Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-phenyl-propionic acid, sodium salt, and 4-benzyl-piperidine were condensed to give the title compound, mp 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=4)(=[O:26])=[O:25])=[CH:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccc(C)cc4s3)cc2)cc1

Procedure:
To 2-(4-aminophenyl)-6-methylbenzothiazole (5 g, 20.8 mmol) in pyridine (60 mL) was added para-toluenesulphonyl chloride (5.953 g, 31.2 mmol, 1.5 eq.) in pyridine (40 mL). The reaction mixture was heated at reflux for 10 mins, then cooled and water (100 mL) added. The white precipitate formed was collected on a filter, washed with water and dried under vacuum to give N-[4-(6-methylbenzothiazol-2-yl)phenyl]-4-methylbenzenesulfonamide as a white solid. The yield was 8.091 g (99%).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@H]1C
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@H]1C

Procedure:
The procedure of Reference Example 2 was repeated by using the thus synthesized methyl (3R*,4S*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate crude product (12.28 g) and benzyl chloroformate (21.3 mL, 149.3 mmol) to obtain 4.23 g (14.52 mmol, 2 steps, 15%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 1-(4-bromophenyl)propan-1-one (10 g, 46.9 mmol) in toluene/ethanol (47/47 ml) is added 4-trifluoromethylphenylboronic acid (10.63 g, 51.6 mmol), tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol), and 2 N potassium carbonate (47 mL). The reaction mixture is heated at reflux overnight, cooled to rt, and partitioned between ethyl acetate and water. The organic layer is dried and concentrated, then loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 60% giving 1-(4′-trifluoromethylbiphenyl-4-yl)propan-1-one (11.52 g).
Reaction SMILES: C(O)C.[CH3:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[OH:13])=O>O>[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[OH:13])[CH3:4]
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: O
Solvent: CCO
Product: CCc1ccc(O)cc1O

Procedure:
In a three necked round bottom flask (equipped with a condenser, additional funnel and mechanical stirrer) was added the catalyst or combination of the catalysts. 100 ml of a mixture of 50:50 ethanol:water was added and the reaction was heated to reflux conditions. 2,4-dihydroxy acetophenone in 100 ml of water:ethanol mixture with or without acids was placed in the additional funnel and was added to the mixture (dropwise-2-4 hrs). The reaction was filtered through a milipore filter and concentrated in vacuo to give a solid. This solid was crystalized from 1,2-dichloroethane to give 4-ethyl resorcinol. The unreacted 2,4-dihydroxy acetophenone is recovered from the media and recycled. The structure of 4-ethyl resorcinol and 2,4-dihydroxy acetophenone were characterized by NMR, Gas Chromatography, IR and Mass spectroscopy
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([CH3:18])[N:11]=1.[Se](=O)=[O:20]>COCCOCCOC.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([CH:18]=[O:20])[N:11]=1
Reactant: Cc1nc(Nc2ccc(F)cc2F)ccc1C#N
Reactant: O=[Se]=O
Solvent: COCCOCCOC
Solvent: CC(=O)O
Product: N#Cc1ccc(Nc2ccc(F)cc2F)nc1C=O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,4-difluorophenylamino)-2-methylnicotinonitrile (350 mg, 1.4 mmol) and selenium dioxide (238 mg, 2.14 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (7.00 mL) and 0.2 mL of glacial acetic acid was heated in an oil bath at 120° C. for 10 min. The temperature of the oil bath was slowly warmed to 155° C. in 30 min and stirred at this temperature for 3 h. The reaction mixture was cooled to RT, filtered through a pad of Celite washing with EtOAc, and concentrated. The remaining brown solution was purified on an ISCO 12 g column and the product eluted with 50-80% EtOAc in hexanes to afford 6-(2,4-difluorophenylamino)-2-formylnicotinonitrile in residual amount of 1-methoxy-2-(2-methoxyethoxy)ethane. MS (ESI, pos.ion) m/z: M+1=260.0
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:13]1.CO.[O-:24][C:25]#[N:26].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:26][C:25]([NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:13]1)=[O:24]
Reactant: N#C[O-]
Reactant: NCCN1CCC(O[N+](=O)[O-])CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NCCN1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.53 g. 1-(2-aminoethyl)-4-nitroxypiperidine fumarate are dissolved in 15 ml. methanol and 5 ml. water. 1.62 g. Potassium cyanate is added thereto and the reaction mixture is stirred overnight at ambient temperature. A pH value of 10 is adjusted by the addition of potassium carbonate. The reaction mixture is extracted with ethyl acetate and the extracts are dried with anhydrous sodium sulphate. After evaporation and trituration of the residue with diethyl ether, the resultant crystals are filtered off with suction. There is obtained 1 g. of the title compound, i.e. 86% of theory; m.p. 114°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=[NH:15])=[N:6]1.[C:21](/[C:23](/[N:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[CH:24]\[O-])#[N:22].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[C:23]([N:26]([CH3:27])[C:28](=[O:29])[O:30][CH3:31])=[CH:24][N:16]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: COC(=O)N(C)/C(C#N)=C/[O-]
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)N(C)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C

