiOH (1N, 5 mL) was added at 0° C. After stirring at room temperature for 1 hour, the mixture was acidified to pH 3 using dilute hydrochloric acid and concentrated. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=10:1:trace) to give the product (0.132 g, 22.0%). mp 118-120° C. 1HNMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.65 (d, J=4.68 Hz, 2H), 7.22-7.45 (m, 2H), 7.11 (s, 1H), 5.53 (dd, J=9.51, 1.90 Hz, 1H), 3.10 (dd, J=15.66, 2.49 Hz, 1H), 2.31 (s, 3H), 2.15 (dd, J=15.52, 9.66 Hz, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[OH:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH3:19]>>[OH:15][CH2:16][CH:17]([NH:20][C:4]1[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:20][CH:17]([CH2:16][OH:15])[CH2:18][CH3:19])[N:3]=1)[CH2:18][CH3:19]
Reactant: CCC(N)CO
Reactant: CC(C)c1n[nH]c2c(Cl)nc(Cl)nc12
Product: CCC(CO)Nc1nc(NC(CC)CO)c2[nH]nc(C(C)C)c2n1
Temperature: 120 °C
Yield: 80 %

Procedure:
The mixture of 5,7-dichloro-3-isopropylpyrazolo[4,3-d]pyrimidine (100 mg; 0.331 mmol) and 2 mL 1-(R,S)-(hydroxymethyl)propylamine was heated at 120° C. for 6 hours. The reaction mixture was evaporated to dryness in vacuo. The product was purified by column chromatography on silica gel. The mixture of chloroform/methanol (96/4) was used as a mobile phase. Yield=80%; white syrupy; MS (ES+): 337.4 (100%, M+H+). 1H-NMR (300 MHz, CDCl3): 0.90-1.03 m (6H), 1.26 d (6H), 1.50-1.71 m (4H), 2.48 bs (1H), 3.07 m (1H), 3.40 m (1H), 3.59-3.90 m (4H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)=O)[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:14]([C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=4)[CH2:22][N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]43)=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CN1CCCC1c1cccc(OCCCN2CCCCC2)c1)c1ccc(OC(F)(F)F)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)Oc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Yield: 79 %

Procedure:
2-{2-[3-(3-Piperidin-1-yl-Propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.35 g (79%) of the desired product as a viscous oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H33F3N2O3, 474.2; m/z found, 475.5 [M+H]+. 1H NMR (MeOH-d4): 7.77 (d, J=8.7, 2H), 7.11 (d, J=8.5, 2H), 7.05 (t, J=7.9, 1H), 6.82 (d, J=1.4, 1H), 6.78 (d, J=7.5, 1H), 6.64 (dd, J=2.3, 8.1, 1H), 3.80 (m, 3H), 3.3 (m, 2H), 2.31 (m, 5H), 2.21 (m, 1H), 1.96 (m, 1H), 1.81 (m, 3H), 1.60 (m, 2H), 1.45 (m, 4H), 1.31 (m, 2H).
Reaction SMILES: F[H-]F.[NH4+].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1.C([Si](CC)(CC)[C:16]([F:19])([F:18])[F:17])C>C(#N)C>[OH:11][C:8]1([C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:5](=[O:12])[CH:6]=[CH:7]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: F[H-]F
Agent: [NH4+]
Solvent: CC#N
Product: O=C1C=CC(O)(C(F)(F)F)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
A mixture of 74 mg (1.3 mmol) of ground ammonium bifluoride (NH4HF2), 119 mg (1.1 mmol) of 1,4-benzoquinone, and 2 mL of acetonitrile was treated with 239 mg (1.3 mmol) of triethyltrifluoromethylsilane and stirred vigorously at room temperature for 4 hours. The mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates gave a black solid which was triturated with dichloromethane. The resulting mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates afforded a brown solid which was purified by PTLC (one 2 mm silica gel plate eluted with a 2% methanol-98% dichloromethane) to give 83 mg (42% yield) of 4-hydroxy-4-tri -fluoromethyl-2,5-cyclohexadien-1-one.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(O[K])(C)(C)C.O>CN(C=O)C>[C:2]1([C:8]2[CH:13]=[C:12]([CH:14]=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([N:16]([CH3:25])[CH3:15])=[CH:18][CH:19]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(C=Cc2ccnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.5 %

