Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[N:13]=[C:14]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[NH:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[NH:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[N:13]=[C:14]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[NH:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([N:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nc(C3CCOC3)[nH]c2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-c2nc(C3CCOC3)[nH]c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
The mixture of 2,4-dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)benzoic acid (compound 171.2, 100 mg, 0.30 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 71 mg, 0.37 mmol), EDCI (95 mg, 0.50 mmol), HOBt (20 mg, 0.10 mmol) and DIEA (207 μL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (3×10 mL), dried over MgSO4 and concentrated under reduce pressure. The residue was purified by preparative TLC with 6% methanol in dichloromethane and lyophilized to give 16 mg (12%) of the title compound as a white solid. m/z (ES+) 441 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[O:11][C:12](=O)[C:13]1[C:18]([I:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:20][C:16]1[CH:15]=[C:14]2[C:13](=[C:18]([I:19])[CH:17]=1)[C:12](=[O:11])[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:21]2
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 4-chloro-benzyl amine (1.3 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.374 g, 1.0 mmol), and K2CO3 (0.277 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.204 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.15 (s, 2H), 4.74 (s, 2H), 7.10 (d, 1H), 7.23-7.33 (m, 4H), 7.67 (d, 11H). GC-MS: m/z 401 (M)+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.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>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)CNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)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+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCC(C)(C)C)s4)cc23)CC1
Yield: 21 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (2,2-dimethylpropyl)amine (0.037 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 21 mg of the title compound (21%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([N:28]=[N+]=[N-])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>C1COCC1.[Pd]>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([NH2:28])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1

Procedure:
4.58 g (10.4 mMol) 5-(6-azido-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 150 ml THF are hydrogenated in the presence of 0.8 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off and the filtrate concentrated. The residue is dissolved in EtOAc and H2O and the aqueous layer extracted twice with EtOAc. The organic layers are washed with brine, dried (Na2SO4) and concentrated, yielding the title compound: m.p.: 186-187° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C@@H:12]([CH2:25][NH2:26])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:28]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[C@@H:12]([CH2:25][NH:26][C:42]([NH:41][C:38]3[CH:39]=[CH:40][C:35]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:36][CH:37]=3)=[O:43])[C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: C[C@@H](c1ccccc1)N1CCc2c(sc(N)c2C(=O)OC(C)(C)C)[C@@H]1CN
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)N1CCc2c(sc(N)c2C(=O)OC(C)(C)C)[C@@H]1CNC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of 2-amino-7-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (250 mg, 0.645 mmol) in dichloromethane (10 ml) was added 4-phenoxyphenyl isocyanate (136 mg, 0.645 mmol) and the reaction mixture was stirred 16 hours at room temperature, before the solvent was removed in vacuo which afforded 386 mg (100%) of 2-amino-7-(S)-(3-(4-phenoxy-phenyl)-ureidomethyl)-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [Mg].BrCC.[CH2:5]([OH:9])[CH2:6][C:7]#[CH:8].Br[CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:5]([OH:9])[CH2:6][C:7]#[C:8][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC#CCC#CCBr
Reactant: C#CCCO
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCCCCC#CCC#CCC#CCCO
Reaction time: 1 h
Yield: 72.3 %