Procedure:
Under argon, 0.80 g (2.61 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 6A, 0.51 g (2.86 mmol) of sodium (E)-2-cyano-2-[(methoxycarbonyl)(methyl)amino]ethenolate from Example 10A and 0.53 g (0.73 ml, 5.23 mmol) of triethylamine are added to 50 ml of toluene. The mixture is heated under reflux for 9 hours. It is then cooled to RT again and is mixed and extracted with dichloromethane and water. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo in a rotary evaporator. The residue is mixed with 5 ml of diethyl ether and crystallizes therewith. The crystals are filtered off with suction, dried and purified by preparative RP-HPLC.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>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>[CH:18]1([C@@H:23]([N:27]2[CH:31]=[C:30]([C:2]3[C:3]4[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=4[N:5]=[CH:6][N:7]=3)[CH:29]=[N:28]2)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cnn([C@@H](CC#N)C3CCCC3)c2)OC1(C)C
Reactant: CCOC(OCC)n1ccc2c(Cl)ncnc21
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: C1COCCO1
Solvent: O
Product: CCOC(OCC)n1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 95 °C
Reaction time: 21 h
Yield: 78 %

Procedure:
Into a 100 ml round bottom flask equipped with a stir bar, condenser and 3-way valve connected to nitrogen and vacuum was charged 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-c]pyrimidine (3b, 3.30 g, 0.0129 mol), (3S)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((S)-24, 5.12 g, 0.0146 mol, 1.13 equiv), 1,4-dioxane (33.4 mL, 0.428 mol), water (16.7 mL, 0.929 mol) and potassium carbonate (K2CO3, 8.03 g, 0.0581 mol, 4.5 equiv) at room temperature. The resulting reaction mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (1.49 g, 0.00129 mol, 0.10 equiv). The mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 21 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (45 mL) and water (20 mL). The resulting mixture was stirred until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were washed with 20% aqueous brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate/hexane gradient elution) afford (3S)-3-cyclopentyl-3-{4-[7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}propanenitrile ((S)-25, 4.11 g, 5.27 g theoretical, 78% yield) as colorless oil, which was solidified upon standing at room temperature. For (S)-25: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.71 (d, 1H, J=3.8 Hz), 7.12 (d, 1H, J=3.8 Hz), 6.76 (s, 1H), 4.53 (td, 1H, J=19.4, 4.3 Hz), 3.68 (m, 2H), 3.52 (m, 2H), 3.26 (dd, 1H, J=9.6, 17.3 Hz), 3.19 (dd, 1H, J=4.3, 17.2 Hz), 2.41 (m, 1H), 1.80 (m, 1H), 1.63-1.09 (m, 13H); C22H28N6O2 (MW, 408.50), LCMS (EI) m/e 409 (M++H).
Reaction SMILES: C([O:3][C:4](=[O:51])[C@H:5]([C:11]1[C:12]([CH3:50])=[N:13][C:14]2[N:15]([N:28]=[C:29]([C:31]3[CH:32]=[C:33]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:34]=[CH:35][CH:36]=3)[CH:30]=2)[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]1)[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.O[Li].O>CO.O>[CH2:25]([O:24][C:20]1([CH3:23])[CH2:19][CH2:18][N:17]([C:16]2[N:15]3[N:28]=[C:29]([C:31]4[CH:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=5[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:34]=[CH:35][CH:36]=4)[CH:30]=[C:14]3[N:13]=[C:12]([CH3:50])[C:11]=2[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:51])=[O:3])[CH2:22][CH2:21]1)[CH:26]=[CH2:27]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)nn23)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 21.7 %