Procedure:
To a mixture of 2-phenyl-4-methylpyridine hydrochloride (1 g, 4.86 mmol) and 4-dimethylaminobenzaldehyde (0.725 g, 4.86 mmol) in anhydrous DMF (30 ml) was added solid tBuOK and the resulting mixture was stirred 5 hours at room temperature under nitrogen. Water (200 ml) was then added, the resulting yellow precipitate was filtered off and successively washed with water and Et2O to afford 650 mg (44%) of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41]4)[CH2:49][CH2:48]3)=[O:23])[CH:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CCN4CCCC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (69 mg, 0.20 mmol), CDI (63 mg, 0.39 mmol) and 1-[2-(pyrrolidin-1-yl)ethyl]piperazine (72 mg, 0.39 mmol) in THF (4 mL). The crude product was purified using prep method A.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.O.[NH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[NH2:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(=O)Nc1nc2ccc(Br)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cccc(N)c3)nc2s1
Temperature: 94.5 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
N-(5-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (1.504 g, 5.527 mmol), 3-aminophenylboronic acid monohydrate (1.316 g, 8.493 mmol), Pd(dppf)C12-DCM complex (604.4 mg, 0.7401 mmol), and potassium carbonate (2.292 g, 16.58 mmol) were suspended in 1,4-dioxane (45 ml) and water (15 ml) was added. Argon was bubbled through the solution for about 30 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (90-99° C.) and stirred under argon for 4 hours. The reaction was cooled to room temperature, filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated, treated with DCM and MeOH, and filtered. The solid was collected and set aside, and the filtrate was concentrated, treated with Et2O, and filtered. Solid washed with Et2O. This solid was combined with the first batch and dried under high vacuum first at room temperature, and then at ˜50° C. This solid was treated with deionized water and filtered, and the solid was washed with water, collected, and dried under high vacuum in water bath (˜50° C.) to afford N-(5-(3-aminophenyl)thiazolo[5,4-b]pyridin-2-yl)acetamide (1.22 g, 78% yield). MS (ESI pos. ion) m/z: 285. Calculated exact mass for C14H12N4OS 284.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (13.8 g, 50 mmol), Pd(Ph3P)4 (5.8 g, 0.15 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF/H2O (1:1, 250 mL) was stirred under argon at 80° C. overnight. DMF was evaporated off under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column (Petroleum Ether/EtOAc 50:1) on silica gel to give [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.02-8.07 (m, 2 H), 7.95 (d, J=8.4 Hz, 1 H), 7.71-7.79 (m, 3 H), 7.37-7.44 (m, 2 H), 1.53 (s, 9 H).
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([O:35][CH2:36][C:37]([CH3:43])([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>C1(C)C=CC=CC=1>[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][N:24]([C:33]([O:35][CH2:36][C:37]([CH3:42])([CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)COC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COC(=O)N1C[C@H](CN[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.5 ml toluene solution of 227 mg of 3-methoxy-2,2-dimethyl-3-oxopropyl (3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate was mixed with 1.5 ml of 4 M hydrogen chloride/1,4-dioxane at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was mixed with toluene, washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (toluene-methanol) to obtain 3-methoxy-2,2-dimethyl-3-oxopropyl (3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a crude product.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[CH:7]=1
Reactant: FC(F)(F)c1cnn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(C(F)(F)F)cn1
Yield: 18.8 %

Procedure:
0.60 g of 1-(chloromethyl)-4-(trifluoromethyl)-1H-pyrazole and 0.54 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.99 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-chloroform to obtain 0.19 g of {[4-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (22), hereinafter) shown by below formula.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:29][C:30](=[O:33])[NH:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.C(=O)(O)[O-].[Na+]>O>[CH2:22]([NH:29][C:30](=[O:33])[NH:31]/[N:32]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(=O)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NCc2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 69.8 %