Procedure:
In a 1 L three-necked, flame-dried round bottom flask fitted with a reflux condenser and a rubber septum was placed 3.86 g (159 mmol) of magnesium in 250 mL of anhydrous tetrahydrofuran. Bromoethane (17.3 g; 1586 mmol) in 250 mL anhydrous tetrahydrofuran was added dropwise, under argon, and the reflux rate was controlled with the aid of an ice-water bath. The mixture was heated to reflux and stirred for 1 hour. 3-Butyn-1-ol (5.56 g, 79.3 mmol), dissolved in 150 mL of anhydrous tetrahydrofuran, was slowly added dropwise with stirring (2 hours). Following addition, the reaction was heated to reflux. After stirring for 90 minutes, 0.5 g (2.63 mmol) of cuprous (I) iodide was added. After 75 minutes 9.0 g (39.65 mmol) of 1-bromo-2,5-undecadiyne dissolved in 150 mL of anhydrous tetrahydrofuran was added. The mixture was heated at reflux for 12 h and an additional 0.25 g (1.32 mmol) of cuprous (I) iodide was added. The mixture was heated at reflux for 7 hours, cooled and quenched by addition of 400 mL of ice-water saturated with ammonium chloride. After filtration (Celite), the filtrate was extracted with 3×400 mL of ether. The ether layers were washed with 2×300 mL of saturated ammonium chloride solution, 3×200 mL of water, 250 mL of brine, dried (Na2SO4), and concentrated in vacuo to yield 6.2 g of yellow-brown oil. The residue was partially purified by crystallization (petroleum ether) at -20° C. to produce 5.75 g (75%) of an unstable yellow oil (room temperature) which was utilized immediately in the next reaction. IR (neat,cm-1) 3365, 2956, 2933, 2225; 1H NMR (CDCl3) δ 3.70 (t, J=6.2 Hz, 2H), 3.17-3.13 (m, 4H), 2.45 (dt, J=1.5, 5.9, 12.0 Hz, 2H), 2.15 (dt, J=2.1, 6.9, 13.9 Hz, 2H), 1.68 (br, 1H), 1.55-1.43 (m, 2H), 1.43-1.26 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); HRMS calculated for C15H20O (M+) 216.1514, found 216.1519.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:33](O)([CH3:35])[CH3:34]>ClCCl>[CH:33]([O:18][C:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:20])[O:3][C:2]2([CH3:21])[CH3:1])[CH:13]=[N:14][CH:15]=1)=[O:19])([CH3:35])[CH3:34]
Reactant: CC(C)O
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)OC(=O)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.075 g, 0.262 mmol) (Example 23) is dissolved in dichloromethane (2 mL). Catalytic amount of dimethylformamide (0.002 mL, 0.0262 mmol) is added to the reaction mixture and cooled to 0° C. Oxalyl chloride (0.016 mL, 0.655 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 2 h and concentrated in vacuo. The residue obtained is redissolved in dichloromethane, and isopropanol (10 mL) is added. The reaction mixture is stirred at room temperature for 1 h, whereupon the volatiles are removed in vacuo. Saturated aqueous sodium bicarbonate is added and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane-ethyl acetate, 1:1) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS (ESI) m/z 329.0 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt δ ppm 1.34 (s, 3 H), 1.48 (d, J=5.9 Hz, 3 H), 1.49 (d, J=5.9 Hz, 3 H), 1.62 (s, 3 H), 5.42 (sept, J=5.9 Hz, 1 H), 7.02 (s, 1 H), 7.67 (d, J=7.6 Hz, 1 H), 7.75-7.81 (m, 1 H), 7.82-7.90 (m, 1 H), 8.33 (dd, J=7.8, 1.5 Hz, 1 H), 8.38 (d, J=1.3 Hz, 1 H), 8.76 (d, J=1.0 Hz, 1 H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:18][C:19]1[CH:20]=[C:21]([O:27][CH3:28])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:7]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncnc(Cl)n2)cc1OC
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (12.6 g, 84 mmol) was dissolved in DMF (100 mL) under N2 and cooled to 0° C. DIEA (11.7 g, 90 mmol) was added, followed by 4-aminoveratrole (13.35 g, 87 mmol). The reaction solution was stirred with gradual warming to RT. The reaction was quenched after 3.5 h with water, which causes a gray precipitate to form. This precipitate was recovered by vacuum filtration, washed with cold water, dried under high vacuum, then eluted through a 28×4.5 cm column of silica gel (0.1% NH4OH buffered 1%, 2%, 3%, 4%, and 5% MeOH/CH2Cl2 step gradient) giving (4-chloro-[1,3,5]triazin-2-yl)-(3,4-dimethoxy-phenyl)-amine as an off white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:2][C:1](=[O:3])[CH2:4][CH2:5][C:6]1[C:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)[CH3:22]
Reactant: O=C(O)CCc1c[nH]c2c1C(=O)CCC2
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1c[nH]c2c1C(=O)CCC2
Yield: 99 %