Procedure:
To a solution of (S)-ethyl-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (32 mg, 0.048 mmol, 1 equiv) in MeOH (1.0 mL) and water (0.1 mL) was added LiOH.H2O (60 mg, 1.43 mmol, 30 equiv). The reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was then filtered and purified via preparative HPLC with the following conditions: Column. XBridge Phenyl, 19×mm, 5-1 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Product (7 mg, 23%) isolated. 1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.36-7.30 (m, 2H), 7.10 (d, J=11.6 Hz, 1H), 7.04 (s, 1H), 6.88-6.81 (m, 1H), 6.31 (d, J=6.1 Hz, 1H), 5.58 (s, 1H), 4.66-4.60 (m, 1H), 4.53 (q, J=7.0 Hz, 1H), 4.37 (t, J=12.1 Hz, 1H), 3.64-3.55 (m, 4H), 2.88 (br. s., 1H), 2.53 (s, 3H), 2.40-2.32 (m, 1H), 2.31-2.24 (m, 1H), 1.96-1.59 (m, 4H), 1.32 (s, 3H), 1.16 (s, 9H), 1.13 (d, J=6.1 Hz, 3H). LCMS (M+1)=643.5.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:5])[CH3:4].[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37]I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:3]([O:6][CH2:7][C:8]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])([CH2:18][CH3:19])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:37][CH2:36][CH2:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)(=[O:5])[CH3:4]
Reactant: ICCCCc1ccccc1
Reactant: CCC(CCc1ccc(O)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CCc1ccc(OCCCCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a suspension of sodium hydride (0.65 g) in dimethylformamide (16 ml) was added a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-hydroxyphenyl)butyl acetate (6.0 g) in dimethylformamide (50 ml) at 0° C. and the mixture was stirred at room temperature for an hour. 4-Phenyl-butyl iodide (90 g) was added to the solution at 0° C. and the mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to give the subject compound (3.6 g). 1H-NMR (270 MHz, CDCl3) δ: 0.89 (3H, t, J=7.3 Hz), 1.45 (9H, s), 1.65-2.01 (8H, m), 2.08 (3H, s), 2.50 (2H, t, J=8.6 Hz), 2.67 (2H, t, J=6.6 Hz), 3.94 (2H, t, J=5.94 Hz), 4.22 (2H, dd, J=16, 11 Hz), 4.42 (1H, br. s), 6.80 (2H, d, J=8.6 Hz) 7.07 (2H, d, J=8.6 Hz), 7.16 (3H, t, J=7.3 Hz), 7.26-7.31 (2H, m)
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=[N:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(NN=Cc2cc(I)ccc2F)cc1
Yield: 98.1 %

Procedure:
4-hydrazinylbenzoic acid (1.54 g, 10 mmol), 2-fluoro-5-iodobenzaldehyde (2.52 g, 10 mmol) and caesium carbonate (3.27 g, 10 mmol) was stirred in DMF (10 mL) at r.t. for 70 min. Water (40 mL) was then added and the clear solution was acidified with aqueous HCl (1.7 M). The light yellow precipitate that formed was collected by filtration, washed with water and dried in vacuo to give 4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (3.77 g, 98%)
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH2:13][CH:14]=[CH2:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:13]([C:12]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:16][C:31](=[O:33])[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1)[CH:14]=[CH2:15]
Reactant: C=CCC(O)(CCNCCc1ccccc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(c2ccccc2)CCN(CCc2ccccc2)C(=O)O1
Temperature: 85 °C
Yield: 543.3 %