Procedure:
A suspension of 137 mg of 1-(2-diisopropylaminoethyl)isatin and 120 mg of 4-benzylsemicarbazide hydrochloride in 2 ml of a mixture of ethanol and water (2:1) was stirred for 11 hours at room temperature, and an aqueous sodium bicarbonate solution was added to the reaction mixture. The precipitates were collected by filtration, washed with water and recrystallized from aqueous ethanol to obtain 147 mg of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-benzylsemicarbazone). Chemical properties of the product were identical with those of the product obtained by Example 5.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[C:22]1(=[O:32])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24](=[O:31])[O:23]1.S(=O)(=O)(O)O>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]([C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=2[C:22]([OH:32])=[O:23])=[O:31])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)C2=C(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.2 g magnesium turnings (83.5 mmol) in 15 ml tetrahydrofuran were added 0.1 mL 1,2-dibromethane to start the Grignard reaction followed by slow addition of 13.0 g 2-(4-bromphenyl)-1,1,1,3,3,3-hexamethyldisilazane (41 mmol) in 70 mL tetrahydrofuran over a period of 20 minutes at room temperature with subsequent stirring for further 30 minutes. The resulting mixture was added dropwise at −78° C. to a solution of 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (5.6 g) in 70 mL tetrahydrofuran. The reaction mixture was slowly warmed to room temperature. Sulfuric acid (2 mL, 1 M) was added and the solvent was removed under reduced pressure. The residue was added carefully to 20 mL of 0.5 M sulfuric acid solution and the desired product started to precipitate and was extracted with ethyl acetate. Acidification of the water phase and extraction with ethyl acetate was continued until pH˜4-5 (at least three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvent was subsequently evaporated under reduced pressure. Purification of the raw material by column chromatography with ethyl acetate/hexane 1:1 and subsequently 100% ethyl acetate resulted in the desired product.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([CH2:18][C:19]#[N:20])=[CH:15][CH:14]=[CH:13]2>CO>[OH:6][N:5]=[C:19]([NH2:20])[CH2:18][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[Br:7])[CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: N#CCc1cccc2cccc(Br)c12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1cccc2cccc(Br)c12)=NO
Reaction time: 24 h
Yield: 62.2 %

Procedure:
A mixture of NaOMe (25 wt % in MeOH, 1.6 ml, 6.83 mmol), MeOH (3 mL), and hydroxylamine hydrochloride (0.47 g, 6.83 mmol) was heated for 30 minutes. 8-Bromo-2-naphthalenylacetonitrile (1.12 g, 4.55 mmol) and MeOH (5 mL) were added and heating was continued for 24 hours. The mixture was concentrated, and suspended in H2O (40 mL) and ether (2 mL). The off-white solid was collected by filtration and triturated with ether to give the title compound (790 mg, 62%), m.p. 123°-125° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13]([OH:15])=O)=O)(C)(C)C.[F:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[F:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][C:13]([C@:9]2([CH3:16])[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:15])=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (5)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.0 g, 4.37 mmol) and 6-fluoropyridin-3-amine (1.47 g, 13.1 mmol), 1-hydroxybenzotriazole (0.65 mg, 4.81 mmol), and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide (2.5 g, 13.1 mmol) in N-methylpyrrolidinone (10 mL) was added diisopropylethylamine (3.8 mL, 21.8 mmol). The reaction mixture was heated to 65° C. for 12 h and the solvent was evaporated to dryness. The residue was separated by preparative HPLC. The crude product was dissolved in methanol and 4N HCl in dioxane (4 mL) was added. The reaction mixture was stirred at room temperature overnight and the crude product was used in the next step without further purification. LC/MS [M+H]+: 224; Ret time (Method F): 0.78 min.
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH:9]=[CH2:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH:9]=[CH2:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: C=Cc1cc(Cl)c(Br)cc1N
Reactant: OB(O)c1ccccc1Cl
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: O
Solvent: C1COCCO1
Product: C=Cc1cc(Cl)c(-c2ccccc2Cl)cc1N
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture of 5-bromo-4-chloro-2-vinylbenzenamine (600 mg, 2.6 mmol), 2-chlorophenylboronic acid (1.25 g, 12.9 mmol), Pd(PPh3)4 (300 mg, 0.2 6 mmol), Na2CO3 (1.4 g, 13.0 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (500 mg, 73.1% yield). ESI-MS m/z: 263.1[M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][C:24](=[O:27])[CH2:25]Cl>O>[CH3:22][O:23][C:24](=[O:27])[CH2:25][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
300 g of 3-nitrophenol are added to 800 ml of DMF. Then 240 g of sodium carbonate are added portionwise. Subsequently 270 g of chloroacetic acid methylester is added at 22° C. Then the mixture is stirred at 85° C. for six hours. After being cooled down to 25° C. it is given to 3 kg of water and 1 kg of ice. The resulting suspension is filtered off. The filter cake is washed with 300 g of water and dried in vacuum. Yield: 407 g.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[CH3:40]I.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:40])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)N(C)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 60% sodium hydride (30 mg) was added at 0° C. to a solution of Compound 1 (253.8 mg) in tetrahydrofuran (5 mL), and the mixture was stirred for 30 minutes at room temperature. Under cooling with ice, methyl iodide (0.16 mL) was added thereto, and the resultant mixture was stirred for 88 hours at room temperature. Water was added to the reaction mixture, and the solvent was distilled off. The residue was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant crude product was subjected to purification through silica gel column chromatography (ethyl acetate-hexane=1:4 to 1:2), to thereby yield 139.3 mg of the title compound as a colorless oil.