Procedure:
3-Carboxyethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (3, 52.0 g, 0.251 mol) in ethanol (100 mL) was added with sulfuric acid (1.0 mL). The reaction mixture was heated at reflux for 12 h. The solution was concentrated under reduced pressure and the resultant solids were washed with water (200 mL×2). The solids were air-dried to give 3-(3-ethoxy-3-oxopropyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole (4, 59.0 g, 0.251 mol) as yellow solids in >99% yield.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C:25]12([CH2:35][O:36][C:37]3[C:45]([Cl:46])=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][C:38]=3[Cl:47])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.COC[CH2:51][S:52]([NH2:55])(=[O:54])=[O:53].CS(N)(=O)=O>>[C:25]12([CH2:35][O:36][C:37]3[C:45]([Cl:46])=[CH:44][C:40]([C:41]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:42])=[CH:39][C:38]=3[Cl:47])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Yield: 74 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-(adamantan-1-ylmethoxy)-3,5-dichlorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.72 g, 74%): 1H NMR (300 MHz, DMSO-d6) δ 12.20 (br s, 1H), 8.01 (s, 2H), 3.55 (s, 2H), 3.33 (s, 3H), 1.99-1.91 (m, 3H), 1.72-1.57 (m, 12H); MS (ES−) m/z 430.1, 432.1 (M−1).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:30])([C:20]([F:29])([F:28])[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:18]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][C:17]([F:16])([F:30])[C:20]([F:28])([F:29])[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
6.8 g of trifluoromethanesulfonic anhydride was added dropwise to 5.0 g of 2,2,3,3,4,4,5,5,5-nonafluoropentanol at 0° C., and the mixture was stirred at room temperature for 5 hours and at 100° C. for 3 hours. Thereafter, the reaction mixture was poured to ice water and then extracted with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 4.7 g of 2,2,3,3,4,4,5,5,5-nonafluoropentyl trifluoromethanesulfonate.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([N:32]=[C:2]=[O:4])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8.74 g of triphosgene in 125 ml of methylene chloride cooled to 0° C. is added dropwise a solution of p-(tetradecyloxy)aniline, 7.95 g of triethylamine and 239.93 mg of dimethylaminopyrydine in 125 ml of methylene chloride over 30 minutes. Stirring at ambient temperature is continued for 4 hours. The solvent is evaporated and the residue stirred with ether and filtered. The cake is washed with additional ether and the combined flitrates evaporated to give the desired product as an oil.
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
Reactant: CC(C)(O)c1cc(-c2cccc(Cl)c2)ccc1N
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.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[O:37])=[CH:39][CH:40]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 4-phenylbenzoyl chloride (45 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:18])[C:7]([N:9]1[CH2:13][CH:12]([F:14])[CH:11]=[C:10]1[C:15]([OH:17])=[O:16])=[O:8])(=O)C.C(SCC(C)C(N1CCC=C1C(O)=O)=O)(=O)C>>[F:14][CH:12]1[CH2:13][N:9]([C:7](=[O:8])[CH:6]([CH3:18])[CH2:5][SH:4])[C:10]([C:15]([OH:17])=[O:16])=[CH:11]1
Reactant: CC(=O)SCC(C)C(=O)N1CC(F)C=C1C(=O)O
Agent: CC(=O)SCC(C)C(=O)N1CCC=C1C(=O)O
Product: CC(CS)C(=O)N1CC(F)C=C1C(=O)O

Procedure:
By substituting (±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-4-fluoro-1H-pyrrole-2-carboxylic acid for the (±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid in the procedure of Example 2, (±)-4,5-dihydro-4-fluoro-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([O:23]CC)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:19])([F:20])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([OH:23])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
Ethyl 4-phenyl-8-(trifluoromethyl)quinoline-3-carboxylate (35.96 g, 104.14 mmol) was taken into THF/MeOH (300 mL of 1:1 mixture) along with 2 M NaOH (200 mL) and heated at 70° C. for 20 minutes. The organics were removed and the remaining aqueous layer was cooled to 0° C. and acidified with concentrated HCl. The mixture was concentrated and the resulting material was passed through a silica gel column using CH2Cl2, then 20% MeOH in CH2Cl2. The fractions were combined and the volume was reduced and then diluted to twice the volume with hexane and placed in a freezer overnight. A solid precipitated which was filtered and dried to yield the carboxylic acid as a brown solid (14.03 g). MS (ESI) m/z 318 ([M+H]+); MS (ESI) m/z 316 ([M−H]−).
Reaction SMILES: [OH:1][CH2:2]/[C:3](=[C:14]1\[C:15](=[O:20])[NH:16][C:17](=[O:19])[S:18]\1)/[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3](=[C:14]1[S:18][C:17](=[O:19])[N:16]([CH3:21])[C:15]1=[O:20])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)/C(=C(\CO)c2cccc3ccccc23)S1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CI
Product: CN1C(=O)SC(=C(CO)c2cccc3ccccc23)C1=O
Yield: 74.9 %

Procedure:
(E)-5-[2-Hydroxy-1-(1-naphthalenyl)ethylidene]-2,4-thiazolidinedione (1.49 g, 5.22 mmol) was added to suspension of potassium carbonate (7.22 g, 52.2 mmol) in acetone. After 30 minutes iodomethane (0.65 mL, 10.4 mmol) was added. After 30 min the mixture was filtered, and concentrated to give a brown oil which was dissolved in chloroform. The resulting solution was washed with water then dried over magnesium sulfate and concentrated in vacuo to give an oil which was chromatographed on silica gel (chloroform/acetonitrile) to give a glass (1.17 g). Recrystallization from carbon tetrachloride/hexane/ether gave analytically pure E isomer of the title compound as yellow needles (0.90 g).