Procedure:
To a solution of 1-phenethylamino-3-phenyl-hex-5-en-3-ol (120 mg, 0.41 mmol) and Et3N (0.5 mL) in anhydrous CH2Cl2 (5 mL) was added triphosgene (40 mg, 0.134 mmol) in portions at 0° C. under N2. Then the solution was refluxing at 80-90° C. overnight. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC to afford 6-allyl-3-phenethyl-6-phenyl-[1,3]oxazinan-2-one (234 mg, yield: 19%). 1H NMR (CDCl3): 2.07-2.17 (m, 2H), 2.44-2.60 (m, 2H), 2.62-2.84 (m, 4H), 3.25 (m, 1H), 3.52 (m, 1H), 3.09 (m, 1H), 5.04 (m, 2H), 5.47-5.58 (m, 1H), 6.94 (m, 2H), 7.10 (m, 3H), 7.27 (m, 3H), 7.31 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:17]2[CH2:18][C@@H:14]([N:12]3[N:11]=[N:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[N:13]3)[CH2:15][C@H:16]2[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])[CH2:25][CH2:26]2)=[O:20])=[CH:38][CH:37]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2ccc(Cl)cc2)CC1
Yield: 10.8 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 4-chloro-benzaldehyde (20 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (8.3 mg, 11%) as light yellow oil. MS m/e=589.1 (75%); 591.1 (25%) [M+H]+.
Reaction SMILES: [Br-].[F:2][C:3]([F:31])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>C1COCC1>[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH:6]=[C:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)[CH2:42][CH2:43]1
Reactant: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(=Cc3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 2-(trifluoromethyl)benzyl triphenylphosphonium bromide (prepared according to the procedure described in J. Chem. Soc. Perkin Trans. I 1995, 18, 2293-2308) (0.737 g) in THF (10 mL) was treated with n-butyllithium (724 μL, of a 1.6M solution in hexanes) at 0° C., treated with ethyl 4-(4-oxo-1-piperidinyl)benzoate (prepared according to the procedure described in Synthesis 1981, 606-608, 0.32 g), and gradually warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1.O>CO>[C:1]([O:4][CH2:13][C:12]([C:11]1[CH:16]=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)=[O:15])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)COC(C)=O)cc1
Yield: 64.5 %

Procedure:
To a solution of 63 g potassium acetate in 750 ml of methanol, 92.9 g of 4-methoxyphenacyl bromide was dropped in. The resulting solution was refluxed for 4 hours, then cooled and poured into water. The aqueous layer was extracted with ether, then the combined organic phases were washed with water, dried, and evaporated to dryness. The resulting solid was recrystallized from methanol to yield 54.5 g crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[OH:16].[CH3:19][C:20]([CH3:22])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:20]([CH3:22])([CH3:19])[O:16][C:15]([CH3:18])([CH3:17])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Nc2ccc(-c3cccc(Cl)c3)cc2C(C)(C)O1
Temperature: 33 °C
Yield: 66.3 %

Procedure:
A mixture of (4-amino-3′-chloro-biphenyl-3-yl)-dimethyl-methanol (0.46 g, 1.8 mmol), acetone (0.16 g, 2.7 mmol), and p-toluenesulfonic acid (0.017 g, 0.09 mmol) in dry toluene (6 mL) was heated at 33° C. under a blanket of nitrogen overnight. Upon completion of the reaction, the toluene was removed and the compound purified via a flash chromatography (silica gel, 15% ethyl acetate/hexane) to give 6-(3-chloro-phenyl)-2,2,4,4-tetramethyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (0.36 g, 68%) as a yellow oil. The oil was dissolved in ether at −78° C. and then treated with a solution of 1N HCl in ether to give the hydrochloride salt of the title compound as a yellow solid: 1H-NMR (DMSO-d6) δ 7.70 (bs, 1H), 7.61 (d, 1H, J=7.82 Hz), 7.52 (bs, 1H), 7.44 (m, 2H), 7.33 (d, 1H, J=8.21 Hz), 6.87 (d, 1H, J=7.85 Hz), 1.5 (s, 6H), 1.4 (s, 6H); MS (ESI) m/z 302 ([M+H]+, 100%); Anal. Calc. For C18H20ClNO: C, 63.91; H, 6.26; N, 4.14. Found: C, 64.08; H, 6.43; N, 4.14.